DRONABINOL capsule
For Healthcare Providers >

1. Can Cause Serious Side Effects, Including:
2. A Prescription Medicine Used In Adults To Treat:
3. Tell Your Doctor About All Of Your Medical Conditions, Including If You:
4. May Cause Serious Side Effects, Including:
5. The Most Common Side Effects Of Dronabinol Capsules Include:
6. Active Ingredient:
7. Ingredients:
8. Manufactured For:
9. Manufactured By:
10. Patient Information
11. How Should I Take Dronabinol Capsules?
12. What Are The Possible Side Effects Of Dronabinol Capsules? Dronabinol Capsules May Cause Serious Side Effects, Including:
13. [dronabinol Capsules Are A Prescription Medicine Used In Adults To Treat:
14. Do Not Take Dronabinol Capsules If You:
15. Before Taking Dronabinol Capsules, Tell Your Doctor About All Of Your Medical Conditions, Including If You:
16. How Should I Take Dronabinol Capsules?
17. Dronabinol Capsules May Cause Serious Side Effects, Including:
18. How Should I Store Dronabinol Capsules?
19. Distributed By:
20. Revised: 12/2018document Id:
21. Dronabinol Capsules Can Cause Serious Side Effects, Including:
22. Dronabinol Capsules Are A Prescription Medicine Used In Adults To Treat:
23. What Are The Ingredients In Dronabinol Capsules?
24. Inactive Ingredients:
25. Principal Display Panel Text For Container Label:
26. Principal Display Panel Text For Carton Label:
27. Revised: 11/2017document Id:

Can Cause Serious Side Effects, Including: ⮝

• Worseningmental(psychiatric)symptoms.Psychiatric symptoms can worsen in people who have mania, depression, or schizophrenia and who take dronabinol capsules. Dronabinol capsules taken with medicines that cause psychiatric symptoms can worsen psychiatric symptoms. Elderly people who take dronabinol capsules may have a greater risk of having psychiatric symptoms. Tell your doctor if you have new or worsening mood symptoms, including symptoms of mania, depression, or schizophrenia.

• Problemsthinkingclearly.Tell your doctor if you have trouble remembering things, concentrating, have increased sleepiness, or confusion. Elderly people may have a greater risk of having problems thinking clearly.

• Changes in your blood pressure.Dronabinol capsules may increase or decrease your blood pressure, especially when you start taking dronabinol capsules or when your dose is changed. Tell your doctor if you have signs or symptoms of changes in your blood pressure including: headaches, vision problems, dizziness, feeling lightheaded, fainting, or a fast heartbeat. Elderly people, especially those with dementia, and people with heart problems may have an increased risk of changes in blood pressure and an increased risk of falls.

What aredronabinol capsules?

• Dronabinol capsulesare

A Prescription Medicine Used In Adults To Treat: ⮝

• loss of appetite (anorexia) in people with AIDS (Acquired Immune Deficiency Syndrome) who have lost weight.

• nausea and vomiting caused by anti-cancer medicine (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines.

Dronabinol capsules are a controlled substance (CIII) because it contains dronabinol, which can be a target for people who abuse prescription medicines or street drugs. Keep your dronabinol capsules in a safe place to protect it from theft. Never give your dronabinol capsules to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.

It is not known if dronabinol capsules are safe and effective in children.Do not take dronabinol capsulesifyou:

• had an allergic reaction to dronabinol. Signs and symptoms of an allergic reaction to dronabinol include: swelling of the lips, hives, a rash over your whole body, mouth sores, skin burning, flushing, and throat tightness.

• had an allergic reaction to sesame oil.

Beforetakingdronabinol capsules,

Tell Your Doctor About All Of Your Medical Conditions, Including If You: ⮝

• have or had heart problems.

• have or had problems with drug abuse or dependence.

• have or had problems with alcohol abuse or dependence.

• have or had mental health problems including mania, depression, or schizophrenia.

• have had a seizure or have a medical condition that may increase your risk of having a seizure.

• are pregnant or plan to become pregnant. Dronabinol capsules may harm your unborn baby. Avoid the use of dronabinol capsules if you are pregnant.

• are breastfeeding or plan to breastfeed. The Centers for Disease Control and Prevention recommends that mothers with HIV not breastfeed because they can pass the HIV through their breast milk to the baby. It is not known if dronabinol capsules pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take dronabinol capsules. Do not breastfeed while taking dronabinol capsules and for 9 days after your last dose of dronabinol capsules if you are being treated for nausea and vomiting caused by anti-cancer medicine.

Tell your doctor about all the medicines you take or have taken in the last 14 days,including prescription and over the-counter medicines, vitamins, and herbal supplements. Dronabinol capsules and certain other medicines can affect each other, causing serious side effects.

How should I takedronabinol capsules?

• Take dronabinol capsules exactly as your doctor tells you to. Your doctor may change your dose after
  • Do not drive, operate machinery, or do other dangerous activities until you know how dronabinol capsules affect you. Dronabinol capsules taken with other medicines that cause dizziness, confusion, and sleepiness may make these symptoms worse.

  What are the possible side effects ofdronabinol capsules?Dronabinol capsules

May Cause Serious Side Effects, Including: ⮝

• Seizures.Dronabinol capsules may increase your risk of seizures. Stop taking dronabinol capsules and call your doctor and get medical care right away if you have a seizure during treatment with dronabinol capsules.

• Drugandalcohol abuse.You may have an increased risk of abusing dronabinol capsules if you have a history of drug or alcohol abuse or dependence, including marijuana. Tell your doctor if you develop abuse behaviors such as increased irritability, nervousness, restlessness or want more or higher doses of dronabinol capsules during your treatment.

• Nausea,vomiting, or stomach-area (abdominal) pain.Tell your doctor if you have nausea, vomiting, or abdominal pain or if your nausea, vomiting, or abdominal pain gets worse during treatment with dronabinol capsules.

The Most Common Side Effects Of Dronabinol Capsules Include: ⮝

• dizziness
• feeling extremely happy (euphoria)
• overly suspicious or feeling people want to harm you (paranoid reaction)
• sleepiness
• abnormal thoughts
• stomach-area (abdominal) pain
• nausea
• vomiting

These are not all the possible side effects of dronabinol capsules. Tell your doctor if you have any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088.

How should I storedronabinol capsules?

• Store dronabinol capsules in a cool place such as in a refrigerator, at a temperature between 36 F to 46 F (2 C to 8 C).

• Do notfreeze dronabinol capsules.

• Keep the dronabinol capsules container closed tightly.

Keep dronabinol capsules and all medicines out of the reach of children.

Generalinformationabout the safe and effective use ofdronabinol capsules

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use dronabinol capsules for a condition for which it was not prescribed. Do not give dronabinol capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about dronabinol capsules that is written for health professionals.

What are the ingredients indronabinol capsules?

Active Ingredient: ⮝

dronabinol

Inactive

Ingredients: ⮝

Capsules for oral administration are supplied as oval, soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each capsule strength is formulated with the following inactive ingredients: 2.5 mg capsules contain gelatin, glycerin, sesame oil, titanium dioxide, and FD&C Red No. 40; 5 mg capsules contain gelatin, glycerin, sesame oil, titanium dioxide, FD&C Yellow No. 6, FD&C Red No. 40 and FD&C Blue No. 1; and 10 mg capsules contain gelatin, glycerin, sesame oil, titanium dioxide and FD&C Yellow No. 6.

Manufactured For: ⮝

Lannett Company, Inc.

Philadelphia, PA 19154

Manufactured By: ⮝

SWISS CAPS AG

Husenstrasse 35

9533 Kirchberg

Switzerland

For more information call 1-844-834-0530.

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

CIB71920A

Rev. 04/2018

Patient Information ⮝

* Ingredients in imprint ink

8437501/0618 DRONABINOL (droe nab' i nol) CAPSULES, USP

for oral use, CIII

How Should I Take Dronabinol Capsules? ⮝

• Take dronabinol capsules exactly as your doctor tells you to. Your doctor may change your dose after
  • Do not drive, operate machinery, or do other dangerous activities until you know how dronabinol capsules affects you. Dronabinol capsules taken with other medicines that cause dizziness, confusion, and sleepiness may make these symptoms worse.

What Are The Possible Side Effects Of Dronabinol Capsules? Dronabinol Capsules May Cause Serious Side Effects, Including: ⮝

• "
• Seizures.Dronabinol capsules may increase your risk of seizures. Stop taking dronabinol capsules and call your doctor and get medical care right away if you have a seizure during treatment with dronabinol capsules.
• Drug and alcohol abuse.You may have an increased risk of abusing dronabinol capsules if you have a history of drug or alcohol abuse or dependence, including marijuana. Tell your doctor if you develop abuse behaviors such as increased irritability, nervousness, restlessness or want more or higher doses of dronabinol capsules during your treatment.
• Nausea, vomiting, or stomach-area (abdominal) pain.Tell your doctor if you have nausea, vomiting, or abdominal pain or if your nausea, vomiting, or abdominal pain gets worse during treatment with dronabinol capsules.

[dronabinol Capsules Are A Prescription Medicine Used In Adults To Treat: ⮝

• loss of appetite (anorexia) in people with AIDS (Acquired Immune Deficiency Syndrome) who have lost weight.
• nausea and vomiting caused by anti-cancer medicine (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines.

Dronabinol capsules is a controlled substance (CIII) because it contains dronabinol, which can be a target for people who abuse prescription medicines or street drugs. Keep your dronabinol capsules in a safe place to protect it from theft. Never give your dronabinol capsules to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.
It is not known if dronabinol capsules are safe and effective in children.

Do Not Take Dronabinol Capsules If You: ⮝

• had an allergic reaction to dronabinol. Signs and symptoms of an allergic reaction to dronabinol include: swelling of the lips, hives, a rash over your whole body, mouth sores, skin burning, flushing, and throat tightness.
• had an allergic reaction to sesame oil.

Before Taking Dronabinol Capsules, Tell Your Doctor About All Of Your Medical Conditions, Including If You: ⮝

• have or had heart problems.
• have or had problems with drug abuse or dependence.
• have or had problems with alcohol abuse or dependence.
• have or had mental health problems including mania, depression, or schizophrenia.
• have had a seizure or have a medical condition that may increase your risk of having a seizure.
• are pregnant or plan to become pregnant. Dronabinol capsules may harm your unborn baby. Avoid the use of dronabinol capsules if you are pregnant.
• are breastfeeding or plan to breastfeed. The Centers for Disease Control and Prevention recommends that mothers with HIV not breastfeed because they can pass the HIV through their breast milk to the baby. It is not known if dronabinol capsules passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take dronabinol capsules. Do not breastfeed while taking dronabinol capsules and for 9 days after your last dose of dronabinol capsules if you are being treated for nausea and vomiting caused by anti-cancer medicine.

Tell your doctor about all the medicines you take or have taken in the last 14 days,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Dronabinol capsules and certain other medicines can affect each other, causing serious side effects.

How Should I Take Dronabinol Capsules? ⮝

• Take dronabinol capsules exactly as your doctor tells you to. Your doctor may change your dose after
  • Do not drive, operate machinery, or do other dangerous activities until you know how dronabinol capsules affects you. Dronabinol capsules taken with other medicines that cause dizziness, confusion, and sleepiness may make these symptoms worse.

