PRAMIPEXOLE DIHYDROCHLORIDE tablet
For Healthcare Providers >

1. Patient Information
2. Manufactured For:
3. Manufactured By:
4. What Are Pramipexole Dihydrochloride Tablets?
5. Before Taking Pramipexole Dihydrochloride Tablets, Tell Your Doctor If You:
6. How Should I Take Pramipexole Dihydrochloride Tablets?
7. What Are The Possible Side Effects Of Pramipexole Dihydrochloride Tablets?pramipexole Dihydrochloride Tablets May Cause Serious Side Effects, Including:
8. How Should I Store Pramipexole Dihydrochloride Tablets?
9. What Are The Ingredients In Pramipexole Dihydrochloride Tablets?active Ingredient:
10. Inactive Ingredients:
11. What Is Pramipexole Dihydrochloride Tablet?
12. What Should I Tell My Doctor Before Taking Pramipexole Dihydrochloride?before Taking Pramipexole Dihydrochloride, Tell Your Doctor If You:
13. Especially Tell Your Doctor If You Take:
14. How Should I Take Pramipexole Dihydrochloride?
15. What Should I Avoid While Taking Pramipexole Dihydrochloride Tablets?
16. This Patient Information Leaflet Summarizes The Most Important Information About Pramipexole Dihydrochloride Tablets. If You Would Like More Information, Talk With Your Doctor. You Can Ask Your Pharmacist Or Doctor For Information About Pramipexole Dihydrochloride Tablets That Is Written For Healthcare Professionals.what Are The Ingredients In Pramipexole Dihydrochloride Tablets?active Ingredient:

Patient Information ⮝

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dosing Instruction

Instruct patients to take pramipexole dihydrochloride tablets only as prescribed. If a dose is missed, advise patients not to double their next dose.

Pramipexole dihydrochloride tablets can be taken with or without food. If patients develop nausea, they should be advised that taking pramipexole dihydrochloride tablets with food may reduce the occurrence of nausea.

Pramipexole is the active ingredient that is in both pramipexole dihydrochloride tablets and extended-release pramipexole tablets. Ensure that patients do not take both extended-release pramipexole and pramipexole dihydrochloride tablets.

Sedating Effects
Alert patients to the potential sedating effects associated with pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine) [see Warnings and Precautions (5.1)].

Impulse Control Symptoms Including Compulsive Behaviors
Alert patients and their caregivers to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking pramipexole dihydrochloride [see Warnings and Precautions (5.3)].

Hallucinations and Psychotic-like Behavior
Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease [see Warnings and Precautions (5.4)].

Postural (Orthostatic) Hypotension
Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride tablets [see Warnings and Precautions (5.2)].

Pregnancy
Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

Lactation
Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant [see Use in Specific Populations (8.2)].

Manufactured For: ⮝

Macleods Pharma USA, INC,.
Plainsboro, NJ 08536

Manufactured By: ⮝

Macleods Pharmaceutical Ltd.
Baddi, Himachal Pradesh, India.

Revised May 2018

PATIENT INFORMATION

PATIENT INFORMATION
Pramipexole Dihydrochloride
(PRAM-i-PEX-ole dye-HYE-droe-KLOR-ide)
Tablets

Read this Patient Information before you start taking pramipexole dihydrochloride tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What Are Pramipexole Dihydrochloride Tablets? ⮝

Pramipexole dihydrochloride tablets are a prescription medicine used to treat:
signs and symptoms of Parkinson's disease (PD)
moderate to severe primary Restless Legs Syndrome (RLS)

It is not known if pramipexole dihydrochloride tablets are safe and effective in children.

Before Taking Pramipexole Dihydrochloride Tablets, Tell Your Doctor If You: ⮝

feel sleepy during the day from a sleep problem other than Restless Legs Syndrome
have low blood pressure, or if you feel dizzy or faint, especially when getting up from sitting or lying down
have trouble controlling your muscles (dyskinesia)
have kidney problems
drink alcohol. Alcohol can increase the chance that pramipexole dihydrochloride tablets will make you feel sleepy or fall asleep when you should be awake.
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if pramipexole dihydrochloride tablets will harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if pramipexole dihydrochloride passes into your breast milk. You and your doctor should decide if you will take pramipexole dihydrochloride tablets or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, includingprescription and nonprescription medicines, vitamins, and herbal supplements.

The combination of pramipexole dihydrochloride tablets and other medicines may affect each other and may cause side effects. Pramipexole dihydrochloride tablets may affect the way other medicines work, and other medicines may affect how pramipexole dihydrochloride tablets work.

How Should I Take Pramipexole Dihydrochloride Tablets? ⮝

Take pramipexole dihydrochloride tablets exactly as your doctor tells you to take it.
Your doctor will tell you how much pramipexole dihydrochloride tablets to take and when to take it. Do not take more or less pramipexole dihydrochloride tablets than your doctor tells you to.
Your doctor may change your dose if needed.
Pramipexole dihydrochloride tablets can be taken with or without food. Taking pramipexole dihydrochloride tablets with food may lower your chances of getting nausea.
If you take more pramipexole dihydrochloride tablets than your doctor recommends, call your doctor or go to the nearest hospital emergency room right away.
If you miss a dose,do not double your next dose.Skip the dose you missed and take your next regular dose.
If you have Parkinson's disease and your doctor tells you to stop taking pramipexole dihydrochloride tablets, you should stop pramipexole dihydrochloride tablets slowly as directed by your doctor. If you stop pramipexole dihydrochloride tablets too quickly you may have withdrawal symptoms such as:
fever
confusion
severe muscle stiffness

Do not stop taking pramipexole dihydrochloride tablets without talking to your doctor.

What Are The Possible Side Effects Of Pramipexole Dihydrochloride Tablets?pramipexole Dihydrochloride Tablets May Cause Serious Side Effects, Including: ⮝

falling asleep during normal daily activities.Pramipexole dihydrochloride tablets may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating.
o Some people taking the medicine in pramipexole dihydrochloride tablets have had car accidents because they fell asleep while driving.
o Some patients did not feel sleepy before they fell asleep while driving. You could fall asleep without any warning.
Tell your doctor right away if you fall asleep while you are doing activities such as talking, eating, driving, or if you feel sleepier than normal for you.
low blood pressure when you sit or stand up quickly.You may have:
dizziness
nausea
fainting
sweating
Sit and stand up slowly after you have been sitting or lying down.

unusual urges.Some people who take certain medicines to treat Parkinson's disease, including pramipexole dihydrochloride tablets, have reported problems, such as gambling, compulsive eating, compulsive buying, and increased sex drive.

If you or your family members notice that you are developing unusual urges or behaviors, talk to your doctor.

hallucinations and other psychotic-like behavior(seeing visions, hearing sounds or feeling sensations that are not real, confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs and disorganized thinking). Your chance of having hallucinations and other psychotic-like behavior is higher if you are elderly (age 65 or older).
If you have hallucinations or other psychotic-like changes, talk with your doctor right away.
uncontrolled sudden movements(dyskinesia).
If you have new dyskinesia or your existing dyskinesia gets worse tell your doctor.
posture changes.Talk with your doctor if you have posture changes you cannot control. These may include your neck bending forward, bending forward at the waist, or tilting sideways when you sit, stand, or walk.
The most common side effects in people taking pramipexole dihydrochloride tablets for Restless Legs Syndrome are nausea and headache.

The most common side effects in people taking pramipexole dihydrochloride tablets for Parkinson's disease are:
nausea
dizziness
insomnia
constipation
muscle weakness
abnormal dreams
confusion
memory problems (amnesia)
urinating more often than normal

These are not all the possible side effects of pramipexole dihydrochloride tablets. Tell your doctor if you have any side effect that bothers you.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How Should I Store Pramipexole Dihydrochloride Tablets? ⮝

Store pramipexole dihydrochloride tablets at 20 to 25 C (68 to 77 F); excursions permitted to 15 C to 30 C (59 F to 86 F).
Keep pramipexole dihydrochloride tablets out of the light.
Keep pramipexole dihydrochloride tablets and all medicines out of the reach of children.

General Information about the safe and effective use of pramipexole dihydrochloride tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use pramipexole dihydrochloride tablets for a condition for which it was not prescribed. Do not give pramipexole dihydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about pramipexole dihydrochloride tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about pramipexole dihydrochloride tablets that is written for healthcare professionals.

For more information about pramipexole dihydrochloride tablets call Macleods Pharma USA, Inc. at 1-888-943-3210.

What Are The Ingredients In Pramipexole Dihydrochloride Tablets?active Ingredient: ⮝

pramipexole dihydrochloride monohydrate

Inactive Ingredients: ⮝

mannitol, pregelatinized starch, colloidal silicon dioxide, povidone, and magnesium stearate

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Macleods Pharma USA, INC,.
Plainsboro, NJ 08536

Manufactured by:
Macleods Pharmaceutical Ltd.
Baddi, Himachal Pradesh, India.

Revised: May 2018

The brands listed are trademarks of their respective owners and are not trademarks of Macleods Pharmaceutical Ltd.

The makers of these brands are not affiliated with and do not endorse Macleods Pharmaceutical Ltd. or its products.

PM01805507

What Is Pramipexole Dihydrochloride Tablet? ⮝

Pramipexole dihydrochloride tablet is a prescription medicine used to treat:
signs and symptoms of Parkinson s disease (PD)

It is not known if pramipexole dihydrochloride is safe and effective in children.

What Should I Tell My Doctor Before Taking Pramipexole Dihydrochloride?before Taking Pramipexole Dihydrochloride, Tell Your Doctor If You: ⮝

feel sleepy during the day from a sleep problem
have low blood pressure, or if you feel dizzy or faint, especially when getting up from sitting or lying down
have trouble controlling your muscles (dyskinesia)
have kidney problems
drink alcohol. Alcohol can increase the chance that pramipexole dihydrochloride will make you feel sleepy
or fall asleep when you should be awake.
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if pramipexole dihydrochloride will harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if pramipexole dihydrochloride passes into your breast milk. You and your doctor should decide if you will take pramipexole dihydrochloride or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, includingprescription and nonprescription medicines, vitamins, and herbal supplements.

The combination of pramipexole dihydrochloride and other medicines may affect each other and may cause side effects. Pramipexole dihydrochloride may affect the way other medicines work, and other medicines may affect how pramipexole dihydrochloride works.

