DRONABINOL: 1,740 Adverse Event Reports & Safety Profile

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

AND USAGE Dronabinol oral solution is 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 oral solution 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 )

AND ADMINISTRATION Administration ( 2.1 ): Always use the enclosed calibrated oral dosing syringe. The calibrated oral syringe measures a maximum dronabinol oral solution dose of 5 mg. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Take dronabinol oral solution with a full glass of water (6 to 8 ounces). Dronabinol oral solution can be administered via silicone enteral feeding tubes.

Anorexia

Associated with Weight Loss in Adult Patients with AIDS ( 2.2 ): The recommended starting dosage is 2.1 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 ( 2.3 ): The recommended starting dosage is 4.2 mg/m 2 , administered 1 to 3 hours prior to 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 Important Administration Instructions Oral Administration Always use the enclosed calibrated oral dosing syringe when administering dronabinol oral solution to ensure the dose is measured and administered accurately. The calibrated oral syringe measures a maximum dronabinol oral solution dose of 5 mg. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Take each dose of dronabinol oral solution with a full glass of water (6 to 8 ounces). For information on dosing dronabinol oral solution with regard to meals, see Dosage and Administration 2.2 and 2.3 . Administration via Feeding Tube (silicone only, greater than or equal to 14 French) Dronabinol oral solution can be administered via enteral feeding tubes that are manufactured using silicone, size greater than or equal to 14 French, such as Naso-Gastric (NG), Gastrostomy Tube (G-tube), Percutaneous Endoscopic Gastrostomy tube (PEG-tube) and Gastro-Jejunostomy tube (GJ-tube). Do not use tubes manufactured of polyurethane. Draw up the prescribed dose with the calibrated dosing syringe packaged with dronabinol oral solution. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Using the calibrated dosing syringe, administer the dose via the feeding tube. Using a catheter-tip syringe, flush the feeding tube with 30 mL of water.

2.2 Anorexia Associated with Weight Loss in Adult Patients with AIDS Starting Dosage The recommended adult starting dosage of dronabinol oral solution is 2.1 mg orally twice daily, one hour before lunch and one hour before dinner. In elderly patients, or patients unable to tolerate 2.1 mg twice daily, consider initiating dronabinol oral solution at 2.1 mg once daily one hour before dinner or at bedtime to reduce the risk of central nervous system (CNS) symptoms <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span>. Dosing later in the day may reduce the frequency of Central Nervous System (CNS) adverse reactions. CNS adverse reactions are dose-related <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> ; 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 2.1 mg once daily one hour before dinner or in the evening at bedtime.

Dosage

Titration If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.1 mg one hour before lunch and 4.2 mg one hour before dinner. Increase the dose of dronabinol oral solution gradually in order to reduce the frequency of dose-related adverse reactions [see Warnings and Precautions (5.1) ]. Most patients respond to 2.1 mg twice daily, but the dose may be further increased to 4.2 mg one hour before lunch and 4.2 mg one hour before dinner, as tolerated to achieve a therapeutic effect.

Maximum

Dosage: 8.4 mg twice daily.

2.3 Nausea and Vomiting Associated with Cancer Chemotherapy in Adult Patients Who Failed Conventional Antiemetics Starting Dosage The recommended starting dosage of dronabinol oral solution is 4.2 mg/m 2 orally administered 1 to 3 hours prior to chemotherapy and then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses per day. Calculate the starting dose by following the steps below: Starting dose (mg) = Patient body surface area (BSA) in m 2 multiplied by 4.2 mg/m 2 Round dose to the nearest 0.1 mg increment Convert from milligrams (mg) to milliliters (mL): Starting dose (mg) rounded to the nearest 0.1 mg increment divided by 5 = Starting dose in milliliters (mL) To correspond with the calibrated oral dosing syringe, the dose may need to be rounded to the nearest 0.1 mL increment. In elderly patients, consider initiating dronabinol oral solution at 2.1 mg/m 2 once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS symptoms <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> . Because food delays the absorption of dronabinol oral solution, administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals. Because food can substantially change the systemic exposure to dronabinol and its active metabolite, 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 effect, as tolerated to achieve a clinical effect, in increments of 2.1 mg/m 2 .

Maximum

Dosage: 12.6 mg/m 2 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 2.1 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

Dronabinol oral solution is contraindicated in patients: with a history of a hypersensitivity reaction to dronabinol. Reported hypersensitivity reactions to dronabinol include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness [see Adverse Reactions ( 6.2 )] . with a history of a hypersensitivity reaction to alcohol. who are receiving, or have recently received, disulfiram- or metronidazole-containing products within 14 days [see Warning and Precautions ( 5.3 )] . Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Sensitivity to dronabinol or alcohol. ( 4 ) History of hypersensitivity reaction to alcohol. ( 4 ) Patients receiving, or have received, disulfiram- or metronidazole-containing products within the past 14 days. ( 4 , 5.3 , 7.1 )

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 Wellhouse Pharma, LLC at 1-844-558-8289 or FDA at MedWatch phone number 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 ( 5.4 )]

Paradoxical

Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions ( 5.6 )] Toxicity in Preterm Neonates [see Warnings and Precautions ( 5.7 )] The safety of dronabinol oral solution has been established based on studies of dronabinol capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol capsules 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 adverse reactions 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 of dronabinol capsules 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 of dronabinol capsules 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 another oral formulation of dronabinol. 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Injury, poisoning and procedural complications : fall <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 )]</span> . Nervous system disorders: seizures <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> , disorientation, movement disorder, loss of consciousness. Psychiatric disorders: delirium, insomnia, panic attack. Vascular disorders: syncope <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>.