Dronabinol Capsules May Cause Serious Side Effects, Including: ⮝

• Seizures.Dronabinol capsules may increase your risk of seizures. Stop taking dronabinol capsules and call your doctor and get medical care right away if you have a seizure during treatment with dronabinol capsules.
• Drug and alcohol abuse.You may have an increased risk of abusing dronabinol capsules if you have a history of drug or alcohol abuse or dependence, including marijuana. Tell your doctor if you develop abuse behaviors such as increased irritability, nervousness, restlessness or want more or higher doses of dronabinol capsules during your treatment.
• Nausea, vomiting, or stomach-area (abdominal) pain.Tell your doctor if you have nausea, vomiting, or abdominal pain or if your nausea, vomiting, or abdominal pain gets worse during treatment with dronabinol capsules.

The most common side effects of dronabinol capsules include:

• dizziness
• feeling extremely happy (euphoria)
• overly suspicious or feeling people
  want to harm you (paranoid reaction)
• sleepiness

• abnormal thoughts
• stomach-area (abdominal) pain
• nausea
• vomiting

These are not all the possible side effects of dronabinol capsules. Tell your doctor if you have any side effect that bothers you or does not go away. 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 Dronabinol Capsules? ⮝

• Store dronabinol capsules in a cool place such as in a refrigerator, at a temperature between 46 F to 59 F (8 C to 15 C).
• Do notfreeze dronabinol capsules.
• Keep the dronabinol capsules container closed tightly.

Keep dronabinol capsules and all medicines out of the reach of children.General information about the safe and effective use of dronabinol capsules
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use dronabinol capsules for a condition for which it was not prescribed. Do not give dronabinol capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about dronabinol capsules that is written for health professionals.

Distributed By: ⮝

Ascend Laboratories, LLC, Parsippany, NJ 07054
For more information, call 1-877-ASC-RX01 (1-877-272-7901).

This Patient Information has been approved by the U.S. Food and Revised: December, 2017
Drug Administration.

1248C99 08/17

NDC 67877-568-60

ASCEND Laboratories, LLC

CIII

Dronabinol Capsules, USP

2.5 mg

PRESCRIPTION PREPACK

UNIT-OF-USE

Rx Only

60 Capsules

NDC 67877-569-60

ASCEND Laboratories, LLC

CIII

Dronabinol Capsules, USP

5 mg

Rx Only

60 Capsules

NDC 67877-570-60

ASCEND Laboratories, LLC

CIII

Dronabinol Capsules, USP

10 mg

Rx Only

60 Capsules

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-568 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength dronabinol(UNII: 7J8897W37S) (dronabinol - UNII:7J8897W37S) dronabinol 2.5 mg

Inactive Ingredients Ingredient Name Strength glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) GELATIN, UNSPECIFIED(UNII: 2G86QN327L) TITANIUM DIOXIDE(UNII: 15FIX9V2JP)

Product Characteristics Color WHITE (white) Score no score Shape ROUND (ROUND) Size 8mm Flavor Imprint Code UM Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67877-568-60 1 in 1 CARTON 05/10/2017 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018651 05/10/2017

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-569 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength dronabinol(UNII: 7J8897W37S) (dronabinol - UNII:7J8897W37S) dronabinol 5 mg

Inactive Ingredients Ingredient Name Strength FERRIC OXIDE RED(UNII: 1K09F3G675) ferrosoferric oxide(UNII: XM0M87F357) glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) titanium dioxide(UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED(UNII: 2G86QN327L)

Product Characteristics Color BROWN (brown) Score no score Shape ROUND (ROUND) Size 8mm Flavor Imprint Code UM Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67877-569-60 1 in 1 CARTON 05/10/2017 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018651 05/10/2017

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-570 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength dronabinol(UNII: 7J8897W37S) (dronabinol - UNII:7J8897W37S) dronabinol 10 mg

Inactive Ingredients Ingredient Name Strength FERRIC OXIDE RED(UNII: 1K09F3G675) ferric oxide yellow(UNII: EX438O2MRT) glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) titanium dioxide(UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED(UNII: 2G86QN327L)

Product Characteristics Color ORANGE (orange) Score no score Shape ROUND (ROUND) Size 8mm Flavor Imprint Code UM Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67877-570-60 1 in 1 CARTON 05/10/2017 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018651 05/10/2017

Labeler -Ascend Laboratories, LLC (141250469)

Revised: 12/2018document Id: ⮝

bf1e78ab-ef4f-4e8a-214b-6a97d78c629b34391-3Set id: 0bb05433-4ffb-4b0e-42f4-7549b3646bc1Version: 19Effective Time: 20181203Ascend Laboratories, LLC

Dronabinol Capsules Can Cause Serious Side Effects, Including: ⮝

• Worsening mental (psychiatric) symptoms. Psychiatric symptoms can worsen in people who have mania, depression, or schizophrenia and who take dronabinol capsules. Dronabinol capsules taken with medicines that cause psychiatric symptoms can worsen psychiatric symptoms. Elderly people who take dronabinol capsules may have a greater risk of having psychiatric symptoms. Tell your doctor if you have new or worsening mood symptoms, including symptoms of mania, depression, or schizophrenia.
• Problems thinking clearly.Tell your doctor if you have trouble remembering things, concentrating, have increased sleepiness, or confusion. Elderly people may have a greater risk of having problems thinking clearly.
• Changes in your blood pressure.Dronabinol capsules may increase or decrease your blood pressure, especially when you start taking dronabinol capsules or when your dose is changed. Tell your doctor if you have signs or symptoms of changes in your blood pressure including: headaches, vision problems, dizziness, feeling lightheaded, fainting, or a fast heartbeat. Elderly people, especially those with dementia, and people with heart problems may have an increased risk of changes in blood pressure and an increased risk of falls.

Dronabinol Capsules Are A Prescription Medicine Used In Adults To Treat: ⮝

• loss of appetite (anorexia) in people with AIDS (Acquired Immune Deficiency Syndrome) who have lost weight.
• nausea and vomiting caused by anti-cancer medicine (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines.

Dronabinol capsules are a controlled substance (CIII) because it contains dronabinol, which can be a target for people who abuse prescription medicines or street drugs. Keep your dronabinol capsules in a safe place to protect them from theft. Never give your dronabinol capsules to anyone else because the capsules may cause death or harm them. Selling or giving away this medicine is against the law.

It is not known if dronabinol capsules are safe and effective in children.

What Are The Ingredients In Dronabinol Capsules? ⮝

Active ingredient: dronabinol

Inactive Ingredients: ⮝

2.5 mg capsules contain gelatin, glycerin, sesame oil, FD&C red No. 40, D&C yellow No. 10, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide and purified water; 5 mg capsules contain gelatin, glycerin, sesame oil, FD&C yellow No. 6, FD&C red No. 40, FD&C blue No. 1, titanium dioxide, shellac glaze, simethicone, isopropyl alcohol, ammonium hydroxide, n-butyl alcohol, propylene glycol and purified water; 10 mg capsules contain gelatin, glycerin, sesame oil, FD&C yellow No. 6, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide and purified water.

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

AKORN
Manufactured by USGP,
a division of PROCAPS forAkorn, Inc.,
Lake Forest, IL 60045

Made in Colombia.

DRA0N
Rev. 10/17

Principal Display Panel Text For Container Label: ⮝

NDC 17478-761-06 60 Capsules

Dronabinol

Capsules USP

2.5 mg CIII

Do not use if seal around the cap imprinted

with SEALED for YOUR PROTECTION is

broken or missing.

Rx only Akorn Logo

Principal Display Panel Text For Carton Label: ⮝

NDC 17478-763-06

Dronabinol

Capsules USP

10 mg CIII

Do not use if seal around the cap imprinted

with SEALED for YOUR PROTECTION is

broken or missing.

60 Capsules

Rx only Akorn Logo

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-761 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Dronabinol(UNII: 7J8897W37S) (Dronabinol - UNII:7J8897W37S) Dronabinol 2.5 mg

Inactive Ingredients Ingredient Name Strength gelatin(UNII: 2G86QN327L) glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) FD&C red no. 40(UNII: WZB9127XOA) D&C yellow no. 10(UNII: 35SW5USQ3G) titanium dioxide(UNII: 15FIX9V2JP) ferrosoferric oxide(UNII: XM0M87F357) shellac(UNII: 46N107B71O) isopropyl alcohol(UNII: ND2M416302) butyl alcohol(UNII: 8PJ61P6TS3) propylene glycol(UNII: 6DC9Q167V3) ammonia(UNII: 5138Q19F1X) water(UNII: 059QF0KO0R)

Product Characteristics Color brown (beige) Score no score Shape ROUND (ROUND) Size 3mm Flavor Imprint Code 61 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-761-06 1 in 1 CARTON 06/20/2014 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA079217 06/20/2014

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-762 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Dronabinol(UNII: 7J8897W37S) (Dronabinol - UNII:7J8897W37S) Dronabinol 5 mg

Inactive Ingredients Ingredient Name Strength gelatin(UNII: 2G86QN327L) glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) FD&C yellow no. 6(UNII: H77VEI93A8) FD&C red no. 40(UNII: WZB9127XOA) FD&C blue no. 1(UNII: H3R47K3TBD) titanium dioxide(UNII: 15FIX9V2JP) shellac(UNII: 46N107B71O) dimethicone(UNII: 92RU3N3Y1O) silicon dioxide(UNII: ETJ7Z6XBU4) isopropyl alcohol(UNII: ND2M416302) ammonia(UNII: 5138Q19F1X) butyl alcohol(UNII: 8PJ61P6TS3) propylene glycol(UNII: 6DC9Q167V3) water(UNII: 059QF0KO0R)

Product Characteristics Color brown (brown) Score no score Shape ROUND (ROUND) Size 3mm Flavor Imprint Code 62 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-762-06 1 in 1 CARTON 06/20/2014 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA079217 06/20/2014

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-763 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Dronabinol(UNII: 7J8897W37S) (Dronabinol - UNII:7J8897W37S) Dronabinol 10 mg

Inactive Ingredients Ingredient Name Strength gelatin(UNII: 2G86QN327L) glycerin(UNII: PDC6A3C0OX) sesame oil(UNII: QX10HYY4QV) FD&C yellow no. 6(UNII: H77VEI93A8) titanium dioxide(UNII: 15FIX9V2JP) ferrosoferric oxide(UNII: XM0M87F357) shellac(UNII: 46N107B71O) isopropyl alcohol(UNII: ND2M416302) butyl alcohol(UNII: 8PJ61P6TS3) propylene glycol(UNII: 6DC9Q167V3) ammonia(UNII: 5138Q19F1X) water(UNII: 059QF0KO0R)

Product Characteristics Color orange (orange) Score no score Shape ROUND (ROUND) Size 3mm Flavor Imprint Code 63 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-763-06 1 in 1 CARTON 06/20/2014 1 60 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA079217 06/20/2014

Labeler -Akorn, Inc. (062649876)

Revised: 11/2017document Id: ⮝

8c067dc9-5bfd-4c27-bc5d-253f67d5963534391-3Set id: a0409d82-a61e-4b9e-8717-ced299ccedb2Version: 3Effective Time: 20171128Akorn, Inc.