Especially Tell Your Doctor If You Take: ⮝

medicines called neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide. Pramipexole dihydrochloride may not work as well if you take these medicines.
extended-release pramipexole (pramipexole dihydrochloride tablets ER). Pramipexole is the active ingredient in both pramipexole dihydrochloride tablets and pramipexole dihydrochloride tablets ER. If you are taking pramipexole dihydrochloride tablets ER, you should not take pramipexole dihydrochloride tablets.
any other medicines that make you sleepy or may increase the effects of pramipexole dihydrochloride tablets, such as cimetidine (Tagamet).

Ask your doctor for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How Should I Take Pramipexole Dihydrochloride? ⮝

Take pramipexole dihydrochloride tablets exactly as your doctor tells you to take it.
Your doctor will tell you how much pramipexole dihydrochloride tablets to take and when to take it. Do not take more or less pramipexole dihydrochloride tablets than your doctor tells you to.
Your doctor may change your dose if needed.
Pramipexole dihydrochloride tablets can be taken with or without food. Taking pramipexole dihydrochloride tablets with food may lower your chances of getting nausea.
If you take more pramipexole dihydrochloride tablets than your doctor recommends, call your doctor or go to the nearest hospital emergency room right away.
If you miss a dose,do not double your next dose. Skip the dose you missed and take your next regular dose.
If you have Parkinson s disease and your doctor tells you to stop taking pramipexole dihydrochloride tablets, you should stop pramipexole dihydrochloride tablets slowly as directed by your doctor. If you stop pramipexole dihydrochloride tablets too quickly you may have withdrawal symptoms such as:
fever
confusion
severe muscle stiffness
Do not stop taking pramipexole dihydrochloride tablets without talking to your doctor.

What Should I Avoid While Taking Pramipexole Dihydrochloride Tablets? ⮝

Do not drink alcohol while taking pramipexole dihydrochloride tablets. It can increase your chance of having serious side effects. See What are the possible side effects of pramipexole dihydrochloride tablets?
Do not drive a car, operate a machine, or do other dangerous activities until you know how pramipexole dihydrochloride tablets affects you. Sleepiness caused by pramipexole dihydrochloride tablets can happen as late as 1 year after you start your treatment.

What are the possible side effects of pramipexole dihydrochloride tablets?
Pramipexole dihydrochloride tablets may cause serious side effects, including:
falling asleep during normal daily activities.Pramipexole dihydrochloride tablets may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating.
oSome people taking the medicine in pramipexole dihydrochloride tablets have had car accidents because they fell asleep while driving.
oSome patients did not feel sleepy before they fell asleep while driving. You could fall asleep without any warning.
Tell your doctor right away if you fall asleep while you are doing activities such as talking, eating, driving, or if you feel sleepier than normal for you.

low blood pressure when you sit or stand up quickly. You may have:
dizziness
nausea
fainting
sweating
Sit and stand up slowly after you have been sitting or lying down.

unusual urges. Some people who take certain medicines to treat Parkinson s disease, including pramipexole dihydrochloride tablets, have reported problems, such as gambling, compulsive eating, compulsive buying, and increased sex drive.
If you or your family members notice that you are developing unusual urges or behaviors, talk to your doctor.
hallucinations and other psychotic-like behavior(seeing visions, hearing sounds or feeling sensations that are not real, confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs and disorganized thinking). Your chance of having hallucinations and other psychotic-like behavior is higher if you are elderly (age 65 or older).
If you have hallucinations or other psychotic-like changes, talk with your doctor right away.
uncontrolled sudden movements(dyskinesia).
If you have new dyskinesia or your existing dyskinesia gets worse tell your doctor.
skin cancer(melanoma). Some people with Parkinson s disease may have a higher chance of having melanoma than people who do not have Parkinson s disease. It is not known if the chance of having melanoma is higher because of the medicines to treat Parkinson s disease, like pramipexole dihydrochloride tablets, or from the Parkinson s disease. People who take pramipexole dihydrochloride tablets should have regular skin examinations to check for melanoma.

The most common side effects in people taking pramipexole dihydrochloride tablets for Parkinson s disease are:
nausea
dizziness
insomnia
constipation
muscle weakness
abnormal dreams
confusion
memory problems (amnesia)
urinating more often than normal

These are not all the possible side effects of pramipexole dihydrochloride tablets Tell your doctor if you have any side effect that bothers you.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This Patient Information Leaflet Summarizes The Most Important Information About Pramipexole Dihydrochloride Tablets. If You Would Like More Information, Talk With Your Doctor. You Can Ask Your Pharmacist Or Doctor For Information About Pramipexole Dihydrochloride Tablets That Is Written For Healthcare Professionals.what Are The Ingredients In Pramipexole Dihydrochloride Tablets?active Ingredient: ⮝

Pramipexole dihydrochloride monohydrate USP

1. Package Label-principal Display Panel - 0.125 Mg (90 Tablets Bottle)
2. Package Label-principal Display Panel - 0.25 Mg (90 Tablets Bottle)
3. Package Label-principal Display Panel - 0.5 Mg (90 Tablets Bottle)
4. Package Label-principal Display Panel - 0.75 Mg (90 Tablets Bottle)
5. Package Label-principal Display Panel - 1 Mg (90 Tablets Bottle)
6. Package Label-principal Display Panel - 1.5 Mg (90 Tablets Bottle)
7. Pramipexole Dihydrochloride
8. Pramipexole Dihydrochloride
9. Description
10. Clinical Pharmacology
11. Clinical Studies
12. Warnings
13. Precautions
14. Drug Abuse And Dependence
15. Overdosage
16. How Supplied
17. Animal Toxicology
18. Spl Patient Package Insert
19. Highlights Of Prescribing Information
20. Recent Major Changes
21. Indications And Usage
22. Dosage And Administration
23. Dosage Forms And Strengths
24. Contraindications
25. Warnings And Precautions
26. Adverse Reactions
27. Drug Interactions
28. Use In Specific Populations
29. 1 Indications & Usage
30. 2 Dosage & Administration
31. 3 Dosage Forms & Strengths
32. 4 Contraindications
33. 5 Warnings And Precautions
34. 6 Adverse Reactions
35. 7 Drug Interactions
36. 8 Use In Specific Populations
37. 10 Overdosage
38. 11 Description
39. 12 Clinical Pharmacology
40. 13 Nonclinical Toxicology
41. 14 Clinical Studies
42. 16 How Supplied/storage And Handling
43. Pramipexole Dihydrochloride 0.5mg Tab
44. Package Label.principal Display Panel - 0.125 Mg
45. Package Label.principal Display Panel - 0.25 Mg
46. Package Label.principal Display Panel - 0.5 Mg
47. Package Label.principal Display Panel - 1 Mg
48. Package Label.principal Display Panel - 1.5 Mg
49. Pramipexole Dihydrochloride 0.5mg Tab.
50. 1 Indications And Usage
51. 2 Dosage And Administration
52. 3 Dosage Forms And Strengths
53. Pramipexole Dihydrochlor. 0.125mg Tab
54. Packaging Information
55. Package/label Display Panel Carton -0.125 Mg
56. Package/label Display Panel Blister 0.125 Mg
57. Package/label Display Panel Carton 0.25 Mg
58. Package/label Display Panel Blister 0.25 Mg
59. Package/label Display Panel Carton 0.5 Mg
60. Package/label Display Panel Blister 0.5 Mg
61. Package/label Display Panel Carton 1 Mg
62. Package/label Display Panel Blister 1 Mg

Package Label-principal Display Panel - 0.125 Mg (90 Tablets Bottle) ⮝

NDC 65862-604-90
Pramipexole
Dihydrochloride Tablets
0.125 mg
Rx only 90 Tablets
AUROBINDO

Package Label-principal Display Panel - 0.25 Mg (90 Tablets Bottle) ⮝

NDC 65862-605-90
Pramipexole
Dihydrochloride Tablets
0.25 mg
Rx only 90 Tablets

AUROBINDO

Package Label-principal Display Panel - 0.5 Mg (90 Tablets Bottle) ⮝

NDC 65862-606-90
Pramipexole
Dihydrochloride Tablets
0.5 mg
Rx only 90 Tablets
AUROBINDO

Package Label-principal Display Panel - 0.75 Mg (90 Tablets Bottle) ⮝

NDC 65862-607-90
Pramipexole
Dihydrochloride
Tablets
0.75 mg
Rx only 90 Tablets
AUROBINDO

Package Label-principal Display Panel - 1 Mg (90 Tablets Bottle) ⮝

NDC 65862-608-90
Pramipexole
Dihydrochloride
Tablets
1 mg
Rx only 90 Tablets
AUROBINDO

Package Label-principal Display Panel - 1.5 Mg (90 Tablets Bottle) ⮝

NDC 65862-609-90
Pramipexole
Dihydrochloride
Tablets
1.5 mg
Rx only 90 Tablets

AUROBINDO

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-604 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score no score Shape ROUND (Flat, Beveled Edge) Size 6mm Flavor Imprint Code Y;41 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-604-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-604-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-604-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-604-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-605 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.25 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score 2 pieces Shape OVAL (Biconcave, Beveled Edge) Size 7mm Flavor Imprint Code Y;42 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-605-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-605-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-605-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-605-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-606 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score 2 pieces Shape OVAL (Biconcave, Beveled Edge) Size 8mm Flavor Imprint Code Y;43 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-606-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-606-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-606-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-606-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-607 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.75 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score no score Shape OVAL (Biconcave, Beveled Edge) Size 11mm Flavor Imprint Code Y;44 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-607-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-607-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-607-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-607-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-608 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score 2 pieces Shape ROUND (Flat, Beveled Edge) Size 9mm Flavor Imprint Code Y;45 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-608-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-608-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-608-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-608-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-609 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) POVIDONE K90 (UNII: RDH86HJV5Z)

Product Characteristics Color WHITE (White to Off-white) Score 2 pieces Shape ROUND (Flat, Beveled Edge) Size 11mm Flavor Imprint Code Y;46 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-609-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 2 NDC:65862-609-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/26/2012 3 NDC:65862-609-78 10 in 1 CARTON 10/26/2012 3 NDC:65862-609-10 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202633 10/26/2012

Labeler - Aurobindo Pharma Limited (650082092)

