ALPRAZOLAM tablet
For Healthcare Providers >

1. What Are Alprazolam Tablets?
2. Active Ingredient:
3. Inactive Ingredients:
4. What Are Alprazolam Tablets?
5. Alprazolam Tablets May Cause Serious Side Effects, Including:
6. Patient Information
7. What Is The Most Important Information I Should Know About Alprazolam Tablets?
8. Alprazolam Tablets Are A Prescription Medicine Used:
9. Do Not Take Alprazolam Tablets If:
10. Alprazolam Tablets May Cause Serious Side Effects, Including:
11. Manufactured By:

What Are Alprazolam Tablets? ⮝

• Alprazolam tablets are a prescription medicine used:
  • to treat anxiety disorders
  • for the short-term relief of the symptoms of anxiety
  • to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)
• Alprazolam are a federal controlled substance (C-IV) because it can be abused or lead to dependence.Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
• It is not known if alprazolam tablets are safe and effective in children.
• Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.
• It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months.
• It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks.

Active Ingredient: ⮝

alprazolam

Inactive Ingredients: ⮝

colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&C Blue No. 2 lake.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dispense with Medication Guide

Distributed by:
American Health Packaging
Columbus, OH 43217

8437701/0518

What Are Alprazolam Tablets? ⮝

• Alprazolam Tablets are a prescription medicine used:
  • to treat anxiety disorders
  • for the short-term relief of the symptoms of anxiety
  • to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)
• Alprazolam is a federal controlled substance (C-IV) because it can be abused or lead to dependence.Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
• It is not known if alprazolam tablets are safe and effective in children.
• Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.
• It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months.
• It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks.

Alprazolam Tablets May Cause Serious Side Effects, Including: ⮝

• • Store alprazolam tablets between 20 C to 25 C (68 F to 77 F). Protect from light.
  • Keep alprazolam tablets and all medicines out of the reach of children.

  General information about the safe and effective use of alprazolam tablets.

  • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
  • Do not use alprazolam tablets for a condition for which it was not prescribed.
  • Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.
  • You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.

  For more information, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395, or go towww.bpirx.com.

Patient Information ⮝

Alprazolam Tablets, USP (al pra' zoe lam)

What Is The Most Important Information I Should Know About Alprazolam Tablets? ⮝

Alprazolam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.

Alprazolam tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you.

Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse.

Do not take more alprazolam tablets than prescribed.

Alprazolam Tablets Are A Prescription Medicine Used: ⮝

to treat anxiety disorders

for the short-term relief of the symptoms of anxiety

to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)

Alprazolam tablets are a federal controlled substance (C-IV) because they can be abused or lead to dependence.Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.

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

Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.

It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months.

It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks.

Do Not Take Alprazolam Tablets If: ⮝

you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets.

Alprazolam tablets can cause you to be drowsy. Do not drive a car or operate heavy machinery until you know how alprazolam tablets affect you.

You should not drink alcohol while taking alprazolam tablets. Drinking alcohol can increase your chances of having serious side effects.

Alprazolam Tablets May Cause Serious Side Effects, Including: ⮝

Store alprazolam tablets at 20 to 25 C (68 to 77 F).

Protect from light.

Keep alprazolam tabletsand all medicines out of the reach of children.

General information about the safe and effective use of alprazolam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use alprazolam tablets for a condition for which it was not prescribed.

Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.

Manufactured By: ⮝

Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 1/2017
ALP:R11mmh

1. No Title 1572548443
2. No Title 1572550420
3. No Title 1572552166
4. No Title 1572553871
5. Package/label Display Panel Blister - 0.5 Mg
6. Principal Display Panel - 0.5mg
7. Principal Display Panel - 1mg
8. Warning: Risks From Concomitant Use With Opioids
9. No Title 1572450718
10. Description
11. Clinical Pharmacology
12. Clinical Studies
13. Indications And Usage
14. Contraindications
15. Warnings
16. Precautions
17. Adverse Reactions
18. Drug Abuse And Dependence
19. Overdosage
20. Dosage And Administration
21. How Supplied
22. Principal Display Panel - 1 Mg
23. Alprazolam
24. No Title 1572451055
25. Principal Display Panel - 0.25 Mg
26. Package/label Principal Display Panel
27. No Title 1572453060
28. Package Label.principal Display Panel
29. Package Label.principal Display Panel
30. No Title 1572453287
31. No Title 1572453288
32. Packaging Information
33. Package/label Display Panel Carton 0.25 Mg
34. Package/label Display Panel Blister 0.25 Mg
35. Package/label Display Panel Carton 0.5 Mg
36. Package/label Display Panel Blister 0.5 Mg
37. Principal Display Panel - 0.5 Mg
38. Warning: Risks From Concomitant Use With Opioids
39. Description
40. Clinical Pharmacology
41. Clinical Studies
42. Indications And Usage
43. Contraindications
44. Warnings
45. Precautions
46. Adverse Reactions
47. Drug Abuse And Dependence
48. Overdosage
49. Dosage And Administration
50. How Supplied
51. Animal Studies
52. Repackaging Information
53. Principal Display Panel - 0.25mg

No Title 1572548443 ⮝

MEDICATION GUIDE Alprazolam Tablets (al pra' zoe lam), C-IV
What is the most important information I should know about alprazolam tablets? Alprazolam tablets is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Alprazolam tablets can make you sleepy or dizzy, and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. Do not take more alprazolam tablets than prescribed.
What is alprazolam tablets? Alprazolam tablets is a prescription medicine used: to treat anxiety disorders for the short-term relief of the symptoms of anxiety to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) Alprazolam tablets is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if alprazolam tablets is safe and effective in children. Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets. It is not known if alprazolam tablets is safe and effective when used to treat anxiety disorder for longer than 4 months. It is not known if alprazolam tablets is safe and effective when used to treat panic disorder for longer than 10 weeks.
Do not take alprazolam tablets if: you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets. you are taking antifungal medicines including ketoconazole and itraconazole
Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have liver or kidney problems have lung disease or breathing problems are pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant. are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
How should I take alprazolam tablets? See What is the most important information I should know about alprazolam tablets? Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it. If you take too much alprazolam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking alprazolam tablets? Alprazolam tablets can cause you to be drowsy. Do not drive a car or operate heavy machinery until you know how alprazolam tablets affects you. You should not drink alcohol while taking alprazolam tablets. Drinking alcohol can increase your chances of having serious side effects.
What are the possible side effects of alprazolam tablets? Alprazolam tablets may cause serious side effects, including: See What is the most important information I should know about alprazolam tablets? Abuse and dependence. Taking alprazolam tablets can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction. Withdrawal symptoms. You may have withdrawal symptoms if you stop taking alprazolam tablets suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping alprazolam tablets to avoid withdrawal symptoms. Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). Mania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression. The most common side effects of alprazolam tablets include drowsiness and lightheadedness. These are not all the possible side effects of alprazolam tablets. 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 alprazolam tablets? Store alprazolam tablets between 68 F to 77 F 20 C to 25 C Keep alprazolam tablets and all medicines out of the reach of children.
General information about the safe and effective use of alprazolam tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alprazolam tablets for a condition for which it was not prescribed. Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.
What are the ingredients in alprazolam tablets? Active ingredient: alprazolam Inactive ingredients: crospovidone, docusate sodium, lactose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium benzoate and starch 1500. In addition, the 0.5 mg tablet contains D&C Yellow No. 10 and the 1 mg and 2 mg tablet contains Green Lake Blend.
Distributed by: Par Pharmaceutical, Chestnut Ridge, NY 10977 1-800-828-9393
This Medication Guide has been approved by the U.S. Food and Drug Administration.	Issued: 01/2017