1. Description
2. Clinical Pharmacology
3. Clinical Trails
4. Indications And Usage
5. Contraindications
6. Warnings
7. Precautions
8. Adverse Reactions
9. Drug Abuse And Dependence
10. Overdosage
11. Dosage And Administration
12. How Supplied
13. Package Label.principal Display Panel
14. Package/label Display Panel
15. 1 Indications And Usage
16. 2 Dosage And Administration
17. 3 Dosage Forms And Strengths
18. 4 Contraindications
19. 5 Warnings And Precautions
20. 6 Adverse Reactions
21. 7 Drug Interactions
22. 8 Use In Specific Populations
23. 9 Drug Abuse And Dependence
24. 10 Overdosage
25. 11 Description
26. 12 Clinical Pharmacology
27. 13 Nonclinical Toxicology
28. 14 Clinical Studies
29. 16 How Supplied/storage And Handling
30. Dronabinol
31. Description
32. Clinical Pharmacology
33. Clinical Trials
34. Individualization Of Dosages
35. Warnings
36. Precautions
37. Drug Abuse And Dependence
38. Overdosage
39. Storage Conditions
40. How Supplied
41. Packaging Information
42. Principal Display Panel 2.5 Mg
43. Principal Display Panel 5 Mg
44. 2.5 Mg 60 Count
45. 5 Mg 60 Count
46. 10 Mg 60 Count
47. Principal Display Panel - 2.5 Mg Capsule Bottle Label
48. Principal Display Panel - 5 Mg Capsule Bottle Label
49. Principal Display Panel - 10 Mg Capsule Bottle Label
50. Highlights Of Prescribing Information
51. Indications And Usage
52. Dosage And Administration
53. Dosage Forms And Strengths
54. Contraindications
55. Warnings And Precautions
56. Adverse Reactions
57. Drug Interactions
58. Use In Specific Populations
59. 1 Indications And Usage
60. 2 Dosage And Administration
61. 3 Dosage Forms And Strengths
62. 4 Contraindications
63. 5 Warnings And Precautions
64. 6 Adverse Reactions
65. 7 Drug Interactions
66. 8 Use In Specific Populations
67. 9 Drug Abuse And Dependence
68. 10 Overdosage
69. 11 Description
70. 12 Clinical Pharmacology
71. 13 Nonclinical Toxicology
72. 14 Clinical Studies
73. 16 How Supplied/storage And Handling
74. Package/label Display Panel Carton 2.5 Mg
75. Package/label Display Panel Blister 2.5 Mg
76. Package/label Display Panel Carton 5 Mg
77. Package/label Display Panel Blister 5 Mg

Description  ⮝

Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following molecular and structural formulas:

Dronabinol, the active ingredient in dronabinol capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Capsules for oral administration: Dronabinol capsules are supplied as oblong, soft gelatin capsules containing 2.5 mg, 5 mg or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, purified water, sesame oil, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. The 2.5 mg and 5 mg also contain FD&C Blue No. 1 and FD&C Red No. 40.

Clinical Pharmacology  ⮝

Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids.

Pharmacodynamics

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing.

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability.

After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of dronabinol capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of dronabinol capsules has been sustained for up to five months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.

Pharmacokinetics

Absorption and Distribution: Dronabinol capsules are almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.

The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time.

The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions

Mean (SD) PK Parameter Values
BID Dose	Cmax ng/mL	Median Tmax (range, hr	AUC (0-12) ng hr/mL
2.5 mg	1.32 (0.62)	1.00 (0.50-4.00)	2.88 (1.57)
5 mg	2.96 (1.81)	2.50 (0.50-4.00)	6.16 (1.85)
10 mg	7.88 (4.54)	1.50 (0.50-3.50)	15.2 (5.52)

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Special Populations: The pharmacokinetic profile of dronabinol capsules has not been investigated in either pediatric or geriatric patients.

Clinical Trails  ⮝

Appetite Stimulation: The appetite stimulant effect of dronabinol capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinol capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

.

Antiemetic: Dronabinol treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of dronabinol was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin s and non-Hodgkin s lymphomas. Dronabinol capsules dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the dronabinol dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit.

Dronabinol Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)

*Nondysphoric events consisted of drowsiness, tachycardia, etc.
Dronabinol Dose	Response Frequency (%)			Adverse Events Frequency (%)
	Complete	Partial	Poor	None	Nondysphoric	Dysphoric
<7 mg/m2	36	32	32	23	65	12
>7 mg/m2	33	31	36	13	58	28

Combination antiemetic therapy with dronabinol capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents.

INDIVIDUALIZATION OF DOSAGES

The pharmacologic effects of dronabinol are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of dronabinol treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day dronabinol capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:

1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high, dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.
   
   
2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be a problem, taking the single dose in the evening or at bedtime may reduce their severity.
   
   
3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in appetite stimulation studies.
   
   

The pharmacologic effects of dronabinol capsules are reversible upon treatment cessation.

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest recommended dosage and titrated to clinical response. Administration of dronabinol capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as compared to either drug alone, without additional toxicity.

Pediatrics: Dronabinol capsules are not recommended for AIDS-related anorexia in pediatric patients because it has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing dronabinol capsules for children because of the psychoactive effects.

Geriatrics: Caution is advised in prescribing dronabinol capsules in elderly patients because they may be more sensitive to the neurological, psychoactive and postural hypotensive effects of the drug. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (See PRECAUTIONS.)

Dronabinol capsules should be used with caution when administered to elderly patients with dementia, who are at increased risk for falls as a result of their underlying disease state which may be exacerbated by the central nervous system effects of somnolence and dizziness associated with dronabinol capsules. These patients should be monitored closely and placed on fall precautions prior to initiating dronabinol therapy. In antiemetic studies, no difference in efficacy was apparent in patients >55 years old.

Indications And Usage  ⮝

Dronabinol capsules are indicated for the treatment of:

1. anorexia associated with weight loss in patients with AIDS; and
   
   
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
   
   

Contraindications  ⮝

Dronabinol capsules are contraindicated in any patient who has a known sensitivity to dronabinol or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by patients allergic to these substances.

Warnings  ⮝

Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Precautions  ⮝

General:

The risk/benefit ratio of dronabinol use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of dronabinol.

Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. (See ADVERSE REACTIONS and OVERDOSAGE.) Dronabinol capsules should be used with caution in patients with a history of seizure disorder because dronabinol capsules may lower the seizure threshold. A causal relationship between dronabinol capsules and these events has not been established. Dronabinol capsules should be discontinued immediately in patients who develop seizures and medical attention should be sought immediately.

Dronabinol capsules should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL PHARMACOLOGY).

Dronabinol capsules should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse dronabinol capsules as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance.

Dronabinol capsules should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because dronabinol capsules may exacerbate these illnesses.

Dronabinol capsules should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects.

Dronabinol capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug. (see INDIVIDUALIZATION OF DOSAGES.)

Dronabinol capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations.

Information for Patients:

Patients receiving treatment with dronabinol capsules should be alerted to the potential for additive central nervous system depression if dronabinol capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates.

Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Patients using dronabinol capsules should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of dronabinol capsules and following dosage adjustments.

Drug Interactions:

In studies involving patients with AIDS and/or cancer, dronabinol capsules have been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of dronabinol capsules, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table.

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity studies in mice and rats have been conducted under the U.S. National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day.

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known.

Pregnancy:

Pregnancy Category C. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20 times MRHD of 15 mg/m2/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

Use of dronabinol capsules is not recommended in nursing mothers since, in addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing baby.

Geriatric Use:

Clinical studies of dronabinol capsules in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of concomitant disease or other drug therapy.

Adverse Reactions  ⮝

Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the U.S. and U.S. territories involving 474 patients exposed to dronabinol capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events during the first 28 days. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo.

A cannabinoid dose-related high (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). (see CLINICAL TRIALS).

The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a minor CNS adverse event during the first 2 weeks and about 4% reported such an event each week for the next 6 weeks thereafter.

PROBABLY CAUSALLY RELATED: Incidence greater than 1%.

Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses).

*Incidence of events 3% to 10%

Body as a whole: Asthenia.

Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush.

Digestive: Abdominal pain*, nausea*, vomiting*.

Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*, euphoria*, (hallucination), paranoid reaction*, somnolence*, thinking abnormal*.

PROBABLY CAUSALLY RELATED: Incidence less than 1%.

Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317).

*Incidence of events 0.3% to 1%

Cardiovascular: Conjunctivitis*, hypotension*.

Digestive: Diarrhea*, fecal incontinence.

Musculoskeletal: Myalgias.

Nervous system: Depression, nightmares, speech difficulties, tinnitus.

Skin and Appendages: Flushing*.

Special senses: Vision difficulties.

CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.

The clinical significance of the association of these events with dronabinol capsules treatment is unknown, but they are reported as alerting information for the clinician.

Body as a whole: Chills, headache, malaise.

Digestive: Anorexia, hepatic enzyme elevation.

Respiratory: Cough, rhinitis, sinusitis.

Skin and Appendages: Sweating

Postmarketing Experience

Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. (see PRECAUTIONS and OVERDOSAGE.) Reports of fatigue have also been received. A causal relationship between dronabinol capsules and these events has not been established.

Drug Abuse And Dependence  ⮝

Dronabinol is one of the psychoactive compounds present in cannabis, and is abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.

Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgment, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of dronabinol capsules for therapeutic purposes.

In an open-label study in patients with AIDS who received dronabinol capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include hot flashes , sweating, rhinorrhea, loose stools, hiccoughs and anorexia.

These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

Overdosage  ⮝

Signs and symptoms following MILD dronabinol intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.

The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.

Management: A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required.

Dosage And Administration  ⮝

Appetite Stimulation: Initially, 2.5 mg dronabinol capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of dronabinol capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day dronabinol capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol capsules because of the increased frequency of dose-related adverse experiences at higher dosages. (see PRECAUTIONS.)

Antiemetic: Dronabinol Capsules are best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose (see PRECAUTIONS).

STORAGE CONDITIONS

Dronabinol Capsules, USP should be packaged in a well-closed container and stored in a refrigerator, 2 to 8 C (36 to 46 F).

Protect from freezing.

How Supplied  ⮝

Dronabinol Capsules (dronabinol solution in sesame oil in soft gelatin capsules)

2.5 mg - cream, oblong softgel capsules printed PAR 867 in black ink.

NDC 49884-867-15 Bottle of 25 capsules
NDC 49884-867-02 Bottle of 60 capsules
NDC 49884-867-01 Bottle of 100 capsules
NDC 49884-867-05 Bottle of 500 capsules


5 mg - opaque brown, oblong softgel capsules printed PAR 868 in black ink.

NDC 49884-868-15 Bottle of 25 capsules
NDC 49884-868-02 Bottle of 60 capsules
NDC 49884-868-01 Bottle of 100 capsules
NDC 49884-868-05 Bottle of 500 capsules


10 mg - orange, oblong softgel capsules printed PAR 869 in black ink.