Establishment
Name	Address	ID/FEI	Business Operations
Aurobindo Pharma Limited		650381903	ANALYSIS(65862-604, 65862-605, 65862-606, 65862-607, 65862-608, 65862-609) , MANUFACTURE(65862-604, 65862-605, 65862-606, 65862-607, 65862-608, 65862-609)

Revised: 9/2019 Document Id: dc4c125e-f686-49dd-bbc0-751ff8b72f02 34391-3 Set id: 3f90971a-e005-4dd3-bb93-b09125ada3c8 Version: 10 Effective Time: 20190913 Aurobindo Pharma Limited

Pramipexole Dihydrochloride ⮝

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1331(NDC:68382-197) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.25 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MANNITOL (UNII: 3OWL53L36A) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics Color BLUE (BLUE) Score 2 pieces Shape ROUND (ROUND) Size 6mm Flavor Imprint Code P2 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1331-0 90 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014 06/30/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078920 07/10/2010 06/30/2017

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1388(NDC:68382-198) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MANNITOL (UNII: 3OWL53L36A) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) D&C RED NO. 27 (UNII: 2LRS185U6K)

Product Characteristics Color PURPLE (LAVENDER) Score 2 pieces Shape CAPSULE (CAPSULE) Size 8mm Flavor Imprint Code P;3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1388-0 30 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078920 07/10/2010

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1451(NDC:68382-200) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MANNITOL (UNII: 3OWL53L36A) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color YELLOW (YELLOW) Score 2 pieces Shape ROUND (ROUND) Size 7mm Flavor Imprint Code P5 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1451-0 90 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078920 07/10/2010

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-1388, 50090-1331, 50090-1451) , REPACK(50090-1388)

Revised: 11/2017 Document Id: 1e043bf1-5768-4138-b05b-68f8d597bb88 34391-3 Set id: 48d1b42e-9070-4703-b0a0-b8a5a7b22e3c Version: 11 Effective Time: 20171116 A-S Medication Solutions

Pramipexole Dihydrochloride ⮝

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-2676(NDC:33342-035) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE K25 (UNII: K0KQV10C35) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score 2 pieces Shape ROUND (round) Size 10mm Flavor Imprint Code CL;6 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-2676-0 90 in 1 BOTTLE; Type 0: Not a Combination Product 12/05/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202164 09/21/2012

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-2676)

Revised: 6/2018 Document Id: 7e4f08fb-4502-40c4-ac88-ae37959728ff 34391-3 Set id: 915209d1-cf94-4b3e-9ebb-876fbf2315e0 Version: 10 Effective Time: 20180621 A-S Medication Solutions

Description ⮝

Pramipexole dihydrochloride tablets contain pramipexole, a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride monohydrate. Its molecular formula is C10 H17 N3 S 2HCl H2O, and its molecular weight is 302.27.

The structural formula is:

Pramipexole dihydrochloride monohydrate is a white to off-white powder and freely soluble in methanol. Melting occurs in the range of 296o to 301oC, with decomposition.

Each pramipexole dihydrochloride tablet intended for oral administration contains 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, mannitol, magnesium stearate, pregelatinized starch and povidone. Additionally each 0.125 mg tablet contains D&C red no. 27 aluminum lake, each 0.25 mg tablet contains FD&C blue no. 1 aluminum lake, each 0.5 mg tablet contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake, each 1 mg tablet contains ferric oxide red and each 1.5 mg tablet contains ferric oxide yellow.

Clinical Pharmacology ⮝

Mechanism of Action

Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

Parkinson s Disease

The precise mechanism of action of pramipexole as a treatment for Parkinson s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson s disease is unknown.

Pharmacokinetics

Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). Steady-state concentrations are achieved within 2 days of dosing.

Absorption

Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.

Distribution

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Metabolism and Elimination

The terminal half-life of pramipexole is about 8 hours in healthy volunteers and 12 hours in elderly volunteers.

Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. Nonrenal routes may contribute to a small extent to pramipexole elimination, although no metabolites have been identified in plasma or urine. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Pharmacokinetics in Special Populations

Because therapy with pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment (see CLINICAL PHARMACOLOGY, Renal Insufficiency).

Gender

Pramipexole clearance is about 30% lower in women than in men, but most of this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.

Age

Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the well-known reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance (see CLINICAL PHARMACOLOGY, Renal Insufficiency).

Parkinson s Disease Patients

A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson s disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson s disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson s disease patients.

Pediatric

The pharmacokinetics of pramipexole in the pediatric population have not been evaluated.

Hepatic Insufficiency

The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Renal Insufficiency

The clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. Also, it took longer to achieve steady state. A lower starting and/or maintenance dose may be appropriate in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering pramipexole to patients with renal disease.

Clinical Studies ⮝

Parkinson s Disease

The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson s disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson s disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole s effectiveness in the management of patients with Parkinson s disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson s disease who were receiving maximally tolerated doses of levodopa.

In all studies, the Unified Parkinson s Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).

Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Studies in Patients with Early Parkinson s Disease

Patients (N=599) in the two studies of early Parkinson s disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.

One of the two early Parkinson s disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to pramipexole dihydrochloride tablets or placebo. Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

The second early Parkinson s disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

Studies in Patients with Advanced Parkinson s Disease

In the advanced Parkinson s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.

Patients in the advanced Parkinson s disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had "on-off" periods.

The advanced Parkinson s disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.

The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with pramipexole dihydrochloride tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

Warnings ⮝

Falling Asleep During Activities of Daily Living

Patients treated with pramipexole dihydrochloride tablets have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole dihydrochloride tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment.

Somnolence is a common occurrence in patients receiving pramipexole dihydrochloride tablets at doses above 1.5 mg/day (0.5 mg TID) for Parkinson s disease. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with pramipexole dihydrochloride tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with pramipexole dihydrochloride tablets such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine - see PRECAUTIONS, Drug Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride tablets, patients should be advised to not drive and to avoid other potentially dangerous activities. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Symptomatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson s disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk (see PRECAUTIONS, Information for Patients).

In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole dihydrochloride tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.

While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded.

Hallucinations

In the three double-blind, placebo-controlled trials in early Parkinson s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson s disease patients and 2.7% of the advanced Parkinson s disease patients compared with about 0.4% of placebo patients in both populations.

Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson s disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

Precautions ⮝

Rhabdomyolysis

A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson s disease treated with pramipexole dihydrochloride tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Renal

Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing pramipexole dihydrochloride tablets to patients with renal insufficiency (see DOSAGE AND ADMINISTRATION).

Dyskinesia

Pramipexole dihydrochloride tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

Retinal Pathology in Albino Rats

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved (see ANIMAL TOXICOLOGY).

Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported in association with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Withdrawal-Emergent Hyperpyrexia and Confusion

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

Fibrotic Complications

Although not reported with pramipexole in the clinical development program, cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, in the postmarketing experience for pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride and these fibrotic complications, a contribution of pramipexole dihydrochloride cannot be completely ruled out in rare cases.

Melanoma

Epidemiological studies have shown that patients with Parkinson s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson s disease or other factors, such as drugs used to treat Parkinson s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using pramipexole dihydrochloride tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Information for Patients (also see Patient Package Insert)

Patients should be instructed to take pramipexole dihydrochloride tablets only as prescribed.

Patients should be alerted to the potential sedating effects associated with pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).

Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson s disease, including pramipexole dihydrochloride tablets. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with pramipexole dihydrochloride tablets. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking pramipexole dihydrochloride tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride tablets.

Patients may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride tablets.

Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy).

Because of the possibility that pramipexole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

If patients develop nausea, they should be advised that taking pramipexole dihydrochloride tablets with food may reduce the occurrence of nausea.

Laboratory Tests

During the development of pramipexole dihydrochloride tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.

Drug Interactions

Carbidopa/levodopa

Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline

In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine

Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine

Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid

Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

Other drugs eliminated via renal secretion

Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole.

CYP interactions

Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 M, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).

Dopamine antagonists

Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride tablets.

Drug/LaboratoryTest Interactions

There are no known interactions between pramipexole dihydrochloride tablets and laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to Chbb: NMRI mice at doses of 0.3, 2, and 10 mg/kg/day [0.3, 2.2, and 11 times the Maximum Recommended Human Dose (MRHD) (MRHD of 1.5 mg TID on a mg/m2 basis)]. Pramipexole was administered in the diet to Wistar rats at 0.3, 2, and 8 mg/kg/day (plasma AUCs were 0.3, 2.5, and 12.5 times the AUC in humans at the MRHD). No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of assays, including the in vitro Ames assay, V79 gene mutation assay for HGPRT mutants, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.

In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis), prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

Pregnancy

Teratogenic Effect

Pregnancy Category C:

When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis). Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 71 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.

There are no studies of pramipexole in human pregnancy. Because animal reproduction studies are not always predictive of human response, pramipexole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers

A single-dose, radio-labeled study showed that drug-related materials were excreted into the breast milk of lactating rats. Concentrations of radioactivity in milk were three to six times higher than concentrations in plasma at equivalent time points.

Other studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of pramipexole dihydrochloride tablets in pediatric patients has not been established.

Geriatric Use

Pramipexole total oral clearance was approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies with Parkinson s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly.

ADVERSE EVENTS

Parkinson s Disease

During the premarketing development of pramipexole, patients with either early or advanced Parkinson s disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson s disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse events, this section will, in general, present adverse-event data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.

Early Parkinson s Disease

In the three double-blind, placebo-controlled trials of patients with early Parkinson s disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson s disease and treated with pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 11% of 235 patients who received placebo. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on pramipexole dihydrochloride tablets vs. 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs. 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs. 0% on placebo]; extrapyramidal syndrome [1.6% on pramipexole dihydrochloride tablets vs. 6.4% on placebo]; headache and confusion [1.3% and 1%, respectively, on pramipexole dihydrochloride tablets vs. 0% on placebo]); and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride tablets vs. 0.4% on placebo]).

Adverse-event Incidence in Controlled Clinical Studies in Early Parkinson s Disease

Table 1 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in early Parkinson s disease that were reported by 1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.