No Title 1572550420 ⮝

C-IV

Revised July 2017

Rx Only

No Title 1572552166 ⮝

C-IV

Revised July 2017

Rx Only

No Title 1572553871 ⮝

C-IV

Revised July 2017

Rx Only

Package/label Display Panel Blister - 0.5 Mg ⮝

Alprazolam
Tablet, USP CIV

0.5 mg

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-510(NDC:51991-704) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A CORN (UNII: AG9B65PV6B) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) SODIUM LAURYL SULFATE (UNII: 368GB5141J) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color white (white to off-white) Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code B704 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-510-01 100 in 1 BOX, UNIT-DOSE 10/21/2019 1 NDC:60687-510-11 1 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 ANDA207507 10/21/2019

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-521(NDC:51991-705) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A CORN (UNII: AG9B65PV6B) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) SODIUM LAURYL SULFATE (UNII: 368GB5141J) MAGNESIUM STEARATE (UNII: 70097M6I30) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color orange (light orange to orange) Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code B705 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-521-01 100 in 1 BOX, UNIT-DOSE 10/21/2019 1 NDC:60687-521-11 1 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 ANDA207507 10/21/2019

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(60687-510, 60687-521)

Revised: 10/2019 Document Id: 95fa8edb-9f28-01d6-e053-2a95a90ae879 34391-3 Set id: c1aac17b-2b9f-4ab6-a083-6a4ea2227fc7 Version: 1 Effective Time: 20191028 American Health Packaging

Principal Display Panel - 0.5mg ⮝

NDC 67544-415 - Alprazolam 0.5mg - Rx Only

Principal Display Panel - 1mg ⮝

NDC 67544-347 - Alprazolam 1mg - Rx Only

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67544-414(NDC:59762-3719) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength POWDERED CELLULOSE (UNII: SMD1X3XO9M) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code G3719 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67544-414-15 15 in 1 BOTTLE; Type 0: Not a Combination Product 06/16/2006 2 NDC:67544-414-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 06/30/2005 3 NDC:67544-414-45 45 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/2006 4 NDC:67544-414-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/30/2005 5 NDC:67544-414-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 6 NDC:67544-414-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 09/07/2005 7 NDC:67544-414-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 02/22/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA018276 10/16/1981

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67544-415(NDC:59762-3720) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength POWDERED CELLULOSE (UNII: SMD1X3XO9M) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color ORANGE Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code G3720 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67544-415-15 15 in 1 BOTTLE; Type 0: Not a Combination Product 05/10/2006 2 NDC:67544-415-20 20 in 1 BOTTLE; Type 0: Not a Combination Product 04/26/2010 3 NDC:67544-415-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 4 NDC:67544-415-45 45 in 1 BOTTLE; Type 0: Not a Combination Product 05/25/2006 5 NDC:67544-415-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 6 NDC:67544-415-55 75 in 1 BOTTLE; Type 0: Not a Combination Product 04/26/2010 7 NDC:67544-415-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 8 NDC:67544-415-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 09/14/2005 9 NDC:67544-415-75 150 in 1 BOTTLE; Type 0: Not a Combination Product 06/08/2006 10 NDC:67544-415-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 05/11/2006 11 NDC:67544-415-92 270 in 1 BOTTLE; Type 0: Not a Combination Product 04/26/2010

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA018276 10/16/1981

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67544-347(NDC:59762-3721) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 1 mg

Inactive Ingredients Ingredient Name Strength POWDERED CELLULOSE (UNII: SMD1X3XO9M) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) FD&C BLUE NO. 2 (UNII: L06K8R7DQK)

Product Characteristics Color BLUE Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code G3721 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67544-347-15 15 in 1 BOTTLE; Type 0: Not a Combination Product 06/22/2006 2 NDC:67544-347-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 3 NDC:67544-347-45 45 in 1 BOTTLE; Type 0: Not a Combination Product 07/13/2006 4 NDC:67544-347-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/23/2005 5 NDC:67544-347-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 09/20/2005 6 NDC:67544-347-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 11/02/2005 7 NDC:67544-347-75 150 in 1 BOTTLE; Type 0: Not a Combination Product 07/20/2006 8 NDC:67544-347-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/2006 9 NDC:67544-347-90 240 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/2006

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA AUTHORIZED GENERIC NDA018276 10/16/1981

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(67544-414, 67544-415, 67544-347)

Revised: 2/2018 Document Id: 51152b89-539c-4c80-bb84-d7f2dc082953 34391-3 Set id: 964d7f43-34a6-45af-a95f-3b9ade17c6a5 Version: 1 Effective Time: 20180205 Aphena Pharma Solutions - Tennessee, LLC

Warning: Risks From Concomitant Use With Opioids ⮝

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see Warnings, Drug Interactions].

• Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

No Title 1572450718 ⮝

C-IV

Revised July 2017

Rx Only

Description  ⮝

Alprazolam tablets, USP contain alprazolam, USP which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

The chemical name of alprazolam, USP is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3- ] [1,4] benzodiazepine and its structural formula is:

Alprazolam, USP is a white to off-white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

Each tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, and 2 mg of alprazolam, USP. The 2 mg tablets are multi-scored and may be divided in half to provide two 1 mg segments, or quarters to provide four 0.5 mg segments.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium benzoate. The 0.5 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake). The 1 mg tablet also contains FD&C blue #2 aluminum lake. The 2 mg tablet also contains D&C yellow #10 aluminum lake.