NDC 49884-869-15 Bottle of 25 capsules
NDC 49884-869-02 Bottle of 60 capsules
NDC 49884-869-01 Bottle of 100 capsules
NDC 49884-869-05 Bottle of 500 capsules


Manufactured by:
Pharmaceutics International, Inc.
Hunt Valley, MD 21031

Manufactured for:
Par Pharmaceutical Companies, Inc.
Spring Valley, NY 10977

Revised: 11/2011

OS867-15-17-02

302850-0B

Package Label.principal Display Panel  ⮝

Bottle of 60 Capsules NDC 49884-867-02

CIII Rx Only

Bottle of 60 Capsules NDC 49884-868-02

CIII Rx Only

Bottle of 60 Capsules NDC 49884-869-02

CIII Rx Only

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49884-867 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color WHITE (cream) Score no score Shape CAPSULE (Oblong softgel) Size 12mm Flavor Imprint Code PAR;867 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49884-867-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 2 NDC:49884-867-02 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/30/2008 01/31/2020 3 NDC:49884-867-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 4 NDC:49884-867-15 25 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/27/2008

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49884-868 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color BROWN (opaque) Score no score Shape CAPSULE (Oblong softgel) Size 12mm Flavor Imprint Code PAR;868 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49884-868-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 2 NDC:49884-868-02 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/30/2008 02/29/2020 3 NDC:49884-868-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 4 NDC:49884-868-15 25 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/27/2008

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49884-869 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 10 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color ORANGE Score no score Shape CAPSULE (Oblong softgel) Size 12mm Flavor Imprint Code PAR;869 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49884-869-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 2 NDC:49884-869-02 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/30/2008 02/29/2020 3 NDC:49884-869-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008 4 NDC:49884-869-15 25 in 1 BOTTLE; Type 0: Not a Combination Product 06/27/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/27/2008

Labeler - Par Pharmaceutical, Inc. (092733690)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmaceutics International Inc.		878265586	MANUFACTURE(49884-867, 49884-868, 49884-869)

Revised: 1/2012 Document Id: 8e792359-de7f-4875-9834-0d74bd6066ed 34391-3 Set id: a6269fc3-ca40-444f-8035-d6a391d037e0 Version: 7 Effective Time: 20120120 Par Pharmaceutical, Inc.

Package/label Display Panel  ⮝

Dronabinol Capsules, USP CIII

5 mg

30 Capsules

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0904-6745(NDC:42858-867) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength FD&C Yellow No. 6 (UNII: H77VEI93A8) Gelatin, unspecified (UNII: 2G86QN327L) Glycerin (UNII: PDC6A3C0OX) Water (UNII: 059QF0KO0R) Sesame Oil (UNII: QX10HYY4QV) Titanium dioxide (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Shellac (UNII: 46N107B71O) Isopropyl alcohol (UNII: ND2M416302) Butyl alcohol (UNII: 8PJ61P6TS3) Propylene glycol (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C Blue No. 1 (UNII: H3R47K3TBD) FD&C Red No. 40 (UNII: WZB9127XOA)

Product Characteristics Color WHITE (Opaque cream capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;867 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0904-6745-61 100 in 1 CARTON 06/26/2018 1 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 ANDA078292 06/26/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0904-6746(NDC:42858-868) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength FD&C Yellow No. 6 (UNII: H77VEI93A8) Gelatin, unspecified (UNII: 2G86QN327L) Glycerin (UNII: PDC6A3C0OX) Water (UNII: 059QF0KO0R) Sesame Oil (UNII: QX10HYY4QV) Titanium dioxide (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Shellac (UNII: 46N107B71O) Isopropyl alcohol (UNII: ND2M416302) Butyl alcohol (UNII: 8PJ61P6TS3) Propylene glycol (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C Blue No. 1 (UNII: H3R47K3TBD) FD&C Red No. 40 (UNII: WZB9127XOA)

Product Characteristics Color BROWN (Opaque brown capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;868 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0904-6746-04 30 in 1 CARTON 06/26/2018 1 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 ANDA078292 06/26/2018

Labeler - Major Pharmaceuticals (191427277)

Revised: 10/2018 Document Id: 35d6dc4a-b482-412e-94c4-3cb32aea4098 34391-3 Set id: 35d6dc4a-b482-412e-94c4-3cb32aea4098 Version: 1 Effective Time: 20181009 Major Pharmaceuticals

1 Indications And Usage  ⮝

Dronabinol capsules are indicated in adults for the treatment of:

• anorexia associated with weight loss in patients with Acquired Immune Deficiency Syndrome (AIDS).
• nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

2 Dosage And Administration  ⮝

2.1 Anorexia Associated with Weight Loss in Adult Patients with AIDS

Starting Dosage

The recommended adult starting dosage of dronabinol capsules is 2.5 mg orally twice daily, one hour before lunch and dinner.

In elderly patients or patients unable to tolerate 2.5 mg twice daily, consider initiating dronabinol capsules at 2.5 mg once daily one hour before dinner or at bedtime to reduce the risk of central nervous system (CNS) symptoms [see Use in Specific Populations (8.5)].

Dosing later in the day may reduce the frequency of CNS adverse reactions. CNS adverse reactions are dose-related [see Warnings and Precautions (5.1)]; therefore monitor patients and reduce the dosage as needed. If CNS adverse reactions of feeling high, dizziness, confusion, and somnolence occur, they usually resolve in 1 to 3 days and usually do not require dosage reduction. If CNS adverse reactions are severe or persistent, reduce the dosage to 2.5 mg in the evening or at bedtime.

Dosage Titration

If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.5 mg one hour before lunch and 5 mg one hour before dinner. Increase the dose of dronabinol capsules gradually in order to reduce the frequency of dose-related adverse reactions [see Warnings and Precautions (5.1)].

Most patients respond to 2.5 mg twice daily, but the dose may be further increased to 5 mg one hour before lunch and 5 mg one hour before dinner, as tolerated to achieve a therapeutic effect.

Maximum Dosage: 10 mg twice daily.

2.2 Nausea and Vomiting Associated with Cancer Chemotherapy in Adult Patients Who Failed Conventional Antiemetics

Starting Dosage

The recommended starting dosage of dronabinol capsules is 5 mg/m2, orally administered 1 to 3 hours prior to the administration of chemotherapy and then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day.

In elderly patients, consider initiating dronabinol capsules at 2.5 mg/m2 once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS symptoms [see Use in Specific Populations (8.5)].

Administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals [see Clinical Pharmacology (12.3)].

The timing of dosing in relation to meal times should be kept consistent for each chemotherapy cycle, once the dosage has been determined from the titration process.

Dosage Titration

The dosage can be titrated to clinical response during a chemotherapy cycle or subsequent cycles, based upon initial response, as tolerated to achieve a clinical effect, in increments of 2.5 mg/m2.

The maximum dosage is 15 mg/m2 per dose for 4 to 6 doses per day.

Adverse reactions are dose-related and psychiatric symptoms increase significantly at the maximum dosage [see Warnings and Precautions (5.1)].

Monitor patients for adverse reactions and consider decreasing the dose to 2.5 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

3 Dosage Forms And Strengths  ⮝

Dronabinol Capsules, USP are supplied as round, soft gelatin capsules for oral use as follows:

• 2.5 mg beige capsules (printed 61 in black ink)
• 5 mg brown capsules (printed 62 in white ink)
• 10 mg orange capsules (printed 63 in black ink)

4 Contraindications  ⮝

Dronabinol capsules are contraindicated in patients with a history of a hypersensitivity reaction to dronabinol or sesame oil. Reported hypersensitivity reactions to dronabinol capsules include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing and throat tightness [see Adverse Reactions (6.2)].

5 Warnings And Precautions  ⮝

5.1 Neuropsychiatric Adverse Reactions

Psychiatric Adverse Reactions

Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Significant CNS symptoms followed oral doses of 0.4 mg/kg (28 mg per 70 kg patient) of dronabinol capsules in antiemetic studies.

Prior to initiating treatment with dronabinol capsules, screen patients for a history of these illnesses. Avoid use in patients with a psychiatric history or, if the drug cannot be avoided, monitor patients for new or worsening psychiatric symptoms during treatment. Also, avoid concomitant use with other drugs that are associated with similar psychiatric effects.

Cognitive Adverse Reactions

Use of dronabinol capsules has been associated with cognitive impairment and altered mental state. Reduce the dose of dronabinol capsules or discontinue use of dronabinol capsules if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of dronabinol capsules [see Use in Specific Populations (8.4, 8.5)].

Hazardous Activities

Dronabinol capsules can cause and may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery. Concomitant use of other drugs that cause dizziness, confusion, sedation, or somnolence such as CNS depressants may increase this effect (e.g., barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol capsules do not affect them adversely.

5.2 Hemodynamic Instability

Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking dronabinol capsules [see Clinical Pharmacology (12.2)]. Patients with cardiac disorders may be at higher risk. Avoid concomitant use of other drugs that are also associated with similar cardiac effects (e.g., amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, desipramine, other tricyclic antidepressants). Monitor patients for changes in blood pressure, heart rate, and syncope after initiating or increasing the dosage of dronabinol capsules.

5.3 Seizures

Seizure and seizure-like activity have been reported in patients receiving dronabinol.

Weigh this potential risk against the benefits before prescribing dronabinol capsules to patients with a history of seizures, including those receiving anti-epileptic medication or with other factors that can lower the seizure threshold. Monitor patients with a history of seizure disorders for worsened seizure control during dronabinol capsules therapy.

If a seizure occurs, advise patients to discontinue dronabinol capsules and contact a healthcare provider immediately.

5.4 Multiple Substance Abuse

Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse dronabinol capsules as well.

Assess each patient's risk for abuse or misuse prior to prescribing dronabinol capsules and monitor patients with a history of substance abuse during treatment with dronabinol capsules for the development of these behaviors or conditions.

5.5 Paradoxical Nausea, Vomiting, or Abdominal Pain

Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9-tetrahydrocannabinol (delta-9-THC), the active ingredient in dronabinol capsules. In some cases, these adverse reactions were severe (e.g., dehydration, electrolyte abnormalities) and required dose reduction or drug discontinuation. Symptoms are similar to cannabinoid hyperemesis syndrome (CHS), which is described as cyclical events of abdominal pain, nausea, and vomiting in chronic, long-term users of delta-9-THC products.

Because patients may not recognize these symptoms as abnormal, it is important to specifically ask patients or their caregivers about the development of worsening of nausea, vomiting, or abdominal pain while being treated with dronabinol capsules. Consider dose reduction or discontinuing dronabinol capsules if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

6 Adverse Reactions  ⮝

6.1 Clinical Trials Experience

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

The following serious adverse reactions are described below and elsewhere in the labeling.

• Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.1)]
• Hemodynamic Instability [see Warnings and Precautions (5.2)]
• Seizures [see Warnings and Precautions (5.3)]
• Paradoxical Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions (5.5)]

Studies of AIDS-related weight loss included 157 patients receiving dronabinol capsules at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol capsules and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to dronabinol capsules in studies.

Studies of different durations were combined by considering the first occurrence of events during the first 28 days.

A cannabinoid dose-related high (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a CNS adverse reaction during the first 2 weeks and about 4% reported such a reaction each week for the next 6 weeks thereafter.

Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence greater than 1%.

* Actual incidence 3% to 10%
System Organ Class	Adverse Reactions
General	Asthenia
Cardiovascular	Palpitations, tachycardia, vasodilation/facial flush
Gastrointestinal	Abdominal pain*, nausea*, vomiting*
Central Nervous System	Dizziness*, euphoria*, paranoid reaction*, somnolence*, thinking abnormal*, amnesia, anxiety/nervousness, ataxia, confusion, depersonalization, hallucination

Less Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence less than or equal to 1%.

System Organ Class	Adverse Reactions
General	Chills, headache, malaise
Cardiovascular	Hypotension, conjunctival injection [see Clinical Pharmacology (12.2)]
Gastrointestinal	Diarrhea, fecal incontinence, anorexia, hepatic enzyme elevation
Musculoskeletal	Myalgias
Central Nervous System	Depression, nightmares, speech difficulties, tinnitus
Respiratory	Cough, rhinitis, sinusitis
Skin	Flushing, sweating
Sensory	Vision difficulties

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dronabinol capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Fatigue

Hypersensitivity reactions: Lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness [see Contraindications (4)]

Injury, poisoning and procedural complications: Fall [see Use in Specific Populations (8.5)]

Nervous system disorders: Seizures [see Warnings and Precautions (5.3)], disorientation, movement disorder, loss of consciousness

Psychiatric disorders: Delirium, insomnia, panic attack

Vascular disorders: Syncope [see Warnings and Precautions (5.2)]

7 Drug Interactions  ⮝

7.1 Additive CNS Effects

Additive CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when dronabinol capsules are taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants [see Warnings and Precautions (5.1)].