Table 1Treatment-Emergent Adverse-Event* Incidence in Double-Blind, Placebo-Controlled Trials in Early Parkinson s Disease (Events 1% of Patients Treatedwith pramipexole dihydrochloride tablets and Numerically More Frequent Than in the Placebo Group)

Body System/	Pramipexole Dihydrochloride Tablets	Placebo
Adverse Event	N=388	N=235
*Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
Body as a Whole
Asthenia	14	12
General edema	5	3
Malaise	2	1
Reaction unevaluable	2	1
Fever	1	0
Digestive System
Nausea	28	18
Constipation	14	6
Anorexia	4	2
Dysphagia	2	0
Metabolic & Nutritional System
Peripheral edema	5	4
Decreased weight	2	0
Nervous System
Dizziness	25	24
Somnolence	22	9
Insomnia	17	12
Hallucinations	9	3
Confusion	4	1
Amnesia	4	2
Hypesthesia	3	1
Dystonia	2	1
Akathisia	2	0
Thinking abnormalities	2	0
Decreased libido	1	0
Myoclonus	1	0
Special Senses
Vision abnormalities	3	0
Urogenital System
Impotence	2	1

Other events reported by 1% or more of patients with early Parkinson s disease and treated with pramipexole dihydrochloride tablets but reported equally or more frequently in the placebo group were infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritis, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and taste perversions.

In a fixed-dose study in early Parkinson's disease, occurrence of the following events increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.

Advanced Parkinson s Disease

In the four double-blind, placebo-controlled trials of patients with advanced Parkinson s disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.

Approximately 12% of 260 patients with advanced Parkinson s disease who received pramipexole dihydrochloride tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 16% of 264 patients who received placebo and concomitant levodopa. The events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [2.7% on pramipexole dihydrochloride tablets vs. 0.4% on placebo]; dyskinesia [1.9% on pramipexole dihydrochloride tablets vs. 0.8% on placebo]; extrapyramidal syndrome [1.5% on pramipexole dihydrochloride tablets vs. 4.9% on placebo]; dizziness [1.2% on pramipexole dihydrochloride tablets vs. 1.5% on placebo]; confusion [1.2% on pramipexole dihydrochloride tablets vs. 2.3% on placebo]); and cardiovascular system (postural [orthostatic] hypotension [2.3% on pramipexole dihydrochloride tablets vs. 1.1% on placebo]).

Adverse-event Incidence in Controlled Clinical Studies in Advanced Parkinson s Disease

Table 2 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by (1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, pramipexole dihydrochloride tablets or placebo was administered to patients who were also receiving concomitant levodopa. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-events incidence rate in the population studied.

Table 2 Treatment-Emergent Adverse-Event* Incidence in Double-Blind, Placebo-Controlled Trials in Advanced Parkinson s Disease (Events 1% of Patients Treated with pramipexole dihydrochloride tablets and Numerically More Frequent than in the Placebo Group)

Body System/	Pramipexole Dihydrochloride Tablets	Placebo*
Adverse Event	N=260	N=264
*Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category. Patients received concomitant levodopa.
Body as a Whole
Accidental injury	17	15
Asthenia	10	8
General edema	4	3
Chest pain	3	2
Malaise	3	2
Cardiovascular System
Postural hypotension	53	48
Digestive System
Constipation	10	9
Dry mouth	7	3
Metabolic & Nutritional System
Peripheral edema	2	1
Increased creatine PK	1	0
Musculoskeletal System
Arthritis	3	1
Twitching	2	0
Bursitis	2	0
Myasthenia	1	0
Nervous System
Dyskinesia	47	31
Extrapyramidal syndrome	28	26
Insomnia	27	22
Dizziness	26	25
Hallucinations	17	4
Dream abnormalities	11	10
Confusion	10	7
Somnolence	9	6
Dystonia	8	7
Gait abnormalities	7	5
Hypertonia	7	6
Amnesia	6	4
Akathisia	3	2
Thinking abnormalities	3	2
Paranoid reaction	2	0
Delusions	1	0
Sleep disorders	1	0
Respiratory System
Dyspnea	4	3
Rhinitis	3	1
Pneumonia	2	0
Skin & Appendages
Skin disorders	2	1
Special Senses
Accommodation abnormalities	4	2
Vision abnormalities	3	1
Diplopia	1	0
Urogenital System
Urinary frequency	6	3
Urinary tract infection	4	3
Urinary incontinence	2	1

Other events reported by 1% or more of patients with advanced Parkinson s disease and treated with pramipexole dihydrochloride tablets but reported equally or more frequently in the placebo group were nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety, rash, paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hypesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis, and lacrimation disorders.

General

Adverse Events; Relationship to Age, Gender, and Race

Among the treatment-emergent adverse events in patients treated with pramipexole dihydrochloride tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson s disease. No gender-related differences were observed in Parkinson's disease patients. Less than 4% of patients enrolled were non-Caucasian, therefore, an evaluation of adverse events related to race is not possible.

Other Adverse Events Observed During Phase 2 and 3 Clinical Trials

Pramipexole dihydrochloride tablets have been administered to 1620 Parkinson s disease patients in Phase 2 and 3 clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing; similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. Adverse events which are not listed above but occurred on at least two occasions (one occasion if the event was serious) in the 2509 individuals exposed to pramipexole dihydrochloride tablets are listed below. The reported events below are included without regard to determination of a causal relationship to pramipexole dihydrochloride tablets.

Blood and lymphatic system disorders

anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia

Cardiac disorders

angina pectoris, arrhythmia supraventricular, atrial fibrillation, atrioventricular block first degree, atrioventricular block second degree, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac failure congestive, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy

Congenital, familial and genetic disorders

atrial septal defect, congenital foot malformation, spine malformation

Ear and labyrinth disorders

deafness, ear pain, hearing impaired, hypoacusis, motion sickness, vestibular ataxia

Endocrine disorders

goiter, hyperthyroidism, hypothyroidism

Eye disorders

amaurosis fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma, vision blurred, visual acuity reduced, vitreous floaters

Gastrointestinal disorders

abdominal discomfort, abdominal distension,, aphthous stomatitis, ascites, cheilitis, colitis, colitis ulcerative, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis,, gastrointestinal hemorrhage, gastroesophageal reflux disease, gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus,, inguinal hernia, intestinal obstruction, irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia

General disorders

chest discomfort, chills, death, drug withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, pitting edema, thirst

Hepatobiliary disorders

biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis

Immune system disorders

drug hypersensitivity

Infections and infestations

abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection

Injury, poisoning and procedural complications

accidental falls, drug toxicity epicondylitis, road traffic accident, sunburn, tendon rupture

Metabolism and nutrition disorders

cachexia, decreased appetite, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased appetite, metabolic alkalosis

Musculoskeletal and connective tissue disorders

bone pain, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, muscle spasms, musculoskeletal stiffness, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis

Neoplasms benign, malignant and unspecified

abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma

Nervous system disorders

ageusia, akinesia, anticholinergic syndrome, aphasia, balance disorder, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, syncope vasovagal, tension headache

Psychiatric disorders

affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, hallucination auditory, hallucination visual, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation

Renal and urinary disorders

chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary retention

Reproductive system and breast disorders

amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage

Respiratory, thoracic and mediastinal disorders

apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, dyspnea exertional, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, pneumonia aspiration, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, rhinitis allergic, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing

Skin and subcutaneous tissue disorders

acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria

Vascular disorders

aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein

Falling Asleep During Activities of Daily Living

Patients treated with pramipexole dihydrochloride tablets have reported falling asleep while engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded WARNING).

Post-Marketing Experience

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride tablets, primarily in Parkinson s disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of events were grouped into a smaller number of standardized categories using the MedDRA dictionary: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus, syncope, vomiting, and weight increase.

Drug Abuse And Dependence ⮝

Pramipexole is not a controlled substance. Pramipexole has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, in a rat model on cocaine self-administration, pramipexole had little or no effect.

Overdosage ⮝

There is no clinical experience with massive overdosage. One patient, with a 10-year history of schizophrenia, took 11 mg/day of pramipexole for 2 days in a clinical trial to evaluate the effect of pramipexole in schizophrenic patients. No adverse events were reported related to the increased dose. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. The patient withdrew from the study at the end of week 2 due to lack of efficacy.

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

How Supplied ⮝

Pramipexole Dihydrochloride Tablets, 0.125 mg are pink color, capsule-shaped, flat, beveled-edged, uncoated tablets debossed with P1 on one side and plain on other side and are supplied are as follows:

NDC 68382-196-16 in bottle of 90 tablets

NDC 68382-196-05 in bottle of 500 tablets

NDC 68382-196-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 0.25 mg are pale blue color, round, flat, beveled-edged, uncoated tablets debossed with P2 on one side and break line on other side and are supplied as follows:

NDC 68382-197-16 in bottle of 90 tablets

NDC 68382-197-05 in bottle of 500 tablets

NDC 68382-197-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 0.5 mg are lavender, capsule-shaped, flat, beveled-edged, uncoated tablets debossed with P breakline 3 on one side and plain on other side and are supplied as follows:

NDC 68382-198-16 in bottle of 90 tablets

NDC 68382-198-05 in bottle of 500 tablets

NDC 68382-198-10in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 1 mg are light peach to peach, round, flat, beveled-edged, uncoated tablets debossed with P4 on one side and break line on other side and are supplied as follows:

NDC 68382-199-16 in bottle of 90 tablets

NDC 68382-199-05 in bottle of 500 tablets

NDC 68382-199-10in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 1.5 mg are yellow color, round, flat, beveled- edged, uncoated tablets debossed with P5 on one side and break line on other side and are supplied as follows:

NDC 68382-200-16 in bottle of 90 tablets

NDC 68382-200-05in bottle of 500 tablets

NDC 68382-200-10 in bottle of 1000 tablets

Storage

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Protect from light.

Dispense in a tight, light-resistant container.

Store in a safe place out of the reach of children.

Animal Toxicology ⮝

Retinal Pathology in Albino Rats

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times the AUC in humans that received 1.5 mg TID). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not diagnosed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater than that seen in control rats utilizing morphometry.

Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the highest clinical dose on a mg/m2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the highest clinical dose on a mg/m2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the highest clinical dose on a mg/m2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.