Clinical Pharmacology  ⮝

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetics

Absorption

Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.

Distribution

In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism/Elimination

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and -hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and -hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and -hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and -hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Alprazolam and its metabolites are excreted primarily in the urine.

Special Populations

Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

Race - Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

Pediatrics - The pharmacokinetics of alprazolam in pediatric patients have not been studied.

Gender - Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking - Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Drug-Drug Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS Drug Interactions).

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90 0.21 mL/min/kg to 2.13 0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1 4.9 to 7.7 1.7 h) following administration of 300 mg/day carbamazepine for 10 days (see PRECAUTIONS Drug Interactions). However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1,000 to 1,200 mg/day); the effect at usual carbamazepine doses is unknown.

The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

Clinical Studies  ⮝

Anxiety Disorders

Alprazolam tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient s Global Impressions and Self-Rating Symptom Scale.

Panic Disorder

Support for the effectiveness of alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.

The average dose of alprazolam was 5 mg/day to 6 mg/day in two of the studies, and the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all three studies, alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37% to 83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

Indications And Usage  ⮝

Anxiety Disorders

Alprazolam tablets, USP are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of 6 months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or 'lump in throat'); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank' because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.

Anxiety associated with depression is responsive to alprazolam.

Panic Disorder

Alprazolam tablets, USP are also indicated for the treatment of panic disorder, with or without agoraphobia.

Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

Contraindications  ⮝

Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.

Alprazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see WARNINGS and PRECAUTIONS Drug Interactions).

Warnings  ⮝

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see Drug Interactions).

Dependence and Withdrawal Reactions, Including Seizures

Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

The importance of dose and the risks of alprazolam as a treatment for panic disorder: Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients.

Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.

In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.

In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with alprazolam tapered completely off therapy compared to 89% to 96% of placebo-treated patients. In a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.

Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule).

Status Epilepticus and its Treatment

The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.

Interdose Symptoms

Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations (see DOSAGE AND ADMINISTRATION).

Risk of Dose Reduction

Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).

CNS Depression and Impaired Performance

Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.

Risk of Fetal Harm

Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.

The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.

Potent CYP3A Inhibitors

Azole antifungal agents - Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS).

Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving alprazolam (caution and consideration of appropriate alprazolam dose reduction are recommended during coadministration with the following drugs)

Nefazodone - Coadministration of nefazodone increased alprazolam concentration two-fold.

Fluvoxamine - Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.

Cimetidine - Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.

Other drugs possibly affecting alprazolam metabolism

Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see PRECAUTIONS Drug Interactions).

Precautions  ⮝

General

Suicide

As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.

Mania

Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

Uricosuric Effect

Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.

Use in Patients with Concomitant Illness

It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam (see CLINICAL PHARMACOLOGY).

Information for Patients

For all users of alprazolam:

To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam should be provided with the following guidance.

1. Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider.
2. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see Drug Interactions).
3. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
4. Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
5. Inform your physician if you are nursing.
6. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
7. Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
8. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.

Additional advice for panic disorder patients:

The use of alprazolam at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of alprazolam.

In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.

Drug Interactions

Use with Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Use with Other CNS Depressants

If alprazolam tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with Imipramine and Desipramine

The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs that inhibit alprazolam metabolism via cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).

Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam)

Fluoxetine - Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.

Propoxyphene - Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.

Oral Contraceptives - Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.

Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam)

Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS).

Drugs demonstrated to be inducers of CYP3A

Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.

Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).

Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

Pregnancy

Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).

Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Labor and Delivery

Alprazolam has no established use in labor or delivery.

Nursing Mothers

Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.

Pediatric Use

Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Adverse Reactions  ⮝

Side effects to alprazolam tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, e.g., drowsiness or light-headedness.

The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.

These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward event] in others.)

Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety Disorders

ANXIETY DISORDERS
	Treatment-Emergent		Incidence of Intervention
	Symptom Incidence		Because of Symptom
	Alprazolam	PLACEBO	Alprazolam
Events reported by 1% or more of alprazolam patients are included.
Number of Patients	565	505	565
% of Patients
Reporting:
Central Nervous System
Drowsiness	41.0	21.6	15.1
Light-headedness	20.8	19.3	1.2
Depression	13.9	18.1	2.4
Headache	12.9	19.6	1.1
Confusion	9.9	10.0	0.9
Insomnia	8.9	18.4	1.3
Nervousness	4.1	10.3	1.1
Syncope	3.1	4.0	*
Dizziness	1.8	0.8	2.5
Akathisia	1.6	1.2	*
Tiredness/Sleepiness	*	*	1.8
Gastrointestinal
Dry Mouth	14.7	13.3	0.7
Constipation	10.4	11.4	0.9
Diarrhea	10.1	10.3	1.2
Nausea/Vomiting	9.6	12.8	1.7
Increased Salivation	4.2	2.4	*
Cardiovascular
Tachycardia/Palpitations	7.7	15.6	0.4
Hypotension	4.7	2.2	*
Sensory
Blurred Vision	6.2	6.2	0.4
Musculoskeletal
Rigidity	4.2	5.3	*
Tremor	4.0	8.8	0.4
Cutaneous
Dermatitis/Allergy	3.8	3.1	0.6
Other
Nasal Congestion	7.3	9.3	*
Weight Gain	2.7	2.7	*
Weight Loss	2.3	3.0	*
*None reported