7.2 Additive Cardiac Effects

Additive cardiac effects (e.g., hypotension, hypertension, syncope, tachycardia) may occur when dronabinol capsules are taken concomitantly with drugs that have similar effects on the cardiovascular system [see Warnings and Precautions (5.2)].

7.3 Effect of Other Drugs on Dronabinol

Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes based on published in vitro studies. Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of dronabinol and/or its active metabolite resulting in an increase in dronabinol-related adverse reactions or loss of efficacy of dronabinol capsules.

Monitor for potentially increased dronabinol-related adverse reactions when dronabinol capsules are co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

7.4 Highly Protein-Bound Drugs

Dronabinol is highly bound to plasma proteins, and therefore, might displace and increase the free fraction of other concomitantly administered protein-bound drugs.

Although this displacement has not been confirmed in vivo, monitor patients for increased adverse reactions to narrow therapeutic index drugs that are highly protein-bound (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of dronabinol capsules.

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Risk Summary

Dronabinol capsules, a synthetic cannabinoid, may cause fetal harm. Avoid use of dronabinol capsules in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) during pregnancy has been associated with adverse fetal/neonatal outcomes [see Clinical Considerations]. Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol at up to 30 times the MRHD (maximum recommended human dose) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses which induced maternal toxicity. In published studies, offspring of pregnant rats administered delta-9-THC during and after organogenesis have been reported to exhibit neurotoxicity with adverse effects on brain development, including abnormal neuronal connectivity and impairments in cognitive and motor function [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the NICU, and stillbirth. Therefore, use of cannabis during pregnancy should be avoided.

Data

Human Data

Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy. The effects of delta-9-THC on the fetus are not known.

Animal Data

Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 1 to 30 times the MRHD of 15 mg/m2/day in AIDS patients or 0.2 to 5 times the MRHD of 90 mg/m2/day in cancer patients, and in rats at 74 to 295 mg/m2 (equivalent to 5 to 20 times the MRHD of 15 mg/m2/day in AIDS patients or 0.8 to 3 times the MRHD of 90 mg/m2/day in cancer patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses that produced less maternal toxicity.

Review of published literature indicates that the endocannabinoid system plays a role in neurodevelopmental processes such as neurogenesis, migration, and synaptogenesis. Exposure of pregnant rats to delta-9-THC (during and after organogenesis) may modulate these processes to result in abnormal patterns of neuronal connectivity and subsequent cognitive impairments in the offspring. Nonclinical toxicity studies in pregnant rats and newborn pups have shown prenatal exposure to THC that resulted in impairment of motor function, alteration in synaptic activity, and interference in cortical projection of neuron development in the offspring. Prenatal exposure has shown effects on cognitive function such as learning, short- and long-term memory, attention, decreased ability to remember task, and ability to discriminate between novel and same objects. Overall, prenatal exposure to THC has resulted in significant and long-term changes in brain development, cognition, and behavior in rat offspring.

8.2 Lactation

Risk Summary

For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving dronabinol capsules.

For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. Because of the possible adverse effects from dronabinol capsules on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with dronabinol capsules and for 9 days after the last dose.

8.4 Pediatric Use

The safety and effectiveness of dronabinol capsules have not been established in pediatric patients.

Pediatric patients may be more sensitive to neurological and psychoactive effects of dronabinol capsules [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies of dronabinol capsules in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of dronabinol capsules [see Warnings and Precautions (5.1, 5.2)].

Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with dronabinol capsules [see Warnings and Precautions (5.1)]. These patients should be monitored closely and placed on fall precautions prior to initiating dronabinol capsules therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and of concomitant disease or other drug therapy [see Dosage and Administration (2.1, 2.2)].

8.6 Effect of CYP2C9 Polymorphism

Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in the presence of CYP2C9 genetic polymorphism. Monitoring for potentially increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function [see Clinical Pharmacology (12.5)].

9 Drug Abuse And Dependence  ⮝

9.1 Controlled Substance

Dronabinol capsules contain dronabinol, a Schedule III controlled substance.

9.2 Abuse

Dronabinol capsules contain dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia.

In an open-label study in patients with AIDS who received dronabinol capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

Patients should be instructed to keep dronabinol capsules in a secure place out of reach of others for whom the medication has not been prescribed.

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with dronabinol capsules, and develops after chronic abuse of marijuana.

A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include hot flashes, sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours.

Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

10 Overdosage  ⮝

Signs and symptoms of dronabinol overdosage include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety, and seizures may occur in patients with existing seizure disorders.

It is not known if dronabinol can be removed by dialysis in cases of overdose.

If over-exposure of dronabinol capsules occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 Description  ⮝

Dronabinol is a cannabinoid designated chemically as (6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-1-ol. Dronabinol has the following empirical and structural formulas:

Dronabinol, the active ingredient in Dronabinol Capsules, USP, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Each Dronabinol Capsule, USP strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, FD&C red No. 40, D&C yellow No. 10, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide and purified water; 5 mg capsule contains gelatin, glycerin, sesame oil, FD&C yellow No. 6, FD&C red No. 40, FD&C blue No. 1, titanium dioxide, shellac glaze, simethicone, isopropyl alcohol, ammonium hydroxide, n-butyl alcohol, propylene glycol and purified water; 10 mg capsule contains gelatin, glycerin, sesame oil, FD&C yellow No. 6, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide and purified water.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Dronabinol is an orally active cannabinoid which has complex effects on the CNS, including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol.

12.2 Pharmacodynamics

Effects on the Cardiovascular System

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing [see Warnings and Precautions (5.2)].

Effects on the Central Nervous System

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 210 mg per day of dronabinol capsules, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol capsules. In clinical studies involving AIDS patients, the appetite stimulant effect of dronabinol capsules was sustained for up to five months at dosages ranging from 2.5 mg to 20 mg per day.

12.3 Pharmacokinetics

Absorption

Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Concentrations of both parent drug and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.

The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day) have been studied in healthy subjects.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Subjects (n=34; 20 to 45 years) under Fasted Conditions

Cmax: maximum observed plasma concentration; Tmax: time to maximum observed plasma concentration; AUC(0-12): area under the plasma concentration-time curve from 0 to 12 hours.
Mean (SD) PK Parameter Values
Twice Daily Dose	Cmax ng/mL	Median Tmax (range), hr	AUC(0-12) ng hr/mL
2.5 mg	1.32 (0.62)	1.00 (0.50 to 4.00)	2.88 (1.57)
5 mg	2.96 (1.81)	2.50 (0.50 to 4.00)	6.16 (1.85)
10 mg	7.88 (4.54)	1.50 (0.50 to 3.50)	15.2 (5.52)

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Effect of Food: In a published study, the effect of food on the pharmacokinetics of dronabinol was studied by concomitant dosing of dronabinol capsules with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed, resulting in a 4-hour delay in mean Tmax and 2.9-fold increase in total exposure (AUCinf), but Cmax was not significantly changed [see Dosage and Administration (2.2)].

Distribution

Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97% [see Drug Interactions (7.4)].

Elimination

The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Metabolism

Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite [see Clinical Pharmacology (12.5)].

Excretion

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Due to its re-distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Drug Interaction Studies

Formal drug-drug interaction studies have not been conducted with dronabinol.

The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood.

Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol [see Warnings and Precautions (5.1)].

12.5 Pharmacogenomics

Published data indicate a potentially 2- to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies, there was no evidence of carcinogenicity in rats at doses up to 50 mg/kg/day dronabinol (approximately 20 times the MRHD in AIDS patients on a body surface area basis) or in mice at doses up to 500 mg/kg/day (approximately 100 times the MRHD in AIDS patients on a body surface area basis).

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. However, dronabinol produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 2 to 10 times the MRHD of 15 mg/m2/day in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m2/day in cancer patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success, and testosterone levels were not affected. The significance of these animal findings in humans is not known.

14 Clinical Studies  ⮝

The effectiveness of dronabinol capsules has been established based on studies for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

14.1 Appetite Stimulation

The appetite stimulant effect of dronabinol capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before dinner. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinol capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol capsules and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol capsules and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

16 How Supplied/storage And Handling  ⮝

Dronabinol Capsules, USP (dronabinol solution in sesame oil in soft gelatin capsules)

2.5 mg beige soft gelatin, round-shape capsule (printed 61 in black ink)

NDC 17478-761-06 (Bottle of 60 capsules).

5 mg brown soft gelatin, round-shape capsule (printed 62 in white ink)

NDC 17478-762-06 (Bottle of 60 capsules).

10 mg orange soft gelatin, round-shape capsule (printed 63 in black ink)

NDC 17478-763-06 (Bottle of 60 capsules).

Storage Conditions

Dronabinol capsules should be packaged in a well-closed container and stored in a cold environment between 2 C and 8 C (36 F and 46 F).

Store in refrigerator.

Protect from freezing.

Protect from light.

Dronabinol ⮝

Rx only

Description ⮝

Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following molecular and structural formulas:

Dronabinol, the active ingredient in dronabinol capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Capsules for oral administration: Dronabinol capsules are supplied as oblong, soft gelatin capsules containing 2.5 mg, 5 mg or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, purified water, sesame oil, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. The 2.5 mg and 5 mg also contain FD&C Blue No. 1 and FD&C Red No. 40.

Clinical Pharmacology ⮝

Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids.

Pharmacodynamics

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing.

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability.

After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of dronabinol capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of dronabinol capsules has been sustained for up to five months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.

Pharmacokinetics

Absorption and Distribution: Dronabinol capsules are almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.

The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time.

The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions
	Mean (SD) PK Parameter Values
BID Dose	Cmax ng/mL	Median Tmax (range), hr	AUC(0-12) ng hr/mL
2.5 mg	1.32 (0.62)	1.00 (0.50-4.00)	2.88 (1.57)
5 mg	2.96 (1.81)	2.50 (0.50-4.00)	6.16 (1.85)
10 mg	7.88 (4.54)	1.50 (0.50-3.50)	15.2 (5.52)

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Special Populations: The pharmacokinetic profile of dronabinol capsules has not been investigated in either pediatric or geriatric patients.

Clinical Trials ⮝

Appetite Stimulation: The appetite stimulant effect of dronabinol capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinol capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

Antiemetic: Dronabinol treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of dronabinol was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin s and non-Hodgkin s lymphomas. Dronabinol capsules dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the dronabinol dose above 7 mg/m 2 increased the frequency of adverse experiences, with no additional antiemetic benefit.

Dronabinol Dose: Response Frequency and Adverse Experiences* (N = 750 treatment courses)
Dronabinol Dose	Response Frequency (%)			Adverse Events Frequency (%)
	Complete	Partial	Poor	None	Nondysphoric	Dysphoric
<7 mg/m 2	36	32	32	23	65	12
>7 mg/m 2	33	31	36	13	58	28

*Nondysphoric events consisted of drowsiness, tachycardia, etc.

Combination antiemetic therapy with dronabinol capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents.