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 oral solution does 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 oral solution. ( 5.2 ) Interaction with Disulfiram and Metronidazole : May cause disulfiram-like reaction. Discontinue products containing disulfiram or metronidazole at least 14 days before and do not administer 7 days after treatment with dronabinol oral solution. ( 4 , 5.3 , 7.1 ) Seizures and Seizure-like Activity : Weigh the potential risk versus benefits before prescribing dronabinol oral solution 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. ( 5.4 )

Multiple Substance

Abuse : Assess risk for abuse or misuse in patients with a history of substance abuse or dependence, prior to prescribing dronabinol oral solution and monitor for the development of associated behaviors or conditions. ( 5.5 )

Paradoxical

Nausea, Vomiting, or Abdominal Pain : Consider dose reduction or discontinuation, if worsening of symptoms while on treatment. ( 5.6 )

Toxicities

Related to Propylene Glycol in Preterm Neonates : The safety and effectiveness of dronabinol oral solution have not been established in pediatric patients. Avoid use in preterm neonates in the immediate postnatal period. ( 5.7 )

5.1 Neuropsychiatric Adverse Reactions Psychiatric Adverse Reactions Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Prior to initiating treatment with dronabinol oral solution, 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 oral solution has been associated with cognitive impairment and altered mental state. Reduce the dose of dronabinol oral solution or discontinue use dronabinol oral solution if signs or symptoms of cognitive impairment develop. Elderly and pediatric patients may be more sensitive to the neurological and psychoactive effects of dronabinol oral solution [see Use in Specific Populations ( 8.4 , 8.5 )] .

Hazardous Activities

Dronabinol oral solution 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, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, and muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol oral solution does not affect them adversely.

5.2 Hemodynamic Instability Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking dronabinol oral solution <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 oral solution.

5.3 Interaction with Disulfiram and Metronidazole Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Use of dronabinol oral solution may cause a disulfiram-like reaction, characterized by abdominal cramps, nausea, vomiting, headaches, and flushing, in patients receiving disulfiram or other drugs that produce this reaction (e.g., metronidazole). Discontinue products containing disulfiram or metronidazole at least 14 days before starting treatment with dronabinol oral solution and do not administer these products within 7 days of completing treatment with dronabinol oral solution <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7.3) ]</span> . When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. However, the contribution of propylene glycol, if any, to the interaction between disulfiram and dronabinol oral solution is unknown.

5.4 Seizures Seizures and seizure-like activity have been reported in patients receiving dronabinol. Weigh this potential risk against the benefits before prescribing dronabinol oral solution 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 oral solution therapy. If a seizure occurs, advise patients to discontinue dronabinol oral solution and contact a healthcare provider immediately.

5.5 Multiple Substance Abuse Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse dronabinol oral solution as well. Dronabinol oral solution contains 50% (w/w) dehydrated alcohol. Assess each patient’s risk for abuse or misuse prior to prescribing dronabinol oral solution and monitor patients with a history of substance abuse during treatment with dronabinol oral solution for the development of these behaviors or conditions.

5.6 Paradoxical Nausea, Vomiting, or Abdominal Pain New or worsening nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9 tetrahydrocannabinol (delta-9-THC), the active ingredient in dronabinol oral solution . 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 or worsening of nausea, vomiting, or abdominal pain while being treated with dronabinol oral solution. Consider dose reduction or discontinuing dronabinol oral solution if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

5.7 Toxicity in Preterm Neonates Dronabinol oral solution contains the excipients dehydrated alcohol (50%, w/w) and propylene glycol (5.5%, w/w). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. Preterm neonates may be at increased risk of propylene glycol-associated adverse reactions due to a diminished ability to metabolize propylene glycol, thereby, leading to accumulation. The safety and effectiveness of dronabinol oral solution have not been established in pediatric patients. Avoid dronabinol oral solution in preterm neonates in the immediate postnatal period because of possible propylene glycol-associated toxicities including: hyperosmolarity, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias, electrocardiogram (ECG) changes, and hemolysis.

INTERACTIONS Inhibitors and Inducers of CYP2C9 and CYP3A4 : May alter dronabinol systemic exposure; monitor for dronabinol-related adverse reactions or loss of efficacy. ( 7.2 )

Highly

Protein-Bound Drugs : Potential for displacement of other drugs from plasma proteins; monitor for adverse reactions to concomitant narrow therapeutic index drugs (e.g., warfarin, cyclosporine, or amphotericin B) when initiating or increasing the dosage of dronabinol oral solution. ( 7.3 )

7.1 Disulfiram and Metronidazole Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). Discontinue products containing disulfiram or metronidazole at least 14 days before starting treatment with dronabinol oral solution and do not administer these products within 7 days of completing treatment with dronabinol oral solution <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )]</span> . When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. However, the contribution of propylene glycol, if any, to the interaction between disulfiram and dronabinol oral solution is unknown.

7.2 Effect of Other Drugs on Dronabinol Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes. 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 oral solution. Monitor for increased dronabinol-related adverse reactions when dronabinol oral solution is co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

7.3 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 (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of dronabinol oral solution.