In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic Disorder

PANIC DISORDER
	Treatment-Emergent
	Symptom Incidence*
	Alprazolam	PLACEBO
*Events reported by 1% or more of alprazolam patients are included.
Number of Patients	1388	1231
% of Patients Reporting:
Central Nervous System
Drowsiness	76.8	42.7
Fatigue and Tiredness	48.6	42.3
Impaired Coordination	40.1	17.9
Irritability	33.1	30.1
Memory Impairment	33.1	22.1
Light-headedness/Dizziness	29.8	36.9
Insomnia	29.4	41.8
Headache	29.2	35.6
Cognitive Disorder	28.8	20.5
Dysarthria	23.3	6.3
Anxiety	16.6	24.9
Abnormal Involuntary Movement	14.8	21.0
Decreased Libido	14.4	8.0
Depression	13.8	14.0
Confusional State	10.4	8.2
Muscular Twitching	7.9	11.8
Increased Libido	7.7	4.1
Change in Libido (Not Specified)	7.1	5.6
Weakness	7.1	8.4
Muscle Tone Disorders	6.3	7.5
Syncope	3.8	4.8
Akathisia	3.0	4.3
Agitation	2.9	2.6
Disinhibition	2.7	1.5
Paresthesia	2.4	3.2
Talkativeness	2.2	1.0
Vasomotor Disturbances	2.0	2.6
Derealization	1.9	1.2
Dream Abnormalities	1.8	1.5
Fear	1.4	1.0
Feeling Warm	1.3	0.5
Gastrointestinal
Decreased Salivation	32.8	34.2
Constipation	26.2	15.4
Nausea/Vomiting	22.0	31.8
Diarrhea	20.6	22.8
Abdominal Distress	18.3	21.5
Increased Salivation	5.6	4.4
Cardio-Respiratory
Nasal Congestion	17.4	16.5
Tachycardia	15.4	26.8
Chest Pain	10.6	18.1
Hyperventilation	9.7	14.5
Upper Respiratory Infection	4.3	3.7
Sensory
Blurred Vision	21.0	21.4
Tinnitus	6.6	10.4
Musculoskeletal
Muscular Cramps	2.4	2.4
Muscle Stiffness	2.2	3.3
Cutaneous
Sweating	15.1	23.5
Rash	10.8	8.1
Other
Increased Appetite	32.7	22.8
Decreased Appetite	27.8	24.1
Weight Gain	27.2	17.9
Weight Loss	22.6	16.5
Micturition Difficulties	12.2	8.6
Menstrual Disorders	10.4	8.7
Sexual Dysfunction	7.4	3.7
Edema	4.9	5.6
Incontinence	1.5	0.6
Infection	1.3	1.7

In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients (see PRECAUTIONS, General).

Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as follows:

DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE

Percentage of 641 Alprazolam-Treated Panic Disorder
Patients Reporting Events
Body System/Event
Neurologic			Gastrointestinal
Insomnia	29.5		Nausea/Vomiting	16.5
Light-headedness	19.3		Diarrhea	13.6
Abnormal involuntary movement	17.3		Decreased salivation	10.6
Headache	17.0		Metabolic-Nutritional
Muscular twitching	6.9		Weight loss	13.3
Impaired coordination	6.6		Decreased appetite	12.8
Muscle tone disorders	5.9
Weakness	5.8		Dermatological
Psychiatric			Sweating	14.4
Anxiety	19.2
Fatigue and Tiredness	18.4		Cardiovascular
Irritability	10.5		Tachycardia	12.2
Cognitive disorder	10.3
Memory impairment	5.5		Special Senses
Depression	5.1		Blurred vision	10.0
Confusional state	5.0

From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets (see WARNINGS).

To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days (see DOSAGE AND ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

Post Introduction Reports: Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Drug Abuse And Dependence  ⮝

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (e.g., 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS).

Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

Controlled Substance Class

Alprazolam is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and alprazolam tablets have been assigned to Schedule IV.

Overdosage  ⮝

Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

The acute oral LD50 in rats is 331 mg/kg to 2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

General Treatment of Overdose

Overdosage reports with alprazolam tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

Dosage And Administration  ⮝

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

Anxiety Disorders and Transient Symptoms of Anxiety

Treatment for patients with anxiety should be initiated with a dose of 0.25 mg to 0.5 mg given three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

Panic Disorder

The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration

Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).

The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.

How Supplied  ⮝

Alprazolam tablets, USP are supplied as follows:

0.25 mg Each white, round tablet imprinted with on one side and 027 and bisect on the other contains 0.25 mg of alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2027-10), 500 (NDC 0228-2027-50), and 1000 (NDC 0228-2027-96).

0.5 mg Each peach, round tablet imprinted with on one side and 029 and bisect on the other contains 0.5 mg of alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2029-10), 500 (NDC 0228-2029-50), and 1000 (NDC 0228-2029-96).

1 mg Each blue, round tablet imprinted with on one side and 031 and bisect on the other contains 1 mg of alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2031-10), 500 (NDC 0228-2031-50), and 1000 (NDC 0228-2031-96).

2 mg Each yellow, rectangle shaped, flat faced, beveled edge tablet imprinted with and 039 on one side and multi-scored on both sides contains 2 mg of alprazolam, USP. Tablets are supplied in bottles of 100 (NDC 0228-2039-10).

Dispense in tight, light-resistant containers as defined in the USP.

Keep container tightly closed.

Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP].

ANIMAL STUDIES

When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

40-9170

Revised July 2017

Principal Display Panel - 1 Mg ⮝

NDC 67544-007 - Alprazolam 1 mg Tablets - Rx Only

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67544-006(NDC:0378-4003) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color ORANGE (peach) Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67544-006-15 15 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 07/28/2017 2 NDC:67544-006-20 20 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 08/03/2017 3 NDC:67544-006-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/05/2016 4 NDC:67544-006-45 45 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 08/04/2017 5 NDC:67544-006-53 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/05/2016 6 NDC:67544-006-60 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/05/2016 7 NDC:67544-006-70 120 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/05/2016 8 NDC:67544-006-75 150 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 07/29/2017 9 NDC:67544-006-80 180 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 07/29/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074215 07/23/2012

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67544-007(NDC:0378-4005) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 1 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FD&C BLUE NO. 2 (UNII: L06K8R7DQK)

Product Characteristics Color BLUE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A1 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67544-007-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/04/2008 2 NDC:67544-007-53 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 06/09/2011 3 NDC:67544-007-60 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 06/09/2011 4 NDC:67544-007-70 120 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 04/05/2016 5 NDC:67544-007-80 180 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 08/22/2011 6 NDC:67544-007-90 240 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 06/28/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074215 01/28/1994

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(67544-006, 67544-007)

Revised: 3/2019 Document Id: 8e0b1f7c-43cc-4e9f-9b18-6d972e94a97b 34391-3 Set id: 07d11887-4198-4be5-b565-76bfd394ad50 Version: 1 Effective Time: 20190321 Aphena Pharma Solutions - Tennessee, LLC

Alprazolam ⮝

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1864(NDC:0781-1061) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM .25 mg

Inactive Ingredients Ingredient Name Strength MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE (WHITE) Score 2 pieces Shape OVAL (OVAL) Size 9mm Flavor Imprint Code GG256 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1864-2 14 in 1 BOTTLE; Type 0: Not a Combination Product 06/08/2015 08/31/2017 2 NDC:50090-1864-0 30 in 1 BOTTLE; Type 0: Not a Combination Product 06/08/2015 06/10/2015

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074112 12/29/1995 08/31/2017

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-2819(NDC:0781-1089) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 2 mg