Individualization Of Dosages ⮝

The pharmacologic effects of dronabinol are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of dronabinol treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day dronabinol capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:

• Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high, dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.
• If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be a problem, taking the single dose in the evening or at bedtime may reduce their severity.
• When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in appetite stimulation studies.

The pharmacologic effects of dronabinol capsules are reversible upon treatment cessation.

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest recommended dosage and titrated to clinical response. Administration of dronabinol capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as compared to either drug alone, without additional toxicity.

Pediatrics: Dronabinol capsules are not recommended for AIDS-related anorexia in pediatric patients because it has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing dronabinol capsules for children because of the psychoactive effects.

Geriatrics: Caution is advised in prescribing dronabinol capsules in elderly patients because they may be more sensitive to the neurological, psychoactive and postural hypotensive effects of the drug. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS.)

Dronabinol capsules should be used with caution when administered to elderly patients with dementia, who are at increased risk for falls as a result of their underlying disease state which may be exacerbated by the central nervous system effects of somnolence and dizziness associated with dronabinol capsules. These patients should be monitored closely and placed on fall precautions prior to initiating dronabinol therapy. In antiemetic studies, no difference in efficacy was apparent in patients >55 years old.

Warnings ⮝

Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Precautions ⮝

General

The risk/benefit ratio of dronabinol use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of dronabinol.

Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. (See ADVERSE REACTIONS and OVERDOSAGE.) Dronabinol capsules should be used with caution in patients with a history of seizure disorder because dronabinol capsules may lower the seizure threshold. A causal relationship between dronabinol capsules and these events has not been established. Dronabinol capsules should be discontinued immediately in patients who develop seizures and medical attention should be sought immediately.

Dronabinol capsules should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL PHARMACOLOGY).

Dronabinol capsules should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse dronabinol capsules as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance.

Dronabinol capsules should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because dronabinol capsules may exacerbate these illnesses.

Dronabinol capsules should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects.

Dronabinol capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug.(See INDIVIDUALIZATION OF DOSAGES.)

Dronabinol capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations.

Information for Patients

Patients receiving treatment with dronabinol capsules should be alerted to the potential for additive central nervous system depression if dronabinol capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates.

Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Patients using dronabinol capsules should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of dronabinol capsules and following dosage adjustments.

Drug Interactions

In studies involving patients with AIDS and/or cancer, dronabinol capsules have been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of dronabinol capsules, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table.

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in mice and rats have been conducted under the U.S. National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day.

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m 2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m 2/day in cancer patients or 2 to 10 times MRHD of 15 mg/m 2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known.

Pregnancy

Pregnancy Category C. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m 2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m 2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m 2/day in AIDS patients, and in rats at 74 to 295 mg/m 2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m 2 in cancer patients or 5 to 20 times MRHD of 15 mg/m 2/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Use of dronabinol capsules is not recommended in nursing mothers since, in addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing baby.

Geriatric Use

Clinical studies of dronabinol capsules in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of concomitant disease or other drug therapy.

Drug Abuse And Dependence ⮝

Dronabinol is one of the psychoactive compounds present in cannabis, and is abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.

Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgment, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of dronabinol capsules for therapeutic purposes.

In an open-label study in patients with AIDS who received dronabinol capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include hot flashes , sweating, rhinorrhea, loose stools, hiccoughs and anorexia.

These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

Overdosage ⮝

Signs and symptoms following MILD dronabinol intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.

The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.

Management: A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required.

Storage Conditions ⮝

Dronabinol Capsules, USP should be packaged in a well-closed container and stored in a refrigerator, 2 to 8 C (36 to 46 F). Protect from freezing.

How Supplied ⮝

Dronabinol Capsules (dronabinol solution in sesame oil in soft gelatin capsules)

2.5 mg - cream, oblong softgel capsules printed "PAR 867" in black ink.
Unit dose packages of 100 (10 x 10) NDC 68084-174-01

5 mg -opaque brown, oblong softgel capsules printed "PAR 868" in black ink.
Unit dose packages of 30 (3 x 10) NDC 68084-175-21

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Par Pharmaceutical as follows:
(2.5 mg / 100 UD) NDC 68084-174-01 packaged from NDC 49884-867
(5 mg / 30 UD) NDC 68084-175-21 packaged from NDC 49884-868

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

8217401/0512

Principal Display Panel 2.5 Mg ⮝

NDC 68084-174-01

Dronabinol
Capsules, USP

CIII

2.5 mg

100 Capsules (10 x 10)

Each capsule contains:
Dronabinol, USP 2.5 mg

USUAL DOSAGE: See Package Insert for
Complete Prescribing Information.

Dronabinol Capsules, USP should be
stored in a refrigerator 2 to 8 C
(36 to 46 F). Protect from freezing.

Keep this and all drugs out of reach of children.

Rx Only

The drug product contained in this package
is from NDC # 49884-867,
Par Pharmaceutical Inc.

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

017401
Rev. 04/2014

Principal Display Panel 5 Mg ⮝

NDC 68084-175-21

Dronabinol
Capsules, USP

CIII

5 mg

30 Capsules (3 x 10)

Each capsule contains:
Dronabinol, USP ..5 mg

USUAL DOSAGE: See Package Insert for Complete
Prescribing Information.

Dronabinol Capsules, USP should be stored in a
refrigerator 2 to 8 C (36 to 46 F).
Protect from freezing.

Keep this and all drugs out of reach of children.

Rx Only

The drug product contained in this package is from
NDC # 49884-868, Par Pharmaceutical Inc.

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

017501
Rev. 04/2014

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-174(NDC:49884-867) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) FERROSOFERRIC OXIDE (UNII: XM0M87F357) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color white (cream) Score no score Shape CAPSULE (Oblong softgel) Size 12mm Flavor Imprint Code PAR;867 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-174-01 100 in 1 BOX, UNIT-DOSE 06/02/2010 01/31/2020 1 NDC:68084-174-11 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 ANDA078292 06/02/2010 01/31/2020

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-175(NDC:49884-868) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color brown (opaque) Score no score Shape CAPSULE (Oblong softgel) Size 12mm Flavor Imprint Code PAR;868 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-175-21 30 in 1 BOX, UNIT-DOSE 09/23/2010 10/31/2019 1 NDC:68084-175-11 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 ANDA078292 09/23/2010 10/31/2019

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(68084-174, 68084-175)

Revised: 12/2018 Document Id: 7df3366d-aedc-9352-e053-2991aa0a8cab 34391-3 Set id: 68b4168b-5782-4e68-a25a-5b4e4408dbce Version: 5 Effective Time: 20181226 American Health Packaging

2.5 Mg 60 Count ⮝

NDC-0527-1450-06

Dronabinol Capsules, USP CIII

2.5 mg

Rx Only

60 Capsules

Lannett

5 Mg 60 Count ⮝

NDC-0527-1451-06

Dronabinol Capsules, USP CIII

5 mg

Rx Only

60 Capsules

Lannett

10 Mg 60 Count ⮝

NDC-0527-1452-06

Dronabinol Capsules, USP CIII

10 mg

Rx Only

60 Capsules

Lannett

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0527-1450 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color RED Score no score Shape OVAL Size 9mm Flavor Imprint Code 2;5 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0527-1450-06 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/18/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201463 05/18/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0527-1451 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) FD&C RED NO. 40 (UNII: WZB9127XOA) FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics Color BROWN Score no score Shape OVAL Size 10mm Flavor Imprint Code 5 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0527-1451-06 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/18/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201463 05/18/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0527-1452 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 10 mg

Inactive Ingredients Ingredient Name Strength GELATIN (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color ORANGE Score no score Shape OVAL Size 13mm Flavor Imprint Code 10 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0527-1452-06 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/18/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201463 05/18/2018

Labeler - Lannett Company, Inc. (002277481)

Establishment
Name	Address	ID/FEI	Business Operations
Lannett Company, Inc.		829757603	ANALYSIS(0527-1450, 0527-1451, 0527-1452)

Establishment
Name	Address	ID/FEI	Business Operations
Swiss Caps AG		481784895	ANALYSIS(0527-1450, 0527-1451, 0527-1452) , MANUFACTURE(0527-1450, 0527-1451, 0527-1452)

Revised: 4/2018 Document Id: ba958bdc-ad35-4a82-aaaf-d69bcc221317 34391-3 Set id: 5752338a-dd73-415d-ba7e-9ca57fd47628 Version: 17 Effective Time: 20180430 Lannett Company, Inc.

Principal Display Panel - 2.5 Mg Capsule Bottle Label ⮝

NDC 42858-867-06
60 Capsules

Dronabinol
Capsules, USP
CIII

2.5 mg
Rx only

Dispense the accompanying
Medication Guide to each patient.

Principal Display Panel - 5 Mg Capsule Bottle Label ⮝

NDC 42858-868-06
60 Capsules

Dronabinol
Capsules, USP
CIII

5 mg
Rx only

Dispense the accompanying
Medication Guide to each patient.

Principal Display Panel - 10 Mg Capsule Bottle Label ⮝

NDC 42858-869-06
60 Capsules

Dronabinol
Capsules, USP
CIII

10 mg
Rx only

Dispense the accompanying
Medication Guide to each patient.

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42858-867 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength FD&C Yellow No. 6 (UNII: H77VEI93A8) Gelatin, unspecified (UNII: 2G86QN327L) Glycerin (UNII: PDC6A3C0OX) Water (UNII: 059QF0KO0R) Sesame Oil (UNII: QX10HYY4QV) Titanium dioxide (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Shellac (UNII: 46N107B71O) Isopropyl alcohol (UNII: ND2M416302) Butyl alcohol (UNII: 8PJ61P6TS3) Propylene glycol (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C Blue No. 1 (UNII: H3R47K3TBD) FD&C Red No. 40 (UNII: WZB9127XOA)

Product Characteristics Color WHITE (Opaque cream capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;867 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42858-867-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/26/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/26/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42858-868 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength FD&C Yellow No. 6 (UNII: H77VEI93A8) Gelatin, unspecified (UNII: 2G86QN327L) Glycerin (UNII: PDC6A3C0OX) Water (UNII: 059QF0KO0R) Sesame Oil (UNII: QX10HYY4QV) Titanium dioxide (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Shellac (UNII: 46N107B71O) Isopropyl alcohol (UNII: ND2M416302) Butyl alcohol (UNII: 8PJ61P6TS3) Propylene glycol (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C Blue No. 1 (UNII: H3R47K3TBD) FD&C Red No. 40 (UNII: WZB9127XOA)

Product Characteristics Color BROWN (Opaque brown capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;868 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42858-868-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/26/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/26/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42858-869 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 10 mg

Inactive Ingredients Ingredient Name Strength FD&C Yellow No. 6 (UNII: H77VEI93A8) Gelatin, unspecified (UNII: 2G86QN327L) Glycerin (UNII: PDC6A3C0OX) Water (UNII: 059QF0KO0R) Sesame Oil (UNII: QX10HYY4QV) Titanium dioxide (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) Shellac (UNII: 46N107B71O) Isopropyl alcohol (UNII: ND2M416302) Butyl alcohol (UNII: 8PJ61P6TS3) Propylene glycol (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color ORANGE (Opaque orange capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;869 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42858-869-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 06/26/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078292 06/26/2018

Labeler - Rhodes Pharmaceuticals L.P. (831928986)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmaceutics International, Inc		878265586	MANUFACTURE(42858-867, 42858-868, 42858-869)

Revised: 8/2018 Document Id: 5467a1be-b888-4f7c-9a62-5faf6c977b05 34391-3 Set id: 3c06ccda-4819-40f8-b2db-fa294bb8a2fa Version: 4 Effective Time: 20180816 Rhodes Pharmaceuticals L.P.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use dronabinol capsules safely and effectively. See full prescribing information for dronabinol capsules.
Dronabinol capsules, for oral use, CIII
Initial U.S. Approval: 1985

Indications And Usage ⮝

Dronabinol capsules is a cannabinoid indicated in adults for the treatment of:

• Anorexia associated with weight loss in patients with AIDS. (1)
• Nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. (1)

Dosage And Administration ⮝

Anorexia Associated with Weight Loss in Adult Patients with AIDS (2.1):

• The recommended adult starting dosage is 2.5 mg orally twice daily, one hour before lunch and dinner.
• See the full prescribing information for dosage titration to manage adverse reactions and to achieve desired therapeutic effect.