The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

Fibro-osseous Proliferative Lesions in Mice

An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2, or 10 mg/kg/day (0.3, 2.2, and 11 times the highest clinical dose on a mg/m2 basis). Lesions occurred at a lower rate in control animals. Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

Spl Patient Package Insert ⮝

Read the Patient Information that comes with pramipexole dihydrochloride tablets before you start taking it and each time you get a refill. There may be some new information.

This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about pramipexole dihydrochloride tablets?

Pramipexole dihydrochloride tablets may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, watching TV, or eating.

• Some people taking pramipexole dihydrochloride tablets have had car accidents because they fell asleep while driving.
• Some patients did not feel sleepy before they fell asleep while driving. You could fall asleep without any warning.

Do not drive a car, operate a machine, or do anything that needs you to be alert until you know how pramipexole dihydrochloride tablets affect you.

Tell your doctor right away if you fall asleep while you are doing activities such as talking with people, watching TV, eating, or driving, or if you feel sleepier than is normal for you.

What is pramipexole dihydrochloride tablet?

Pramipexole dihydrochloride tablet is a prescription medicine to treat:

• signs and symptoms of Parkinson s disease

Pramipexole dihydrochloride tablets have not been studied in children.

Who should not take pramipexole dihydrochloride tablets?

Do not take pramipexole dihydrochloride tablets if you are allergic to pramipexole or any of the inactive ingredients of pramipexole dihydrochloride tablets. See the end of this leaflet for a complete list of ingredients in pramipexole dihydrochloride tablets.

What should I tell my doctor before taking pramipexole dihydrochloride tablets?

Tell your doctor about all of your medical conditions, including if you

• feel sleepy during the day from a sleep problem other than Restless Legs Syndrome
• have low blood pressure, or if you feel dizzy or faint, especially when getting up from a lying or sitting position.
• have trouble controlling your muscles (dyskinesia)
• have kidney problems
• are pregnant or plan to become pregnant. It is not known if pramipexole dihydrochloride tablets will harm your unborn baby
• are breast feeding. It is not known if pramipexole dihydrochloride will pass into your breast milk.

You and your doctor should decide if you will take pramipexole dihydrochloride tablets or breastfeed. You should not do both.

• drink alcohol. Alcohol can increase the chance that pramipexole dihydrochloride tablets will make you feel sleepy or fall asleep when you should be awake

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take any other medicines that make you sleepy. Pramipexole dihydrochloride tablets and other medicines may interact with each other causing side effects. Pramipexole dihydrochloride tablets may affect the way other medicines work, and other medicines may affect how pramipexole dihydrochloride tablets work.

How should I take pramipexole dihydrochloride tablets?

• Take pramipexole dihydrochloride tablets exactly as your doctor tells you to. Your doctor will tell you how many pramipexole dihydrochloride tablets to take and when to take them.
• Your doctor may change your dose until you are taking the right amount of medicine to control your symptoms. Do not take more or less pramipexole dihydrochloride tablets than your doctor tells you to.
• Pramipexole dihydrochloride tablets can be taken with or without food. Taking pramipexole dihydrochloride tablets with food may lower your chances of getting nausea.
• If you miss a dose, do not double your next dose. Skip the dose you missed and take your next regular dose.
• Be sure to tell your doctor right away if you stop taking pramipexole dihydrochloride tablets for any reason. Do not start taking pramipexole dihydrochloride tablets again before speaking with your doctor. If you have Parkinson s disease and are stopping pramipexole dihydrochloride tablets, you should stop pramipexole dihydrochloride tablets slowly over 7 days.

What should I avoid while taking pramipexole dihydrochloride tablets?

• Do not drive a car, operate a machine, or do anything that needs you to be alert until you know how pramipexole dihydrochloride tablets affect you. See "What is the most important information I should know about pramipexole dihydrochloride tablets?" at the beginning of this leaflet.
• Do not drink alcohol while taking pramipexole dihydrochloride tablets. It can increase your chances of feeling sleepy or falling asleep when you should be awake.

What are the possible side effects of pramipexole dihydrochloride tablets?

Pramipexole dihydrochloride tablets can cause serious side effects, including

• falling asleep during normal daily activities. See "What is the most important information I should know about pramipexole dihydrochloride tablets?"
• low blood pressure when you sit or stand up quickly. You may have dizziness, nausea, fainting, or sweating. Sit and stand up slowly after you have been sitting or lying down for a while.
• hallucinations. You may see, hear, feel, or taste something that isn t there. You have a higher chance of having hallucinations if you are over 65 years old.

The most common side effects in people taking pramipexole dihydrochloride tablets for Parkinson s disease are nausea, dizziness, sleepiness, constipation, hallucinations, insomnia, muscle weakness, confusion, and abnormal movements.

These are not all the possible side effects of pramipexole dihydrochloride tablets. For more information ask your doctor or pharmacist.

Be sure to talk to your doctor about any side effects that bother you or that do not go away.

Other Information about pramipexole dihydrochloride tablets

Studies of people with Parkinson s disease show that they may be at an increased risk of developing melanoma, a form of skin cancer, when compared to people without Parkinson s disease. It is not known if this problem is associated with Parkinson s disease or the medicines used to treat Parkinson s disease. Pramipexole dihydrochloride tablet is one of the medicines used to treat Parkinson s disease, therefore, patients being treated with pramipexole dihydrochloride tablets should have periodic skin examinations.

There have been reports of patients taking certain medicines to treat Parkinson s disease, including pramipexole dihydrochloride tablets, that have reported problems with gambling, compulsive eating, compulsive shopping, and increased sex drive. It is not possible to reliably estimate how often these behaviors occur or to determine which factors may contribute to them. If you or your family members notice that you are developing unusual behaviors, talk to your doctor.

How should I store pramipexole dihydrochloride tablets?

• Store pramipexole dihydrochloride tablets at 20 to 25 C (68 to 77 F).
• Keep pramipexole dihydrochloride tablets out of light.
• Keep pramipexole dihydrochloride tablets and all medicines out of the reach of children.

General information about pramipexole dihydrochloride tablets

Medicines are sometimes prescribed for purposes other than those listed in this Patient Information leaflet. Do not take pramipexole dihydrochloride tablets for a condition for which it was not prescribed. Do not share pramipexole dihydrochloride tablets with other people, even if they have the same symptoms you do. It may harm them.

This Patient Information leaflet summarizes the most important information about pramipexole dihydrochloride tablets. For more information, talk with your doctor or pharmacist. They can give you information about pramipexole dihydrochloride tablets that is written for health care professionals. Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

What are the ingredients in pramipexole dihydrochloride tablets?

Active Ingredient: pramipexole dihydrochloride monohydrate

Inactive Ingredients: colloidal silicon dioxide, mannitol, magnesium stearate, pregelatinized starch and povidone. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, mannitol, magnesium stearate, pregelatinized starch and povidone. Additionally each 0.125 mg tablet contains D&C red no. 27 aluminum lake, each 0.25 mg tablet contains FD&C blue no. 1 aluminum lake, each 0.5 mg tablet contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake, each 1 mg tablet contains ferric oxide red and each 1.5 mg tablet contains ferric oxide yellow.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 04/11

Revision Date: 29/04/2011

Pramipexole 0.5mg Tablet

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63629-5034(NDC:68382-198) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength D&C RED NO. 27 (UNII: 2LRS185U6K) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONES (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color PURPLE (LAVENDER) Score 2 pieces Shape CAPSULE (CAPSULE) Size 8mm Flavor Imprint Code P;3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-5034-1 90 in 1 BOTTLE 2 NDC:63629-5034-2 30 in 1 BOTTLE 3 NDC:63629-5034-3 60 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078920 07/10/2010

Labeler - Bryant Ranch Prepack (171714327)

Registrant - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(63629-5034) , RELABEL(63629-5034)

Revised: 5/2014 Document Id: 0b5bd4fc-c750-4f85-afc3-a2a1e585575c 34391-3 Set id: a41fc541-969c-4928-b43a-fc129fefb900 Version: 1000 Effective Time: 20140529 Bryant Ranch Prepack

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use PRAMIPEXOLE DIHYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for PRAMIPEXOLE DIHYDROCHLORIDE.

PRAMIPEXOLE DIHYDROCHLORIDE TABLETS, for oral use
Initial U.S. Approval: 1997

Recent Major Changes ⮝

Warnings and Precautions , Postural Deformity (5.6)
5/2018
Warnings and Precautions, Rhabdomyolysis (5.8) 5/2018
Warnings and Precautions,
Events Reported with Dopaminergic Therapy (5.10);
Melanoma Removed 5/2018

Indications And Usage ⮝

Pramipexole dihydrochloride tablets are a non-ergot dopamine agonist indicated for the treatment of:

Parkinson s disease (PD) (1.1)
Moderate-to-severe primary Restless Legs Syndrome (RLS) (1.2)

Dosage And Administration ⮝

Parkinson s Disease-Normal Renal Function* (2.2)
Week	Dosage (mg)	Total Daily Dose (mg)
1	0.125 TID	0.375
2	0.25 TID	0.75
3	0.5 TID	1.5
4	0.75 TID	2.25
5	1 TID	3
6	1.25 TID	3.75
7	1.5 TID	4.5
* Doses should not be increased more frequently than every 5-7 days. Titrate to effective dose. If used with levodopa, may need to reduce levodopa dose.

Parkinson s Disease-Impaired Renal Function (2.2)
Creatinine Clearance	Starting Dose (mg)	Maximum Dose (mg)
> 50 mL/min	0.125 TID	1.5 TID
30 to 50 mL/min	0.125 BID	0.75 TID
15 to 30 mL/min	0.125 QD	1.5 QD
< 15 mL/min and hemodialysis patients		Data not available

Restless Legs Syndrome* (2.3)
Titration Step	Dose (mg) 2-3 hours before bedtime
1	0.125
2 (if needed)	0.25
3 (if needed)	0.5
* Dosing interval is 4-7 days (14 days in patients with CrCl 20-60 mL/min)

Dosage Forms And Strengths ⮝

Tablets: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg. (3)

Contraindications ⮝

None (4)

Warnings And Precautions ⮝

Falling asleep during activities of daily living: Sudden onset of sleep may occur without warning; advise patients to report symptoms (5.1)

Symptomatic orthostatic hypotension. Monitor during dose escalation (5.2)

Impulse control/Compulsive behaviors: Patients may experience compulsive behaviors and other intense urges (5.3)

Hallucinations and Psychotic-like Behavior: May occur; risk increases with age (5.4)

Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride tablets (5.5)

Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride tablets if postural deformity occurs (5.6)

Adverse Reactions ⮝

Most common adverse reactions (incidence >5% and greater than placebo):
Early PD without levodopa: nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations (6.1)
Advanced PD with levodopa: postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency (6.1)
RLS: nausea, somnolence, fatigue, and headache (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

Dopamine antagonists: May diminish the effectiveness of pramipexole (7.1)

Use In Specific Populations ⮝

Pregnancy: Based on animal data, may cause fetal harm (8.1)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 6/2019

1 Indications & Usage ⮝

1.1 Parkinson's Disease

Pramipexole dihydrochloride tablets are indicated for the treatment Parkinson's disease.