Inactive Ingredients Ingredient Name Strength MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE (WHITE) Score 4 pieces Shape RECTANGLE (RECTANBLE) Size 15mm Flavor Imprint Code GG249 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-2819-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 01/26/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074909 03/25/1998

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-2896(NDC:0781-1079) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 1 mg

Inactive Ingredients Ingredient Name Strength MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) DOCUSATE SODIUM (UNII: F05Q2T2JA0) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color BLUE (BLUE) Score 2 pieces Shape OVAL (OVAL) Size 9mm Flavor Imprint Code GG258 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-2896-1 30 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074112 12/29/1995

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-1864, 50090-2896, 50090-2819) , REPACK(50090-1864, 50090-2896, 50090-2819)

Revised: 12/2017 Document Id: 98965561-6d0b-42fc-a2b9-cf2a03d1b752 34391-3 Set id: 3c0cb60f-1c3a-48a6-ad16-f14351548412 Version: 9 Effective Time: 20171207 A-S Medication Solutions

No Title 1572451055 ⮝

C-IV

Revised July 2017

Rx Only

Principal Display Panel - 0.25 Mg ⮝

NDC 71610-112 - Alprazolam 0.25 mg - Rx Only

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71610-112(NDC:0228-2027) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU)

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code R;027 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71610-112-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 08/06/2018 2 NDC:71610-112-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 08/06/2018 3 NDC:71610-112-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 08/06/2018 4 NDC:71610-112-70 120 in 1 BOTTLE; Type 0: Not a Combination Product 08/06/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074342 10/01/1993

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(71610-112)

Revised: 8/2018 Document Id: ac82c8dd-1fbb-4ec1-a126-8eced3452972 34391-3 Set id: 2717699a-c8b6-4590-937a-cb86eadc5296 Version: 1 Effective Time: 20180823 Aphena Pharma Solutions - Tennessee, LLC

Package/label Principal Display Panel ⮝

NDC 33261-0500-60

ALPRAZOLAM TABLETS, USP C-IV

2 mg

60 tablets

Rx only

Each tablet contains:

Alprazolam, USP 2 mg

Usual Dosage:

See attached product literature. This is a bulk

package, not intended for household use.

Store at 20 to 25 C (68 to 77 F) [See

USP Controlled Room

Temperature].
Keep container tightly closed.

Dispense in a tight, light-resistant

container with a child-resistant closure.

Manufactured for:

DAVA Pharmaceuticals, Inc.

Fort Lee, NJ 07024, USA

By:

ULTRAtab Laboratories, Inc.

Highland, NY 12528, USA

Repackaged By :
Aidarex Pharmaceuticals LLC,
Corona, CA 92880

Rev. 9/10

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-594(NDC:67253-900) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code S900 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-594-00 100 in 1 BOTTLE, PLASTIC 2 NDC:33261-594-02 120 in 1 BOTTLE, PLASTIC 3 NDC:33261-594-10 10 in 1 BOTTLE, PLASTIC 4 NDC:33261-594-15 15 in 1 BOTTLE, PLASTIC 5 NDC:33261-594-30 30 in 1 BOTTLE, PLASTIC 6 NDC:33261-594-42 42 in 1 BOTTLE, PLASTIC 7 NDC:33261-594-45 45 in 1 BOTTLE, PLASTIC 8 NDC:33261-594-60 60 in 1 BOTTLE, PLASTIC 9 NDC:33261-594-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074174 03/28/2007

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-004(NDC:67253-901) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color YELLOW Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code S901 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-004-00 100 in 1 BOTTLE, PLASTIC 2 NDC:33261-004-02 120 in 1 BOTTLE, PLASTIC 3 NDC:33261-004-10 10 in 1 BOTTLE, PLASTIC 4 NDC:33261-004-15 15 in 1 BOTTLE, PLASTIC 5 NDC:33261-004-30 30 in 1 BOTTLE, PLASTIC 6 NDC:33261-004-42 42 in 1 BOTTLE, PLASTIC 7 NDC:33261-004-45 45 in 1 BOTTLE, PLASTIC 8 NDC:33261-004-60 60 in 1 BOTTLE, PLASTIC 9 NDC:33261-004-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074174 03/28/2007

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-005(NDC:67253-902) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 1 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color GREEN Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code S902 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-005-00 100 in 1 BOTTLE, PLASTIC 2 NDC:33261-005-02 120 in 1 BOTTLE, PLASTIC 3 NDC:33261-005-10 10 in 1 BOTTLE, PLASTIC 4 NDC:33261-005-15 15 in 1 BOTTLE, PLASTIC 5 NDC:33261-005-30 30 in 1 BOTTLE, PLASTIC 6 NDC:33261-005-42 42 in 1 BOTTLE, PLASTIC 7 NDC:33261-005-45 45 in 1 BOTTLE, PLASTIC 8 NDC:33261-005-60 60 in 1 BOTTLE, PLASTIC 9 NDC:33261-005-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074174 03/28/2007

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-500(NDC:67253-903) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 2 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE (UNII: J2B2A4N98G) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) SODIUM BENZOATE (UNII: OJ245FE5EU) STARCH, CORN (UNII: O8232NY3SJ) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color GREEN Score 3 pieces Shape RECTANGLE Size 15mm Flavor Imprint Code S903 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-500-00 100 in 1 BOTTLE, PLASTIC 2 NDC:33261-500-02 120 in 1 BOTTLE, PLASTIC 3 NDC:33261-500-10 10 in 1 BOTTLE, PLASTIC 4 NDC:33261-500-15 15 in 1 BOTTLE, PLASTIC 5 NDC:33261-500-30 30 in 1 BOTTLE, PLASTIC 6 NDC:33261-500-42 42 in 1 BOTTLE, PLASTIC 7 NDC:33261-500-45 45 in 1 BOTTLE, PLASTIC 8 NDC:33261-500-60 60 in 1 BOTTLE, PLASTIC 9 NDC:33261-500-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074174 03/28/2007

Labeler - Aidarex Pharmaceuticals LLC (801503249)

Revised: 11/2013 Document Id: 93729350-108f-4474-811d-9e4ca0294eac 34391-3 Set id: fd3d0e37-470d-4216-8070-24a206930eac Version: 1 Effective Time: 20131115 Aidarex Pharmaceuticals LLC

No Title 1572453060 ⮝

C-IV

Revised July 2017

Rx Only

Package Label.principal Display Panel  ⮝

NDC 0228-2027-10

Alprazolam Tablets, USP CIV

0.25 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Actavis

100 Tablets

Rx Only

Package Label.principal Display Panel ⮝

NDC 0228-2039-10

Alprazolam Tablets, USP CIV

2 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Actavis

100 Tablets

Rx Only

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0228-2027 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU)