Nausea and Vomiting Associated with Chemotherapy in Adult Patients Who Failed Conventional Antiemetics (2.2):

• The recommended starting dosage is 5 mg/m2, administered 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day. Administer the first dose on an empty stomach at least 30 minutes prior to eating; subsequent doses can be taken without regard to meals.
• See the full prescribing information for dosage titration to manage adverse reactions and to achieve desired therapeutic effect.

Dosage Forms And Strengths ⮝

• Capsules: 2.5 mg, 5 mg, 10 mg (3)

Contraindications ⮝

• History of a hypersensitivity reaction to dronabinol or sesame oil (4)

Warnings And Precautions ⮝

• Neuropsychiatric Adverse Reactions: May cause psychiatric and cognitive effects and impair mental and/or physical abilities. Avoid use in patients with a psychiatric history. Monitor for symptoms and avoid concomitant use of drugs with similar effects. Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol capsules do not affect them adversely. (5.1)
• Hemodynamic Instability: Patients with cardiac disorders may experience hypotension, hypertension, syncope or tachycardia. Avoid concomitant use of drugs with similar effects and monitor for hemodynamic changes after initiating or increasing the dosage of dronabinol capsules. (5.2)
• Seizures and Seizure-like Activity: Weigh the potential risk versus benefits before prescribing dronabinol capsules to patients with a history of seizures, including those requiring anti-epileptic medication or with other factors that lower the seizure threshold. Monitor patients and discontinue if seizures occur. (5.3)
• Multiple Substance Abuse: Assess risk for abuse or misuse in patients with a history of substance abuse or dependence, prior to prescribing dronabinol capsules and monitor for the development of associated behaviors or conditions. (5.4)
• Paradoxical Nausea, Vomiting, or Abdominal Pain: Consider dose reduction or discontinuation, if worsening of symptoms while on treatment. (5.5)

Adverse Reactions ⮝

• Most common adverse reactions ( 3%) are: abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, thinking abnormal and vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (1-877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Inhibitors and inducers of CYP2C9 and CYP3A4: May alter dronabinol systemic exposure; monitor for potential dronabinol-related adverse reactions or loss of efficacy. (7.3)
• Highly protein-bound drugs: Potential for displacement of other drugs from plasma proteins; monitor for adverse reactions to concomitant highly protein-bound drugs and narrow therapeutic index drugs (e.g., warfarin, cyclosporine, amphotericin B) when initiating or increasing the dosage of dronabinol capsules. (7.4)

Use In Specific Populations ⮝

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Advise HIV-infected women not to breastfeed. Advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with dronabinol capsules and for 9 days after the last dose. (8.2)
• Geriatric Use: Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects. Consider a lower starting dose in elderly patients. (2.1, 2.2, 5.1, 5.2, 8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2017

1 Indications And Usage ⮝

Dronabinol capsules are indicated in adults for the treatment of:

• anorexia associated with weight loss in patients with Acquired Immune Deficiency Syndrome (AIDS).
• nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

2 Dosage And Administration ⮝

2.1 Anorexia Associated with Weight Loss in Adult Patients with AIDS

Starting Dosage

The recommended adult starting dosage of dronabinol capsules is 2.5 mg orally twice daily, one hour before lunch and dinner.

In elderly patients or patients unable to tolerate 2.5 mg twice daily, consider initiating dronabinol capsules at 2.5 mg once daily one hour before dinner or at bedtime to reduce the risk of central nervous system (CNS) symptoms [see Use in Specific Populations (8.5)].

Dosing later in the day may reduce the frequency of CNS adverse reactions. CNS adverse reactions are dose-related [see Warnings and Precautions (5.1)]; therefore monitor patients and reduce the dosage as needed. If CNS adverse reactions of feeling high, dizziness, confusion, and somnolence occur, they usually resolve in 1 to 3 days and usually do not require dosage reduction. If CNS adverse reactions are severe or persistent, reduce the dosage to 2.5 mg in the evening or at bedtime.

Dosage Titration

If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.5 mg one hour before lunch and 5 mg one hour before dinner. Increase the dose of dronabinol capsules gradually in order to reduce the frequency of dose-related adverse reactions [see Warnings and Precautions (5.1)].

Most patients respond to 2.5 mg twice daily, but the dose may be further increased to 5 mg one hour before lunch and 5 mg one hour before dinner, as tolerated to achieve a therapeutic effect.

Maximum Dosage: 10 mg twice daily.

2.2 Nausea and Vomiting Associated with Cancer Chemotherapy in Adult Patients Who Failed Conventional Antiemetics

Starting Dosage

The recommended starting dosage of dronabinol capsules is 5 mg/m2, orally administered 1 to 3 hours prior to the administration of chemotherapy and then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day.

In elderly patients, consider initiating dronabinol capsules at 2.5 mg/m2 once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS symptoms [see Use in Specific Populations (8.5)].

Administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals [see Clinical Pharmacology (12.3)].

The timing of dosing in relation to meal times should be kept consistent for each chemotherapy cycle, once the dosage has been determined from the titration process.

Dosage Titration

The dosage can be titrated to clinical response during a chemotherapy cycle or subsequent cycles, based upon initial response, as tolerated to achieve a clinical effect, in increments of 2.5 mg/m2.

The maximum dosage is 15 mg/m2 per dose for 4 to 6 doses per day.

Adverse reactions are dose-related and psychiatric symptoms increase significantly at the maximum dosage [see Warnings and Precautions (5.1)].

Monitor patients for adverse reactions and consider decreasing the dose to 2.5 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

3 Dosage Forms And Strengths ⮝

Dronabinol capsules are supplied as round, soft gelatin capsules for oral use as follows:

• 2.5 mg white capsules (Identified UM)
• 5 mg dark brown capsules (Identified UM)
• 10 mg orange capsules (Identified UM)

4 Contraindications ⮝

Dronabinol capsules are contraindicated in patients with a history of a hypersensitivity reaction to dronabinol or sesame oil. Reported hypersensitivity reactions to dronabinol capsules include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing and throat tightness [see Adverse Reactions (6.2)].

5 Warnings And Precautions ⮝

5.1 Neuropsychiatric Adverse Reactions

Psychiatric Adverse Reactions

Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Significant CNS symptoms followed oral doses of 0.4 mg/kg (28 mg per 70 kg patient) of dronabinol capsules in antiemetic studies.

Prior to initiating treatment with dronabinol capsules, screen patients for a history of these illnesses. Avoid use in patients with a psychiatric history or, if the drug cannot be avoided, monitor patients for new or worsening psychiatric symptoms during treatment. Also, avoid concomitant use with other drugs that are associated with similar psychiatric effects.

Cognitive Adverse Reactions

Use of dronabinol capsules has been associated with cognitive impairment and altered mental state. Reduce the dose of dronabinol capsules or discontinue use of dronabinol capsules if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of dronabinol capsules [see Use in Specific Populations (8.4, 8.5)].

Hazardous Activities

Dronabinol capsules can cause and may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery. Concomitant use of other drugs that cause dizziness, confusion, sedation, or somnolence such as CNS depressants may increase this effect (e.g., barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol capsules do not affect them adversely.

5.2 Hemodynamic Instability

Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking dronabinol capsules [see Clinical Pharmacology (12.2)]. Patients with cardiac disorders may be at higher risk. Avoid concomitant use of other drugs that are also associated with similar cardiac effects (e.g., amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, desipramine, other tricyclic antidepressants). Monitor patients for changes in blood pressure, heart rate, and syncope after initiating or increasing the dosage of dronabinol capsules.

5.3 Seizures

Seizure and seizure-like activity have been reported in patients receiving dronabinol.

Weigh this potential risk against the benefits before prescribing dronabinol capsules to patients with a history of seizures, including those receiving anti-epileptic medication or with other factors that can lower the seizure threshold. Monitor patients with a history of seizure disorders for worsened seizure control during dronabinol capsules therapy.

If a seizure occurs, advise patients to discontinue dronabinol capsules and contact a healthcare provider immediately.

5.4 Multiple Substance Abuse

Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse dronabinol capsules as well.

Assess each patient s risk for abuse or misuse prior to prescribing dronabinol capsules and monitor patients with a history of substance abuse during treatment with dronabinol capsules for the development of these behaviors or conditions.

5.5 Paradoxical Nausea, Vomiting, or Abdominal Pain

Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9-tetrahydrocannabinol (delta-9-THC), the active ingredient in dronabinol capsules. In some cases, these adverse reactions were severe (e.g., dehydration, electrolyte abnormalities) and required dose reduction or drug discontinuation. Symptoms are similar to cannabinoid hyperemesis syndrome (CHS), which is described as cyclical events of abdominal pain, nausea, and vomiting in chronic, long-term users of delta-9-THC products.

Because patients may not recognize these symptoms as abnormal, it is important to specifically ask patients or their caregivers about the development of worsening of nausea, vomiting, or abdominal pain while being treated with dronabinol capsules. Consider dose reduction or discontinuing dronabinol capsules if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

6 Adverse Reactions ⮝

6.1 Clinical Trials Experience

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

The following serious adverse reactions are described below and elsewhere in the labeling.

• Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.1)]
• Hemodynamic Instability [see Warnings and Precautions (5.2)]
• Seizures [see Warnings and Precautions (5.3)]
• Paradoxical Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions (5.5)]

Studies of AIDS-related weight loss included 157 patients receiving dronabinol capsules at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol capsules and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to dronabinol capsules in studies.

Studies of different durations were combined by considering the first occurrence of events during the first 28 days.

A cannabinoid dose-related high (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a CNS adverse reaction during the first 2 weeks and about 4% reported such a reaction each week for the next 6 weeks thereafter.

Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence greater than 1%.

System Organ Class	Adverse Reactions
General	Asthenia
Cardiovascular	Palpitations, tachycardia, vasodilation/facial flush
Gastrointestinal	Abdominal pain*, nausea*, vomiting*
Central Nervous System	Dizziness*, euphoria*, paranoid reaction*, somnolence*, thinking abnormal*, amnesia, anxiety/nervousness, ataxia, confusion, depersonalization, hallucination
* Actual incidence 3% to 10%

Less Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence less than or equal to 1%.