1.2 Restless Legs Syndrome

Pramipexole dihydrochloride tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

2 Dosage & Administration ⮝

2.1 General Dosing Considerations

Pramipexole dihydrochloride tablets are taken orally, with or without food.

If a significant interruption in therapy with pramipexole dihydrochloride tablets has occurred, re-titration of therapy may be warranted.

2.2 Dosing for Parkinson's Disease

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Pramipexole dihydrochloride tablets should be titrated gradually in all patients. The dose should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth.


Dosing in Patients with Normal Renal Function

Initial Treatment
Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in the following Table 1:


Table 1 Ascending Dosage Schedule of Pramipexole Dihydrochloride tablets for Parkinson's Disease

Week	Dosage (mg)	Total Daily Dose (mg)
1	0.125 three times a day	0.375
2	0.25 three times a day	0.75
3	0.5 three times a day	1.50
4	0.75 three times a day	2.25
5	1 three times a day	3.0
6	1.25 three times a day	3.75
7	1.5 three times a day	4.50

Maintenance Treatment
Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of pramipexole dihydrochloride tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.

When pramipexole dihydrochloride tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline.


Dosing in Patients with Renal Impairment

The recommended dosing of pramipexole dihydrochloride tablets in Parkinson's disease patients with renal impairment is provided in Table 2.

Table 2 Dosing of Pramipexole Dihydrochloride Tablets in Parkinson's Disease Patients with Renal Impairment

Renal Status	Starting Dose (mg)	Maximum Dose (mg)
Normal to mild impairment (creatinine Cl >50 mL/min)	0.125 three times a day	1.5 three times a day
Moderate impairment (creatinine Cl =30 to 50 mL/min)	0.125 twice a day	0.75 three times a day
Severe impairment (creatinine Cl =15 to <30 mL/min)	0.125 once a day	1.5 once a day
Very severe impairment (creatinine Cl <15 mL/min and hemodialysis patients)	The use of pramipexole dihydrochloride tablets has not been adequately studied in this group of patients.

Discontinuation of Treatment

Pramipexole dihydrochloride tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see Warnings and Precautions (5.10)]

2.3 Dosing for Restless Legs Syndrome

The recommended starting dose of pramipexole dihydrochloride tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (Table 3). Although the dose of pramipexole dihydrochloride tablets was increased to 0.75 mg in some patients during long-term open-label treatment, there is no evidence that the 0.75 mg dose provides additional benefit beyond the 0.5 mg dose.
Table 3 Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for RLS

Titration Step	Duration	Dose (mg) to be taken once daily, 2-3 hours before bedtime
1	4-7 days	0.125
2*	4-7 days	0.25
3*	4-7 days	0.5

*if needed
Dosing in Patients with Renal Impairment
The duration between titration steps should be increased to 14 days in RLS patients with moderate and severe renal impairment (creatinine clearance 20-60 ml/min) [see Clinical Pharmacology (12.3)].
Discontinuation of Treatment
In clinical trials of patients being treated for RLS with doses up to 0.75 mg once daily, pramipexole dihydrochloride tablets were discontinued without a taper. In a 26 week placebo-controlled clinical trial, patients reported a worsening of RLS symptom severity as compared to their untreated baseline when pramipexole dihydrochloride tablets treatment was suddenly withdrawn [see Warnings and Precautions (5.10)].

3 Dosage Forms & Strengths ⮝

• 0.125 mg: White coloured, circular, flat, beveled edged uncoated tablet debossed 'CL' on one side of the tablet and '2' on the other side.
• 0.25 mg: White coloured, oval shaped, uncoated tablet with 'CL' and '3' debossed on one side of the tablet with breakline separating 'CL' and '3' and having a breakline on the other side.
• 0.5 mg: White coloured, oval shaped, uncoated tablet with 'CL' and '4' debossed on one side of the tablet with breakline separating 'CL' and '4' and having a breakline on the other side.
• 1 mg: White coloured, flat, circular, beveled edged uncoated tablet with 'CL' and '5' debossed on one side of the tablet with breakline separating 'CL' and '5' and having a breakline on the other side.
• 1.5 mg: White coloured, flat, circular, beveled edged uncoated tablet with 'CL' and '6' debossed on one side of the tablet with breakline separating 'CL' and '6' and having a breakline on the other side.

4 Contraindications ⮝

None.

5 Warnings And Precautions ⮝

5.1 Falling Asleep During Activities of Daily Living and Somnolence

Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment.

Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg three times a day) for Parkinson's disease. In controlled clinical trials in RLS, patients treated with pramipexole dihydrochloride tablets at doses of 0.25-0.75 mg once a day, the incidence of somnolence was 6% compared to an incidence of 3% for placebo-treated patients [see Adverse Reactions (6.1)]. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with pramipexole dihydrochloride tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with pramipexole dihydrochloride tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Symptomatic Orthostatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, both Parkinson's disease patients and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.

While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded. Also, clinical trials in patients with RLS did not incorporate orthostatic challenges with intensive blood pressure monitoring done in close temporal proximity to dosing.

5.3 Impulse Control/Compulsive Behaviors

Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride.

5.4 Hallucinations and Psychotic-like Behavior

In the three double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.

Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

Postmarketing reports with medication used to treat Parkinson's disease, including pramipexole dihydrochloride, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride or after starting or increasing the dose of pramipexole dihydrochloride. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of pramipexole dihydrochloride [see Drug Interactions (7.1)].
In the RLS clinical trials, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved.

5.5 Dyskinesia

Pramipexole dihydrochloride tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity

Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of pramipexole dihydrochloride. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing pramipexole dihydrochloride has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment

Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing pramipexole dihydrochloride tablets to patients with renal impairment [Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.8 Rhabdomyolysis

A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease treated with pramipexole dihydrochloride tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.
Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology

Human Data

A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared pramipexole dihydrochloride tablets and immediate-release ropinirole. Two hundred thirty four Parkinson s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data
Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2)].

5.10 Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported in association with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Hyperpyrexia and Confusion
Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride tablets. If the decision is made to discontinue pramipexole dihydrochloride tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2)].

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the post marketing experience with pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride tablets and these fibrotic complications, a contribution of pramipexole dihydrochloride tablets cannot be completely ruled out.

Rebound and Augmentation in RLS

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in rebound: a worsening of symptoms following treatment cessation with greater intensity than described before starting treatment. In a 26 week placebo controlled clinical trial in patients with RLS, a worsening of symptoms scores (IRLS) beyond their untreated baseline levels was reported more frequently by patients suddenly withdrawn from pramipexole dihydrochloride tablets (up to 0.75 mg once daily) compared to the group assigned to placebo (10% vs. 2%, respectively). The worsening of RLS symptoms was considered generally mild.

Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. In a 26 week placebo controlled clinical trial in patients with RLS, augmentation was reported with greater frequency by patients treated with pramipexole dihydrochloride tablets (up to 0.75 mg once daily) compared to patients who received placebo (12% vs. 9%, respectively). The incidence of augmentation increased with increasing duration of exposure to pramipexole dihydrochloride tablets and to placebo.

The frequency and severity of augmentation and/or rebound after longer-term use of pramipexole dihydrochloride tablets and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.

6 Adverse Reactions ⮝

The following adverse reactions are discussed in greater detail in other sections of the labeling:
Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)].
Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2)].
Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.3)].
Hallucinations and Psychotic-like Behavior [see Warnings and Precautions (5.4)].
Dyskinesia [see Warnings and Precautions (5.5)].
Postural Deformity [see Warnings and Preacautions (5.6)]
Rhabdomyolysis [see Warnings and Precautions (5.8)].
Retinal Pathology [see Warnings and Precautions (5.9)].
Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.10)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Parkinson's Disease

During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse reactions, this section will, in general, present adverse-reaction data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions.

Early Parkinson's Disease
In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most common adverse reactions (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson's disease and treated with pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reaction compared with 11% of 235 patients who received placebo. The adverse reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs 0% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets vs 0% on placebo]); and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Early Parkinson's Disease:
Table 4 lists adverse reactions that occurred in the double-blind, placebocontrolled studies in early Parkinson's disease that were reported by >1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa.

Table 4 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride tablets in Early Parkinson's Disease

Body System/ Adverse Reaction	Pramipexole Dihydrochloride (N=388) %	Placebo (N=235) %
Nervous System
Dizziness	25	24
Somnolence	22	9
Insomnia	17	12
Hallucinations	9	3
Confusion	4	1
Amnesia	4	2
Hypesthesia	3	1
Dystonia	2	1
Akathisia	2	0
Thinking abnormalities	2	0
Decreased libido	1	0
Myoclonus	1	0
Digestive System
Nausea	28	18
Constipation	14	6
Anorexia	4	2
Dysphagia	2	0
Body as a Whole
Asthenia	14	12
General edema	5	3
Malaise	2	1
Reaction unevaluable	2	1
Fever	1	0
Metabolic & Nutritional System
Peripheral edema	5	4
Decreased weight	2	0
Special Senses
Vision abnormalities	3	0
Urogenital System
Impotence	2	1

In a fixed-dose study in early Parkinson's disease, occurrence of the following reactions increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these reactions was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.

Advanced Parkinson's Disease

In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most commonly observed adverse reactions (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.

Approximately 12% of 260 patients with advanced Parkinson's disease who received pramipexole dihydrochloride tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 16% of 264 patients who received placebo and concomitant levodopa. The reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [2.7% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dyskinesia [1.9% on pramipexole dihydrochloride tablets vs 0.8% on placebo]; and cardiovascular system (postural [orthostatic] hypotension [2.3% on pramipexole dihydrochloride tablets vs 1.1% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease:

Table 5 lists adverse reactions that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by > 1% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, pramipexole dihydrochloride tablets or placebo was administered to patients who were also receiving concomitant levodopa.

