Dronabinol

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. 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 )

2 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/m 2 , 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. 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 M2) • 5 mg dark brown capsules (Identified M5) • 10 mg orange capsules (Identified MX) • Capsules: 2.5 mg, 5 mg, 10 mg ( 3 )

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

6 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 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 a …

7 DRUG INTERACTIONS I nh ibitors and inducers of CYP2C9 and CYP3A4 : May alter dronabinol systemic exposure; monitor for potential dronabinol-related adverse reactions or loss of efficacy. (7.3 ) H ighly 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 ) 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 Pr eg n ancy : May cause fetal harm. ( 8.1 ) L actation : Advise HIV-infected women not to breastfeed due to the potential for HIV transmission. Weight should be monitored in breastfed infants of mothers with nausea and vomiting associated with cancer chemotherapy in whom breastfeeding is appropriate. (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 ) 8.1 Pregnancy Risk Summary Dronabinol, 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 (delta-9-THC) 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 rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity including adverse clinical signs, increased stillbirths and mortality of offspring, and reduced pup bodyweight at 2 and 6 times the MRHD for patients with AIDS, and less than or equal to the MRHD for patients with cancer. No evidence of neurodevelopmental adverse effects was observed in the offspring at doses up to 6 times the MRHD for patients with AIDS, and up to the MRHD for patients with cancer (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 neonatal intensive care unit, 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/m 2 , equivalent to 1 to 30 times the MRHD of 15 mg/m 2 /day in patients with AIDS or 0.2 to 5 times the MRHD of 90 mg/m 2 /day in patients with cancer, and in rats at 74 to 295 mg/m 2 (equivalent to 5 to 20 times the MRHD of 15 mg/m 2 /day in patients with AIDS or 0.8 to 3 times the MRHD of 90 mg/m 2 /day in patients with cancer). These studies have revealed no evidence of teratogenicity due to delta-9-THC. At these dronabinol dosages in mice and rats, delta-9-THC 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 lowe …

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.

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: C 21 H 30 O 2 (molecular weight = 314.46) Dronabinol, the active ingredient in dronabinol capsules, USP, is synthetic delta-9­ tetrahydrocannabinol (delta-9-THC). Dronabinol is colorless to yellow-brown 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. Dronabinol capsules, USP are supplied as round, soft gelatin capsules containing either 2.5 mg, 5 mg or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: gelatin, glycerin, titanium dioxide, butylated hydroxytoluene, isopropyl alcohol, propylene glycol, hypromellose, medium chain triglyceride, lecithin and sesame oil. The 2.5 mg and 10 mg capsules also contain FD &C yellow no.6, FD&C red no. 40. The 2.5 mg capsule also contain FD&C blue no.1. The 5 mg and 10 mg capsule also contains ferrosoferric oxide. struct

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Dronabinol capsules, USP (dronabinol solution in sesame oil in soft gelatin capsules) 2.5 mg capsules are supplied as brown to dark brown, round capsules containing clear to light yellow liquid printed with “A” sign in white ink. NDC 31722-960-60 (Bottle of 60 capsules). 5 mg capsules are supplied as white to off white round capsules containing clear to light yellow liquid printed with “A” sign in black ink. NDC 31722-961-60 (Bottle of 60 capsules). 10 mg capsules are supplied as pink round capsules containing clear to light yellow liquid printed with “A” sign in black ink. NDC 31722-962-60 (Bottle of 60 capsules). Storage Conditions Dronabinol capsules should be packaged in a well-closed container and stored in a cool environment between 2° and 8°C (36° and 46°F) and alternatively could be stored in a refrigerator. Protect from freezing.