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code R;027 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0228-2027-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 2 NDC:0228-2027-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 3 NDC:0228-2027-96 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074342 10/01/1993

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0228-2029 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color ORANGE (PEACH) Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code R;029 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0228-2029-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 2 NDC:0228-2029-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 3 NDC:0228-2029-96 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074342 10/01/1993

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0228-2031 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 1 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU) FD&C BLUE NO. 2 (UNII: L06K8R7DQK)

Product Characteristics Color BLUE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code R;031 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0228-2031-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 2 NDC:0228-2031-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 3 NDC:0228-2031-96 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074342 10/01/1993

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0228-2039 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 2 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM BENZOATE (UNII: OJ245FE5EU) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color YELLOW Score 4 pieces Shape RECTANGLE Size 15mm Flavor Imprint Code R;039 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0228-2039-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 2 NDC:0228-2039-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/01/1993 09/30/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA074342 10/01/1993

Labeler - Actavis Pharma, Inc. (119723554)

Revised: 7/2017 Document Id: 5487583a-cef2-4680-af3b-0ce46e050ac8 34391-3 Set id: a23063c0-099a-4256-b95f-3a857bbf704b Version: 10 Effective Time: 20170701 Actavis Pharma, Inc.

No Title 1572453287 ⮝

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, Drug Interactions).

• Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

No Title 1572453288 ⮝

Distributed by:
Par Pharmaceutical
Chestnut Ridge, NY 10977

300 172 990 138
Revised: 01/17

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Breckenridge Pharmaceutical, Inc. as follows:
(0.25 mg / 100 UD) NDC 60687-510-01 packaged from NDC 51991-704
(0.5 mg / 100 UD) NDC 60687-521-01 packaged from NDC 51991-705

Distributed by:
American Health Packaging
Columbus, OH 43217

8451001/0819

Package/label Display Panel Carton 0.25 Mg ⮝

NDC 60687- 510-01

Alprazolam
Tablets, USP CIV

0.25 mg

100 Tablets (10 x 10) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each Tablet Contains:
Alprazolam USP..................................................... 0.25 mg

Usual Dosage: See package insert for full prescribing
information.

Store at 20 to 25 C (68 to 77 F); excursions
permitted between 15 to 30 C (59 to 86 F) [see USP
Controlled Room Temperature]. Protect from light.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is
torn or broken.

The drug product contained in this package is from
NDC # 51991-704, Breckenridge Pharmaceutical, Inc.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

751001
0451001/0819

Package/label Display Panel Blister 0.25 Mg ⮝

Alprazolam

Tablet, USP CIV

0.25 mg

Package/label Display Panel Carton 0.5 Mg ⮝

NDC 60687- 521-01

Alprazolam
Tablets, USP CIV

0.5 mg

100 Tablets (10 x 10) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each Tablet Contains:
Alprazolam USP....................................................... 0.5 mg

Usual Dosage: See package insert for full prescribing
information.

Store at 20 to 25 C (68 to 77 F); excursions
permitted between 15 to 30 C (59 to 86 F) [see USP
Controlled Room Temperature]. Protect from light.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is
torn or broken.

The drug product contained in this package is from
NDC # 51991-705, Breckenridge Pharmaceutical, Inc.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

752101
0452101/0819

Package/label Display Panel Blister 0.5 Mg ⮝

Alprazolam
Tablet, USP CIV

0.5 mg

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-377(NDC:65862-676) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.25 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) SODIUM BENZOATE (UNII: OJ245FE5EU) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)

Product Characteristics Color white Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code 1;8;Y Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-377-01 100 in 1 BOX, UNIT-DOSE 05/01/2019 1 NDC:60687-377-11 1 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 ANDA203346 05/01/2019

ALPRAZOLAM alprazolam tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-388(NDC:65862-677) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM 0.5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) STARCH, CORN (UNII: O8232NY3SJ) DOCUSATE SODIUM (UNII: F05Q2T2JA0) SODIUM BENZOATE (UNII: OJ245FE5EU) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color orange (Peach) Score 2 pieces Shape OVAL Size 9mm Flavor Imprint Code 1;9;Y Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-388-01 100 in 1 BOX, UNIT-DOSE 05/01/2019 1 NDC:60687-388-11 1 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 ANDA203346 05/01/2019

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(60687-377, 60687-388)

Revised: 5/2019 Document Id: 884df604-712d-4a3d-e053-2995a90a3a04 34391-3 Set id: ea95d182-453b-4c43-8402-d65c488d55f2 Version: 2 Effective Time: 20190507 American Health Packaging

Principal Display Panel - 0.5 Mg ⮝

NDC 67544-006 - Alprazolam 0.5 mg Tablets - Rx Only

Warning: Risks From Concomitant Use With Opioids  ⮝

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS: Drug Interactions).

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Description ⮝

Alprazolam tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3- ] [1,4] benzodiazepine.

The structural formula is represented below:

Alprazolam, USP is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

Each alprazolam tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg or 2 mg of alprazolam, USP.

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium benzoate and sodium lauryl sulfate. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 Aluminum Lake and the 1 mg tablet contains FD&C Blue No. 2 Aluminum Lake.

Clinical Pharmacology ⮝

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetics

Absorption

Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 mg to 3.0 mg, peak levels of 8.0 ng/mL to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.

Distribution

In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism/Elimination

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and -hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and -hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and -hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and -hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Alprazolam and its metabolites are excreted primarily in the urine.

Special Populations

Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n = 16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n = 16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n = 17) as compared to between 6.3 and 26.9 hours (mean = 11.4 hours, n = 17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean = 21.8 hours, n = 12) as compared to between 6.3 and 15.8 hours (mean = 10.6 hours, n = 12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

Race

Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

Pediatrics

The pharmacokinetics of alprazolam in pediatric patients have not been studied.

Gender

Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking

Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Drug-Drug Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98-fold; itraconazole, 2.70-fold; nefazodone, 1.98-fold; fluvoxamine, 1.96-fold; and erythromycin, 1.61-fold (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions).

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90 0.21 mL/min/kg to 2.13 0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1 4.9 to 7.7 1.7 h) following administration of 300 mg/day carbamazepine for 10 days (see PRECAUTIONS: Drug Interactions). However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 mg/day to 1200 mg/day); the effect at usual carbamazepine doses is unknown.

The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

Clinical Studies ⮝

Anxiety Disorders

Alprazolam tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam tablets were significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.