System Organ Class	Adverse Reactions
General	Chills, headache, malaise
Cardiovascular	Hypotension, conjunctival injection [see Clinical Pharmacology (12.2)]
Gastrointestinal	Diarrhea, fecal incontinence, anorexia, hepatic enzyme elevation
Musculoskeletal	Myalgias
Central Nervous System	Depression, nightmares, speech difficulties, tinnitus
Respiratory	Cough, rhinitis, sinusitis
Skin	Flushing, sweating
Sensory	Vision difficulties

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dronabinol capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Fatigue

Hypersensitivity reactions: Lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness [see Contraindications (4)]

Injury, poisoning and procedural complications: Fall [see Use in Specific Populations (8.5)]

Nervous system disorders: Seizures [see Warnings and Precautions (5.3)], disorientation, movement disorder, loss of consciousness

Psychiatric disorders: Delirium, insomnia, panic attack

Vascular disorders: Syncope [see Warnings and Precautions (5.2)]

7 Drug Interactions ⮝

7.1 Additive CNS Effects

Additive CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when dronabinol capsules are taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants [see Warnings and Precautions (5.1)].

7.2 Additive Cardiac Effects

Additive cardiac effects (e.g., hypotension, hypertension, syncope, tachycardia) may occur when dronabinol capsules are taken concomitantly with drugs that have similar effects on the cardiovascular system [see Warnings and Precautions (5.2)].

7.3 Effect of Other Drugs on Dronabinol

Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes based on published in vitro studies. Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of dronabinol and/or its active metabolite resulting in an increase in dronabinol-related adverse reactions or loss of efficacy of dronabinol capsules.

Monitor for potentially increased dronabinol-related adverse reactions when dronabinol capsules are co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

7.4 Highly Protein-Bound Drugs

Dronabinol is highly bound to plasma proteins, and therefore, might displace and increase the free fraction of other concomitantly administered protein-bound drugs.

Although this displacement has not been confirmed in vivo, monitor patients for increased adverse reactions to narrow therapeutic index drugs that are highly protein bound (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of dronabinol capsules.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Dronabinol capsules, a synthetic cannabinoid, may cause fetal harm. Avoid use of dronabinol capsules in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) during pregnancy has been associated with adverse fetal/neonatal outcomes [see Clinical Considerations]. Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol at up to 30 times the MRHD (maximum recommended human dose) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses which induced maternal toxicity. In published studies, offspring of pregnant rats administered delta-9-THC during and after organogenesis have been reported to exhibit neurotoxicity with adverse effects on brain development, including abnormal neuronal connectivity and impairments in cognitive and motor function [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the NICU, and stillbirth. Therefore, use of cannabis during pregnancy should be avoided.

Data

Human Data

Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy. The effects of delta-9-THC on the fetus are not known.

Animal Data

Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 1 to 30 times the MRHD of 15 mg/m2/day in AIDS patients or 0.2 to 5 times the MRHD of 90 mg/m2/day in cancer patients, and in rats at 74 to 295 mg/m2 (equivalent to 5 to 20 times the MRHD of 15 mg/m2/day in AIDS patients or 0.8 to 3 times the MRHD of 90 mg/m2/day in cancer patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses that produced less maternal toxicity.

Review of published literature indicates that the endocannabinoid system plays a role in neurodevelopmental processes such as neurogenesis, migration, and synaptogenesis. Exposure of pregnant rats to delta-9-THC (during and after organogenesis) may modulate these processes to result in abnormal patterns of neuronal connectivity and subsequent cognitive impairments in the offspring. Nonclinical toxicity studies in pregnant rats and newborn pups have shown prenatal exposure to THC that resulted in impairment of motor function, alteration in synaptic activity, and interference in cortical projection of neuron development in the offspring. Prenatal exposure has shown effects on cognitive function such as learning, short-and long-term memory, attention, decreased ability to remember task, and ability to discriminate between novel and same objects. Overall, prenatal exposure to THC has resulted in significant and long-term changes in brain development, cognition, and behavior in rat offspring.

8.2 Lactation

Risk Summary

For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving dronabinol capsules.

For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. Because of the possible adverse effects from dronabinol capsules on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with dronabinol capsules and for 9 days after the last dose.

8.4 Pediatric Use

The safety and effectiveness of dronabinol capsules have not been established in pediatric patients.

Pediatric patients may be more sensitive to neurological and psychoactive effects of dronabinol capsules [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies of dronabinol capsules in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of dronabinol capsules [see Warnings and Precautions (5.1, 5.2)].

Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with dronabinol capsules [see Warnings and Precautions (5.1)]. These patients should be monitored closely and placed on fall precautions prior to initiating dronabinol capsule therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and of concomitant disease or other drug therapy [see Dosage and Administration (2.1, 2.2)].

8.6 Effect of CYP2C9 Polymorphism

Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in the presence of CYP2C9 genetic polymorphism. Monitoring for potentially increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function [see Clinical Pharmacology (12.5)].

9 Drug Abuse And Dependence ⮝

9.1 Controlled Substance

Dronabinol capsules are a Schedule III controlled substance.

9.2 Abuse

Dronabinol capsules contains dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia.

In an open-label study in patients with AIDS who received dronabinol capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

Patients should be instructed to keep dronabinol capsules in a secure place out of reach of others for whom the medication has not been prescribed.

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with dronabinol capsules, and develops after chronic abuse of marijuana.

A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include hot flashes, sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours.

Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

10 Overdosage ⮝

Signs and symptoms of dronabinol overdosage include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety, and seizures may occur in patients with existing seizure disorders.

It is not known if dronabinol can be removed by dialysis in cases of overdose.

If over-exposure of dronabinol capsules occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 Description ⮝

Dronabinol is a cannabinoid designated chemically as (6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-1-ol. Dronabinol has the following empirical and structural formulas:

C21H30O2 (molecular weight = 314.46)

Dronabinol, the active ingredient in dronabinol capsules, USP, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Each dronabinol capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, and titanium dioxide; 5 mg capsule contains iron oxide red and iron oxide black, gelatin, glycerin, sesame oil, and titanium dioxide; 10 mg capsule contains iron oxide red and iron oxide yellow, gelatin, glycerin, sesame oil, and titanium dioxide.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Dronabinol is an orally active cannabinoid which has complex effects on the CNS, including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol.

12.2 Pharmacodynamics

Effects on the Cardiovascular System

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing [see Warnings and Precautions (5.2)].

Effects on the Central Nervous System

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter patient variability. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 210 mg per day of dronabinol capsules, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol capsules. In clinical studies involving AIDS patients, the appetite stimulant effect of dronabinol capsules was sustained for up to five months at dosages ranging from 2.5 mg to 20 mg per day.

12.3 Pharmacokinetics

Absorption

Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Concentrations of both parent drug and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.

The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day) have been studied in healthy subjects.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Subjects (n=34; 20-45 years) under Fasted Conditions

Mean (SD) PK Parameter Values
Twice Daily Dose	Cmax ng/mL	Median Tmax (range), hr	AUC(0-12) ng hr/mL
2.5 mg	1.32 (0.62)	1.00 (0.50-4.00)	2.88 (1.57)
5 mg	2.96 (1.81)	2.50 (0.50-4.00)	6.16 (1.85)
10 mg	7.88 (4.54)	1.50 (0.50-3.50)	15.2 (5.52)
Cmax: maximum observed plasma concentration; Tmax: time to maximum observed plasma concentration; AUC(0-12): area under the plasma concentration-time curve from 0 to 12 hours.

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Effect of Food: In a published study, the effect of food on the pharmacokinetics of dronabinol was studied by concomitant dosing of dronabinol capsules with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed, resulting in a 4-hour delay in mean Tmax and 2.9-fold increase in total exposure (AUCinf), but Cmax was not significantly changed [see Dosage and Administration (2.2)].

Distribution

Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97% [see Drug Interactions (7.4)].

Elimination

The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Metabolism

Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite [see Clinical Pharmacology (12.5)].

Excretion

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Due to its re distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Drug Interaction Studies

Formal drug-drug interaction studies have not been conducted with dronabinol.

The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood.

Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol [see Warnings and Precautions (5.1)].

12.5 Pharmacogenomics

Published data indicate a potentially 2-to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies, there was no evidence of carcinogenicity in rats at doses up to 50 mg/kg/day dronabinol (approximately 20 times the MRHD in AIDS patients on a body surface area basis) or in mice at doses up to 500 mg/kg/day (approximately 100 times the MRHD in AIDS patients on a body surface area basis).

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. However, dronabinol produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 2 to 10 times the MRHD of 15 mg/m2/day in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m2/day in cancer patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success, and testosterone levels were not affected. The significance of these animal findings in humans is not known.

14 Clinical Studies ⮝

The effectiveness of dronabinol capsules has been established based on studies for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

14.1 Appetite Stimulation

The appetite stimulant effect of dronabinol capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before dinner. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinol capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol capsules and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol capsules and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

16 How Supplied/storage And Handling ⮝

Dronabinol Capsules, USP

2.5 mg white capsules (Identified UM).
NDC 67877-568-60 (Bottle of 60 capsules).

5 mg dark brown capsules (Identified UM).
NDC 67877-569-60 (Bottle of 60 capsules).

10 mg orange capsules (Identified UM).
NDC 67877-570-60 (Bottle of 60 capsules).

Storage Conditions

Dronabinol capsules should be packaged in a well-closed container and stored in a cool environment between 8 and 15 C (46 and 59 F) and alternatively could be stored in a refrigerator. Protect from freezing.

Package/label Display Panel Carton 2.5 Mg ⮝

NDC 60687- 375-01

Dronabinol
Capsules, USP CIII

2.5 mg

100 Capsules (10 x 10) Rx Only

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

Each Capsule Contains:
Dronabinol, USP................................................................2.5 mg

Usual Dosage: See package insert for full prescribing
information.

Store in a refrigerator 2 to 8 C (36 to 46 F).

Protect from freezing.

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 # 42858-867, Rhodes Pharmaceuticals L.P.

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

737501
0437501/0918

Package/label Display Panel Blister 2.5 Mg ⮝

Dronabinol
Capsule, USP CIII

2.5 mg

Package/label Display Panel Carton 5 Mg ⮝

NDC 60687- 386-21

Dronabinol
Capsules, USP CIII

5 mg

30 Capsules (3 x 10) Rx Only

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

Each Capsule Contains:
Dronabinol, USP............................................................... 5 mg

Usual Dosage: See package insert for full prescribing
information.

Store in a refrigerator 2 to 8 C (36 to 46 F).

Protect from freezing.

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 # 42858-868, Rhodes Pharmaceuticals L.P.

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

738621
0438621/0918

Package/label Display Panel Blister 5 Mg ⮝

Dronabinol
Capsule, USP CIII

5 mg

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-375(NDC:42858-867) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 2.5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color white (Opaque cream capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;867 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-375-01 100 in 1 BOX, UNIT-DOSE 07/16/2018 1 NDC:60687-375-11 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 ANDA078292 07/16/2018

DRONABINOL dronabinol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-386(NDC:42858-868) Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DRONABINOL (UNII: 7J8897W37S) (DRONABINOL - UNII:7J8897W37S) DRONABINOL 5 mg

Inactive Ingredients Ingredient Name Strength FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) SESAME OIL (UNII: QX10HYY4QV) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color brown (Opaque brown capsules) Score no score Shape CAPSULE (oblong softgel) Size 12mm Flavor Imprint Code RP;868 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-386-21 30 in 1 BOX, UNIT-DOSE 08/09/2018 1 NDC:60687-386-11 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 ANDA078292 08/09/2018

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(60687-375, 60687-386)

Revised: 9/2018 Document Id: 76630974-7c55-067e-e053-2a91aa0afac6 34391-3 Set id: 35e04467-d429-4fe8-a7d8-b9d8f8376b5b Version: 3 Effective Time: 20180921 American Health Packaging