Table 5 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride tablets in Advanced Parkinson's Disease

Body System/ Adverse Event	Pramipexole Dihydrochloride (N=260) %	Placebo (N=264) %
Nervous System
Dyskinesia	47	31
Extrapyramidal syndrome	28	26
Insomnia	27	22
Dizziness	26	25
Hallucinations	17	4
Dream abnormalities	11	10
Confusion	10	7
Somnolence	9	6
Dystonia	8	7
Gait abnormalities	7	5
Hypertonia	7	6
Amnesia	6	4
Akathisia	3	2
Thinking abnormalities	3	2
Paranoid reaction	2	0
Delusions	1	0
Sleep disorders	1	0
Cardiovascular System
Postural hypotension	53	48
Body as a Whole
Accidental injury	17	15
Asthenia	10	8
General edema	4	3
Chest pain	3	2
Malaise	3	2
Digestive System
Constipation	10	9
Dry mouth	7	3
Urogenital System
Urinary frequency	6	3
Urinary tract infection	4	3
Urinary incontinence	2	1
Respiratory System
Dyspnea	4	3
Rhinitis	3	1
Pneumonia	2	0
Special Senses
Accommodation abnormalities	4	2
Vision abnormalities	3	1
Diplopia	1	0
Musculoskeletal System
Arthritis	3	1
Twitching	2	0
Bursitis	2	0
Myasthenia	1	0
Metabolic & Nutritional System
Peripheral edema	2	1
Increased creatine PK	1	0
Skin & Appendages
Skin disorders	2	1

Restless Legs Syndrome
Pramipexole dihydrochloride tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year.

The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with pramipexole dihydrochloride tablets for up to 12 weeks. The most common adverse reactions with pramipexole dihydrochloride tablets in the treatment of RLS (observed in >5% of pramipexole-treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.

Approximately 7% of 575 patients treated with pramipexole dihydrochloride tablets during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse reactions compared to 5% of 223 patients who received placebo. The adverse reaction most commonly causing discontinuation of treatment was nausea (1%).

Table 6 lists reactions that occurred in three double-blind, placebo-controlled studies in RLS patients that were reported by 2% of patients treated with pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group.
Table 6 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride Tablets in Restless Legs Syndrome

Body System/Adverse Reaction	Pramipexole Dihydrochloride Tablets 0.125 0.75 mg/day (N=575) %	Placebo (N=223) %
Gastrointestinal disorders
Nausea	16	5
Constipation	4	1
Diarrhea	3	1
Dry mouth	3	1
Nervous system disorders
Headache	16	15
Somnolence	6	3
General disorders and administration site conditions
Fatigue	9	7
Infections and infestations
Influenza	3	1

Table 7 summarizes data for adverse reactions that appeared to be dose related in the 12-week fixed dose study.

Table 7 Dose-Related Adverse Reactions in a 12-Week Double-Blind, Placebo-Controlled Fixed Dose Study in Restless Legs Syndrome (Occurring in 5% of all Patients in the Treatment Phase

Body System/Adverse Reaction	Pramipexole Dihydrochloride Tablets 0.25 mg (N=88) %	Pramipexole Dihydrochloride Tablets 0.5 mg (N=80) %	Pramipexole Dihydrochloride Tablets 0.75 mg (N=90) %	Placebo (N=86) %
Gastrointestinal disorders
Nausea	11	19	27	5
Diarrhea	3	1	7	0
Dyspepsia	3	1	4	7
Psychiatric disorders
Insomnia	9	9	13	9
Abnormal dreams	2	1	8	2
General disorders and administration site conditions
Fatigue	3	5	7	5
Musculoskeletal and connective tissue disorders
Pain in extremity	3	3	7	1
Infections and infestations
Influenza	1	4	7	1
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0	3	6	1

Adverse Reactions: Relationship to Age, Gender, and Race
Among the adverse reactions in patients treated with pramipexole dihydrochloride tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson's disease. Although no gender-related differences were observed in Parkinson s disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients.Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse reactions related to race is not possible.

Laboratory Tests
During the development of pramipexole dihydrochloride tablets, no systematic abnormalities on routine laboratory testing were noted.

6.2 Post Marketing Experience

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride tablets, primarily in Parkinson's disease patients.Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets.
Cardiac Disorders: cardiac failure
Gastrointestinal Disorders: vomiting
Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase
Musculoskeletal and Connective Tissue Disorders: postural deformity [see Warnings and Precautions (5.6)]
Nervous System Disorders: syncope
Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

7 Drug Interactions ⮝

7.1 Dopamine Antagonists

Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride tablets.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary
There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data].

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data
Animal Data
Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not in rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, or 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD.

8.2 Lactation

Risk Summary
There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for pramipexole dihydrochloride and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride or from the underlying maternal condition.

Data
In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma.

8.4 Pediatric Use

The safety and efficacy of pramipexole dihydrochloride tablets in pediatric patients has not been established.

8.5 Geriatric Use

Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours.

In clinical studies with Parkinson s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly.

In clinical studies with RLS patients, 22% of patients were at least 65 years old. There were no apparent differences in efficacy or safety between older and younger patients.

8.6 Renal Impairment

The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering pramipexole dihydrochloride tablets to patients with renal disease [see Dosage and Administration (2.2), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].

10 Overdosage ⮝

There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose.

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

11 Description ⮝

Pramipexole dihydrochloride tablets contain pramipexole, a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C10 H17 N3 S 2HCl H2O, and its molecular weight is 302.26. The structural formula is:

Pramipexole dihydrochloride is a white to off-white powder substance. Melting occurs in the range of 296 C to 301 C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

Pramipexole dihydrochloride tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients consist of mannitol, pregelatinized starch, colloidal silicon dioxide, povidone, and magnesium stearate.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

Parkinson's Disease

The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson s disease is unknown.

Restless Legs Syndrome (RLS)

The precise mechanism of action of pramipexole dihydrochloride tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.

12.2 Pharmacodynamics

The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose- or exposure-related effect on mean QT intervals was observed; however the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.

Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson s disease patients, who were titrated according to labeled recommendations.

12.3 Pharmacokinetics

Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing.

Absorption

Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.

Distribution

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Metabolism

Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.

Elimination

Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Pharmacokinetics in Specific Populations

Because therapy with pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment [see Dosage and Administration (2.2)].

Gender

Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.

Age

Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

Race

No racial differences in metabolism and elimination have been identified.

Parkinson's Disease Patients

A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson's disease patients.

Restless Legs Syndrome Patients
A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is similar to the pharmacokinetic profile of pramipexole in healthy volunteers.

Hepatic Impairment

The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Renal Impairment
Clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [see Warnings and Precautions (5.7) and Dosage and Administration (2.2)]. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance.

Drug Interactions

Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine:Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid:

Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.

CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 M, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day (or approximately 10 times the maximum recommended human dose (MRHD) for Parkinson s disease of 4.5 mg/day on a mg/m2 basis). Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis), prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

13.2 Animal Pharmacology & or Toxicology

Retinal Pathology in Rats
Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater (by morphometric analysis) than that seen in control rats.

Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the MRHD on a mg/m2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the MRHD on a mg/m2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2.0 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the MRHD on a mg/m2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.

The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

Fibro-osseous Proliferative Lesions in Mice
An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2.0, or 10 mg/kg/day (0.3, 2.2, and 11 times the MRHD on a mg/m2 basis). Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

14 Clinical Studies ⮝

14.1 Parkinson's Disease

The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.

In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).

Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Studies in Patients with Early Parkinson's Disease

Patients (N=599) in the two studies of early Parkinson's disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.

One of the two early Parkinson's disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6 month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to pramipexole dihydrochloride tablets or placebo. Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

The second early Parkinson's disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

Studies in Patients with Advanced Parkinson's Disease

In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.
Patients in the advanced Parkinson's disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa duringthe trial, and had "on-off" periods.

The advanced Parkinson's disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.

The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with pramipexole dihydrochloride tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

14.2 Restless Legs Syndrome

The efficacy of pramipexole dihydrochloride tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All patients were administered pramipexole dihydrochloride tablets (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4.6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66.6% were women.

Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with symptoms of RLS.

The two outcome measures used to assess the effect of treatment were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression -Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.

In Study 1, fixed doses of pramipexole dihydrochloride tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with pramipexole dihydrochloride tablets (n=254) had a starting dose of 0.125 mg/day and were titrated to one of the three randomized doses (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the pramipexole dihydrochloride tablets treatment groups compared to placebo are summarized in Table 8. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. There was no clear evidence of a dose-response across the 3 randomized dose groups.

Table 8 Mean Changes from Baseline to Week 12 in IRLS Score and CGI-I (Study 1)

	Pramipexole dihydrochloride Tablets0.25 mg	Pramipexole dihydrochloride Tablets 0.5 mg	Pramipexole dihydrochloride Tablets 0.75 mg	Pramipexole dihydrochloride Tablets Total	Placebo
No. Patients	88	79	87	254	85
IRLS score	-13.1	-13.4	-14.4	-13.6	-9.4
CGI-I responders*	74.7%	67.9%	72.9%	72.0%	51.2%

*CGI-I responders = much improved and very much improved

Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to pramipexole dihydrochloride tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of very much improved or much improved compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15.

In patients who had responded to 6-month open label treatment with pramipexole dihydrochloride tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, and 49 on 0.75 mg.

Study 3 was a 6-week study, comparing a flexible dose of pramipexole dihydrochloride tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to pramipexole dihydrochloride tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for pramipexole dihydrochloride tablets-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for pramipexole dihydrochloride tablets-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to pramipexole dihydrochloride tablets, the distribution of achieved doses was: 35 on 0.125 mg, 51 on 0.25 mg, 65 on 0.5 mg, and 69 on 0.75 mg.

Study 4 was a 3-week study, comparing 4 fixed doses of pramipexole dihydrochloride tablets, 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the pramipexole dihydrochloride tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0.125 mg dose group was not significantly different from placebo. On average, the 0.5 mg dose group performed better than the 0.25 mg dose group, but there was no difference between the 0.5 mg and 0.75 mg dose groups.