Panic Disorder

Support for the effectiveness of alprazolam tablets in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.

The average dose of alprazolam tablets was 5 mg/day to 6 mg/day in two of the studies, and the doses of alprazolam tablets were fixed at 2 mg/day and 6 mg/day in the third study. In all three studies, alprazolam tablets were superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37% to 83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam tablets were superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam tablets during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

Indications And Usage ⮝

Anxiety Disorders

Alprazolam tablets are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of 6 months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness, nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or lump in throat ); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or mind going blank because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.

Anxiety associated with depression is responsive to alprazolam tablets.

Panic Disorder

Alprazolam tablets are also indicated for the treatment of panic disorder, with or without agoraphobia.

Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Demonstrations of the effectiveness of alprazolam tablets by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

Contraindications ⮝

Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.

Alprazolam tablets are contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see WARNINGS and PRECAUTIONS: Drug Interactions).

Warnings ⮝

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam tablets, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam tablets are used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS: Drug Interactions).

Dependence and Withdrawal Reactions, Including Seizures

Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam tablets. These include a spectrum of withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 mg to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

The Importance of Dose and the Risks of Alprazolam Tablets as a Treatment for Panic Disorder

Because the management of panic disorder often requires the use of average daily doses of alprazolam tablets above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam tablets compared to placebo-treated patients.

Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.

In a controlled clinical trial in which 63 patients were randomized to alprazolam tablets and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.

In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with alprazolam tablets tapered completely off therapy compared to 89% to 96% of placebo-treated patients. In a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.

Seizures attributable to alprazolam tablets were seen after drug discontinuance or dose reduction in 8 of 1,980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam tablets greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 mg to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam tablets. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule).

Status Epilepticus and its Treatment

The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam tablets. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.

Interdose Symptoms

Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam tablets have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam tablets. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations (see DOSAGE AND ADMINISTRATION).

Risk of Dose Reduction

Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam tablets should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).

CNS Depression and Impaired Performance

Because of its CNS depressant effects, patients receiving alprazolam tablets should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam tablets.

Risk of Fetal Harm

Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam tablets are assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.

The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.

Potent CYP3A Inhibitors

Azole Antifungal Agents

Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98-fold and 2.70-fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS).

Drugs Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Alprazolam (Caution and Consideration of Appropriate Alprazolam Dose Reduction are Recommended During Coadministration with the Following Drugs)

Nefazodone

Coadministration of nefazodone increased alprazolam concentration two-fold.

Fluvoxamine

Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.

Cimetidine

Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.

Other Drugs Possibly Affecting Alprazolam Metabolism

Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see PRECAUTIONS: Drug Interactions).

Precautions ⮝

General

Suicide

As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.

Mania

Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression.

Uricosuric Effect

Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam tablets.

Use in Patients with Concomitant Illness

It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam tablets. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam tablets (see CLINICAL PHARMACOLOGY).

Information for Patients

For All Users of Alprazolam Tablets

To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam tablets should be provided with the following guidance.

1.

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam tablets are used with opioids and not to use such drugs concomitantly unless supervised by a health care provider.

2.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see Drug Interactions).

3.

Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.

4.

Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.

5.

Inform your physician if you are nursing.

6.

Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.

7.

Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.

8.

Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.

Additional Advice for Panic Disorder Patients

The use of alprazolam tablets at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, alprazolam tablets have the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7% to 29% of patients treated with alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of alprazolam tablets.

In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam tablets are discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.

Drug Interactions

Use with Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Use with Other CNS Depressants

If alprazolam tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with Imipramine and Desipramine

The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs that Inhibit Alprazolam Metabolism via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).

Drugs Demonstrated to be CYP3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam (Caution is Recommended During Coadministration with Alprazolam)

Fluoxetine

Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.

Propoxyphene

Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.

Oral Contraceptives

Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.

Drugs and Other Substances Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Benzodiazepines Metabolized Similarly to Alprazolam or on the Basis of In Vitro Studies with Alprazolam or Other Benzodiazepines (Caution is Recommended During Coadministration with Alprazolam)

Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg/day to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS).

Drugs Demonstrated to be Inducers of CYP3A

Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.

Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).

Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

Pregnancy

Teratogenic Effects

Pregnancy Category D

(see WARNINGS section).

Nonteratogenic Effects

It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Labor and Delivery

Alprazolam tablets have no established use in labor or delivery.

Nursing Mothers

Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam tablets.

Pediatric Use

Safety and effectiveness of alprazolam tablets in individuals below the age of 18 years have not been established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam tablets should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Adverse Reactions ⮝

Side effects to alprazolam tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, e.g., drowsiness or light-headedness.

The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., 4 weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam tablets (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to 10 weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam tablets in patients with panic disorder, with or without agoraphobia.

These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward event] in others.)

Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety Disorders

* Events reported by 1% or more of alprazolam tablets patients are included. None reported
	ANXIETY DISORDERS
	Treatment-Emergent Symptom Incidence*		Incidence of Intervention Because of Symptom
	Alprazolam Tablets	Placebo	Alprazolam Tablets
Number of Patients	565	505	565
% of Patients Reporting:
Central Nervous System
Drowsiness	41.0	21.6	15.1
Light-headedness	20.8	19.3	1.2
Depression	13.9	18.1	2.4
Headache	12.9	19.6	1.1
Confusion	9.9	10.0	0.9
Insomnia	8.9	18.4	1.3
Nervousness	4.1	10.3	1.1
Syncope	3.1	4.0
Dizziness	1.8	0.8	2.5
Akathisia	1.6	1.2
Tiredness/Sleepiness			1.8
Gastrointestinal
Dry Mouth	14.7	13.3	0.7
Constipation	10.4	11.4	0.9
Diarrhea	10.1	10.3	1.2
Nausea/Vomiting	9.6	12.8	1.7
Increased Salivation	4.2	2.4
Cardiovascular
Tachycardia/Palpitations	7.7	15.6	0.4
Hypotension	4.7	2.2
Sensory
Blurred Vision	6.2	6.2	0.4
Musculoskeletal
Rigidity	4.2	5.3
Tremor	4.0	8.8	0.4
Cutaneous
Dermatitis/Allergy	3.8	3.1	0.6
Other
Nasal Congestion	7.3	9.3
Weight Gain	2.7	2.7
Weight Loss	2.3	3.0