Table 9 Mean Changes from Baseline to Week 3 in IRLS Score and CGI-I (Study 4)

	Pramipexole dihydrochloride Tablets 0.125 mg	Pramipexole dihydrochloride Tablets 0.25 mg	Pramipexole dihydrochloride Tablets 0.5 mg	Pramipexole dihydrochloride Tablets 0.75 mg	Pramipexole dihydrochloride Tablets Total	Placebo
No. Patients	21	22	22	21	86	21
IRLS score	-11.7	-15.3	-17.6	-15.2	-15.0	-6.2
CGI-I responders*	61.9%	68.2%	86.4%	85.7%	75.6%	42.9%

*CGI-I responders = much improved and very much improved

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

16 How Supplied/storage And Handling ⮝

Product: 71335-1112

NDC: 71335-1112-1 90 TABLET in a BOTTLE

NDC: 71335-1112-2 30 TABLET in a BOTTLE

NDC: 71335-1112-3 60 TABLET in a BOTTLE

Product: 71335-1185

NDC: 71335-1185-1 30 TABLET in a BOTTLE

NDC: 71335-1185-2 90 TABLET in a BOTTLE

Product: 71335-1196

NDC: 71335-1196-1 90 TABLET in a BOTTLE

NDC: 71335-1196-2 30 TABLET in a BOTTLE

NDC: 71335-1196-3 60 TABLET in a BOTTLE

Pramipexole Dihydrochloride 0.5mg Tab ⮝

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63629-8105(NDC:33342-033) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE K25 (UNII: K0KQV10C35) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (oval) Size 11mm Flavor Imprint Code CL;4 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-8105-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 07/18/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202164 09/21/2012

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(63629-8105) , RELABEL(63629-8105)

Revised: 8/2019 Document Id: fb1ca73f-eb99-4682-8939-316414003fb8 34391-3 Set id: 9dd52a30-35ee-4ac8-9040-92205b48b960 Version: 1 Effective Time: 20190807 Bryant Ranch Prepack

Package Label.principal Display Panel - 0.125 Mg ⮝

NDC 46708-611-90
Pramipexole
Dihydrochloride
Tablets
0.125 mg
Rx only
90 Tablets
Alembic

Package Label.principal Display Panel - 0.25 Mg ⮝

NDC 46708-612-90
Pramipexole
Dihydrochloride
Tablets
0.25 mg
Rx only
90 Tablets
Alembic

Package Label.principal Display Panel - 0.5 Mg ⮝

NDC 46708-613-90
Pramipexole
Dihydrochloride
Tablets
0.5 mg
Rx only
90 Tablets
Alembic

Package Label.principal Display Panel - 1 Mg ⮝

NDC 46708-614-90
Pramipexole
Dihydrochloride
Tablets
1 mg
Rx only
90 Tablets
Alembic

Package Label.principal Display Panel - 1.5 Mg ⮝

NDC 46708-615-90
Pramipexole
Dihydrochloride
Tablets
1.5 mg
Rx only
90 Tablets
Alembic

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-611 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.125 mg

Inactive Ingredients Ingredient Name Strength BETADEX (UNII: JV039JZZ3A) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE (White to off white) Score no score Shape ROUND (Circular) Size 6mm Flavor Imprint Code E;33 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:46708-611-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078894 03/22/2016

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-612 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.25 mg

Inactive Ingredients Ingredient Name Strength BETADEX (UNII: JV039JZZ3A) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape OVAL Size 8mm Flavor Imprint Code E;E;34;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:46708-612-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078894 03/22/2016

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-613 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength BETADEX (UNII: JV039JZZ3A) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape OVAL Size 10mm Flavor Imprint Code E;E;35;35 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:46708-613-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078894 03/22/2016

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-614 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1 mg

Inactive Ingredients Ingredient Name Strength BETADEX (UNII: JV039JZZ3A) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape ROUND (Circular) Size 9mm Flavor Imprint Code E;E;36;36 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:46708-614-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078894 03/22/2016

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-615 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1.5 mg

Inactive Ingredients Ingredient Name Strength BETADEX (UNII: JV039JZZ3A) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape ROUND (Circular) Size 11mm Flavor Imprint Code E;E;37;37 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:46708-615-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078894 03/22/2016

Labeler - Alembic Pharmaceuticals Limited (650574663)

Establishment
Name	Address	ID/FEI	Business Operations
Alembic Pharmaceuticals Limited		650574671	MANUFACTURE(46708-611, 46708-612, 46708-613, 46708-614, 46708-615)

Revised: 9/2019 Document Id: 0a3ed933-ef5b-4091-8ae9-5768ae18514f 34391-3 Set id: 0a3ed933-ef5b-4091-8ae9-5768ae18514f Version: 1 Effective Time: 20190912 Alembic Pharmaceuticals Limited

Pramipexole Dihydrochloride 0.5mg Tab. ⮝

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-1112(NDC:33342-032) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.25 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE K25 (UNII: K0KQV10C35) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (oval) Size 8mm Flavor Imprint Code CL;3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-1112-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 04/07/2014 2 NDC:71335-1112-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 04/07/2014 3 NDC:71335-1112-3 60 in 1 BOTTLE; Type 0: Not a Combination Product 04/07/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202164 09/21/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-1185(NDC:33342-035) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 1.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE K25 (UNII: K0KQV10C35) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score 2 pieces Shape ROUND (round) Size 10mm Flavor Imprint Code CL;6 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-1185-1 30 in 1 BOTTLE; Type 0: Not a Combination Product 04/16/2019 2 NDC:71335-1185-2 90 in 1 BOTTLE; Type 0: Not a Combination Product 04/16/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202164 09/21/2012

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-1196(NDC:33342-033) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) STARCH, CORN (UNII: O8232NY3SJ) POVIDONE K25 (UNII: K0KQV10C35) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (oval) Size 11mm Flavor Imprint Code CL;4 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-1196-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 07/16/2014 2 NDC:71335-1196-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/16/2014 3 NDC:71335-1196-3 60 in 1 BOTTLE; Type 0: Not a Combination Product 07/16/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202164 09/21/2012

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-1112, 71335-1185, 71335-1196) , RELABEL(71335-1112, 71335-1185, 71335-1196)

Revised: 6/2019 Document Id: 1cf5237d-656b-45a4-8486-317ff86f080e 34391-3 Set id: 72716e35-e695-4722-bb6a-819d44aac34b Version: 3 Effective Time: 20190611 Bryant Ranch Prepack

1 Indications And Usage ⮝

1.1 Parkinson's Disease

Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson s disease.

2 Dosage And Administration ⮝

2.1 General Dosing Considerations

Pramipexole dihydrochloride tablets are taken orally, with or without food.

If a significant interruption in therapy with pramipexole dihydrochloride tablets has occurred, re-titration of therapy may be warranted.

2.2 Dosing for Parkinson's Disease

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Pramipexole dihydrochloride tablets should be titrated gradually in all patients. The dose should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth.

Dosing in Patients with Normal Renal Function

Initial Treatment

Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in Table 1:

Table 1 Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for Parkinson's Disease

Week	Dosage (mg)	Total Daily Dose (mg)
1	0.125 three times a day	0.375
2	0.25 three times a day	0.75
3	0.5 three times a day	1.5
4	0.75 three times a day	2.25
5	1 three times a day	3
6	1.25 three times a day	3.75
7	1.5 three times a day	4.5

Maintenance Treatment

Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

In a fixed-dose study in early Parkinson s disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of pramipexole dihydrochloride tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.

When pramipexole dihydrochloride tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson s disease, the dosage of levodopa was reduced by an average of 27% from baseline.

Dosing in Patients with Renal Impairment

The recommended dosing of pramipexole dihydrochloride tablets in Parkinson s disease patients with renal impairment is provided in Table 2.

Table 2 Dosing of Pramipexole Dihydrochloride Tabletsin Parkinson s Disease Patients with Renal Impairment

Renal Status	Starting Dose (mg)	Maximum Dose (mg)
Normal to mild impairment (creatinine Cl >50 mL/min)	0.125 three times a day	1.5 three times a day
Moderate impairment (creatinine Cl =30 to 50 mL/min)	0.125 twice a day	0.75 three times a day
Severe impairment (creatinine Cl =15 to <30 mL/min)	0.125 once a day	1.5 once a day
Very severe impairment (creatinine Cl <15 mL/min and hemodialysis patients)	The use of pramipexole dihydrochloride tablets has not been adequately studied in this group of patients.

Discontinuation of Treatment

Pramipexole dihydrochloride tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see Warnings and Precautions (5.9)].

3 Dosage Forms And Strengths ⮝

• 0.125 mg: White to off white, circular tablet debossed with E on one side and 33 on the other side.
• 0.25 mg: White to off white, oval shaped tablet with break line on both side and debossed with E E on one side and 34 34 on other side.
• 0.5 mg: White to off white, oval shaped tablet with break line on both side and debossed with E E on one side and 35 35 on other side.
• 1 mg: White to off white, circular tablet with break line on both side and debossed with E E on one side and 36 36 on other side.
• 1.5 mg: White to off white, circular tablet with break line on both side and debossed with E E on one side and 37 37 on other side.

Pramipexole Dihydrochlor. 0.125mg Tab ⮝

PRAMIPEXOLE DIHYDROCHLORIDE pramipexole dihydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63629-5042(NDC:13668-091) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAMIPEXOLE DIHYDROCHLORIDE (UNII: 3D867NP06J) (PRAMIPEXOLE - UNII:83619PEU5T) PRAMIPEXOLE DIHYDROCHLORIDE 0.125 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) MANNITOL (UNII: 3OWL53L36A) POVIDONE K30 (UNII: U725QWY32X) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE (white to off white) Score no score Shape ROUND Size 5mm Flavor Imprint Code 91 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-5042-1 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/23/2013 2 NDC:63629-5042-2 60 in 1 BOTTLE; Type 0: Not a Combination Product 07/23/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090865 10/08/2010

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(63629-5042) , RELABEL(63629-5042)

Revised: 10/2019 Document Id: 67f170e3-0ea4-412a-9cc3-a073c807eff9 34391-3 Set id: bd0f7ae1-11ef-4fab-894f-c4c59f75aa99 Version: 1007 Effective Time: 20191001 Bryant Ranch Prepack