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic Disorder

* Events reported by 1% or more of alprazolam tablets patients are included.
PANIC DISORDER
	Treatment-Emergent Symptom Incidence*
	Alprazolam Tablets	Placebo
Number of Patients	1,388	1,231
% of Patients Reporting:
Central Nervous System
Drowsiness	76.8	42.7
Fatigue and Tiredness	48.6	42.3
Impaired Coordination	40.1	17.9
Irritability	33.1	30.1
Memory Impairment	33.1	22.1
Light-headedness/Dizziness	29.8	36.9
Insomnia	29.4	41.8
Headache	29.2	35.6
Cognitive Disorder	28.8	20.5
Dysarthria	23.3	6.3
Anxiety	16.6	24.9
Abnormal Involuntary Movement	14.8	21.0
Decreased Libido	14.4	8.0
Depression	13.8	14.0
Confusional State	10.4	8.2
Muscular Twitching	7.9	11.8
Increased Libido	7.7	4.1
Change in Libido (Not Specified)	7.1	5.6
Weakness	7.1	8.4
Muscle Tone Disorders	6.3	7.5
Syncope	3.8	4.8
Akathisia	3.0	4.3
Agitation	2.9	2.6
Disinhibition	2.7	1.5
Paresthesia	2.4	3.2
Talkativeness	2.2	1.0
Vasomotor Disturbances	2.0	2.6
Derealization	1.9	1.2
Dream Abnormalities	1.8	1.5
Fear	1.4	1.0
Feeling Warm	1.3	0.5
Gastrointestinal
Decreased Salivation	32.8	34.2
Constipation	26.2	15.4
Nausea/Vomiting	22.0	31.8
Diarrhea	20.6	22.8
Abdominal Distress	18.3	21.5
Increased Salivation	5.6	4.4
Cardio-Respiratory
Nasal Congestion	17.4	16.5
Tachycardia	15.4	26.8
Chest Pain	10.6	18.1
Hyperventilation	9.7	14.5
Upper Respiratory Infection	4.3	3.7
Sensory
Blurred Vision	21.0	21.4
Tinnitus	6.6	10.4
Musculoskeletal
Muscular Cramps	2.4	2.4
Muscle Stiffness	2.2	3.3
Cutaneous
Sweating	15.1	23.5
Rash	10.8	8.1
Other
Increased Appetite	32.7	22.8
Decreased Appetite	27.8	24.1
Weight Gain	27.2	17.9
Weight Loss	22.6	16.5
Micturition Difficulties	12.2	8.6
Menstrual Disorders	10.4	8.7
Sexual Dysfunction	7.4	3.7
Edema	4.9	5.6
Incontinence	1.5	0.6
Infection	1.3	1.7

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam tablets: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients (see PRECAUTIONS: General).

Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam tablets, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam tablets and at a greater rate than the placebo treated group were as follows:

DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE

Percentage of 641 Alprazolam Tablets-Treated Panic Disorder Patients Reporting Events
Body System/Event
Neurologic		Gastrointestinal
Insomnia	29.5	Nausea/Vomiting	16.5
Light-headedness	19.3	Diarrhea	13.6
Abnormal involuntary movement	17.3	Decreased salivation	10.6
Headache	17.0	Metabolic-Nutritional
Muscular twitching	6.9	Weight loss	13.3
Impaired coordination	6.6	Decreased appetite	12.8
Muscle tone disorders	5.9
Weakness	5.8	Dermatological
Psychiatric		Sweating	14.4
Anxiety	19.2
Fatigue and Tiredness	18.4	Cardiovascular
Irritability	10.5	Tachycardia	12.2
Cognitive disorder	10.3
Memory impairment	5.5	Special Senses
Depression	5.1	Blurred vision	10.0
Confusional state	5.0

From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam tablets in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets (see WARNINGS).

To discontinue treatment in patients taking alprazolam tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam tablets be decreased by no more than 0.5 mg every 3 days (see DOSAGE AND ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

Drug Abuse And Dependence ⮝

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam tablets. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires reinstitution of treatment at doses of alprazolam tablets sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam tablets at doses within the recommended range for the treatment of anxiety (e.g., 0.75 mg/day to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS).

Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam tablets. It is recommended that all patients on alprazolam tablets who require a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Psychological dependence is a risk with all benzodiazepines, including alprazolam tablets. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam tablets, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam tablets. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

Controlled Substance Class

Alprazolam is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and alprazolam tablets have been assigned to Schedule IV.

Overdosage ⮝

Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

The acute oral LD50 in rats is 331 mg/kg to 2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

General Treatment of Overdose

Overdosage reports with alprazolam tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

Dosage And Administration ⮝

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

Anxiety Disorders and Transient Symptoms of Anxiety

Treatment for patients with anxiety should be initiated with a dose of 0.25 mg to 0.5 mg given three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

Panic Disorder

The successful treatment of many panic disorder patients has required the use of alprazolam tablets at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam tablets in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1,700 patients participating in the panic disorder development program, about 300 received alprazolam tablets in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration

Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam tablets. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE.)

The necessary duration of treatment for panic disorder patients responding to alprazolam tablets is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.

How Supplied ⮝

Alprazolam Tablets, USP are available containing 0.25 mg, 0.5 mg, 1 mg or 2 mg of alprazolam, USP.

The 0.25 mg tablets are white, round, scored tablets debossed with MYLAN over A on one side of the tablet and scored on the other side. They are available as follows:

NDC 0378-4001-05
bottles of 500 tablets

The 0.5 mg tablets are peach, round, scored tablets debossed with MYLAN over A3 on one side of the tablet and scored on the other side. They are available as follows:

NDC 0378-4003-05
bottles of 500 tablets

The 1 mg tablets are blue, round, scored tablets debossed with MYLAN over A1 on one side of the tablet and scored on the other side. They are available as follows:

NDC 0378-4005-05
bottles of 500 tablets

The 2 mg tablets are white, round, scored tablets debossed with MYLAN over A4 on one side of the tablet and quadrisect scored on the other side. They are available as follows:

NDC 0378-4007-01
bottles of 100 tablets

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 as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

Animal Studies ⮝

When rats were treated with alprazolam at 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

Repackaging Information ⮝

Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

Count	0.5 mg	1 mg
15	67544-006-15	-
20	67544-006-20	-
30	67544-006-30	67544-007-30
45	67544-006-45	-
60	67544-006-53	67544-006-53
90	67544-006-60	67544-007-60
120	67544-006-70	67544-007-70
150	67544-006-75	-
180	67544-006-80	67544-007-80
240	-	67544-007-90

Store between 20 -25 C (68 -77 F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20190321JH

Principal Display Panel - 0.25mg ⮝

NDC 67544-414 - Alprazolam 0.25mg - Rx Only