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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]
- Hemodynamic Instability [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Paradoxical Nausea, Vomiting, and Abdominal Pain [see WARNINGS AND PRECAUTIONS]
- Toxicity in Preterm Neonates [see WARNINGS AND PRECAUTIONS]
The safety of SYNDROS 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%.
|System Organ Class||Adverse Reactions|
|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%|
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]|
|Gastrointestinal||Diarrhea, fecal incontinence, anorexia, hepatic enzyme elevation|
|Central Nervous System||Depression, nightmares, speech difficulties, tinnitus|
|Respiratory||Cough, rhinitis, sinusitis|
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 [see CONTRAINDICATIONS].
Injury, poisoning and procedural complications: fall [see Use in Specific Populations].
Nervous system disorders: seizures [see WARNINGS AND PRECAUTIONS], disorientation, movement disorder, loss of consciousness.
Psychiatric disorders: delirium, insomnia, panic attack.
Vascular disorders: syncope [see WARNINGS AND PRECAUTIONS].
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.
PharmacodynamicsEffects 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].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 capsules have 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 cardiovascular and CNS 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 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules 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. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months.
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. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions [see DOSAGE AND ADMINISTRATION]. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter-and intra-subject variability in dronabinol pharmacokinetics (Cmax and AUCinf) was approximately 66% and 47% and 67% and 14%, respectively, following administration of SYNDROS to healthy subjects.
Table 2: Summary of Single-Dose Pharmacokinetic Parameters of Dronabinol After Replicated Oral Administration of SYNDROS (4.2 mg to Healthy Subjects under Fasted Conditions)
|Cmax (ng/mL)||1.9 ± 1.3|
|Tmax (h)||1.0 [0.5 to 4.0]|
|AUC(inf) (ng•h/mL)||3.8 ± 1.8|
|t½ (h)||5.6 ± 2.7|
|* Arithmetic mean ± standard deviation except Tmax for which the median [range] is reported|
Food Effect: The effect of food on the pharmacokinetics of SYNDROS was studied by concomitant dosing of SYNDROS 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: food resulted in approximately a 2.5-fold increase in total exposure (AUCinf) and approximately a 5 hour delay in median Tmax. Food also decreased Cmax by approximately 20% [see DOSAGE AND ADMINISTRATION]).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].Elimination
The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 5 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.
Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. The major metabolite (11-hydroxy-delta-9-THC) is pharmacologically active. 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].
Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion 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 for prolonged periods of time. Following single dose administration, 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].
Published data indicate a 2-to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.
The effectiveness of SYNDROS has been established based on studies of dronabinol capsules 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.
What do I need to tell my doctor BEFORE I take Syndros?
- If you have an allergy to this medicine (Syndros) or any part of this medicine.
- If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
- If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine (Syndros) like certain cough or cold remedies, diet pills, drugs for mental or mood problems, or stimulants like amphetamine. There are many drugs that must not be taken with this drug.
- If you have an allergy to alcohol or you have taken disulfiram or metronidazole within the past 2 weeks. Taking this medicine within 2 weeks after taking disulfiram or metronidazole may cause cramps, upset stomach or throwing up, headaches, and flushing.
- If you are pregnant or may be pregnant. Do not take this medicine (Syndros) if you are pregnant.
- If you are breast-feeding. Do not breast-feed while you take this medicine. You may also need to avoid breast-feeding for some time after your last dose. Talk with your doctor to see if you need to avoid breast-feeding after your last dose.
This is not a list of all drugs or health problems that interact with this medicine (Syndros).
Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take Syndros?
- Tell all of your health care providers that you take this medicine (Syndros). This includes your doctors, nurses, pharmacists, and dentists.
- Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
- To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
- High or low blood pressure can happen after this medicine (Syndros) is started or after the dose is raised. Changes in blood pressure may raise the chance of falling. Older people and people with heart problems may have a higher chance of changes in blood pressure and falling. Talk with the doctor.
- Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
- Avoid drinking alcohol while taking this medicine.
- Do not smoke or use other forms of cannabis (marijuana) while taking this medicine (Syndros). Talk with your doctor.
- Talk with your doctor before you use other drugs and natural products that slow your actions.
- If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
- This medicine may cause mood changes when you start taking it. Be sure there is someone you can trust to help you if needed when you take this drug.
- This medicine may be habit-forming with long-term use.
- Tell your doctor if you have ever had drug abuse, alcohol abuse, or mental or mood problems.
- If you stop taking this medicine all of a sudden, you may have signs of withdrawal. Tell your doctor if you have any bad effects.
- Use with care in children. Talk with the doctor.
- If you are 65 or older, use this medicine (Syndros) with care. You could have more side effects.
- If this medicine is taken by accident, get medical help right away.
- Do not take disulfiram or metronidazole within 7 days after your last dose of this medicine (Syndros).
- This medicine has alcohol and propylene glycol in it. Preterm newborns may have a higher chance of very bad and sometimes deadly side effects caused by propylene glycol. If you have questions, talk with the doctor or pharmacist.
- This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.
How is this medicine (Syndros) best taken?
Use this medicine (Syndros) as ordered by your doctor. Read all information given to you. Follow all instructions closely.
- If you are using this medicine to help you eat more, take this medicine (Syndros) 1 hour before lunch and dinner or as your doctor has told you.
- If you are using this medicine to treat upset stomach and throwing up, follow what your doctor has told you to do about taking this medicine (Syndros) with or without food.
- Only use the measuring device that comes with this liquid drug.
- Take with a full glass of water.
What do I do if I miss a dose?
- Take a missed dose as soon as you think about it.
- If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
- Do not take 2 doses at the same time or extra doses.
Consumer Information Use and Disclaimer
- If your symptoms or health problems do not get better or if they become worse, call your doctor.
- Do not share your drugs with others and do not take anyone else's drugs.
- Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
- Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
- Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
- If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Review Date: October 4, 2017
Syndros Dosage and Administration
Important Administration Instructions
- Always use the enclosed calibrated oral dosing syringe when administering Syndros to ensure the dose is measured and administered accurately.
- The calibrated oral syringe measures a maximum Syndros 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 Syndros with a full glass of water (6 to 8 ounces).
- For information on dosing Syndros with regard to meals, see Dosage and Administration 2.2 and 2.3.
Anorexia Associated with Weight Loss in Adult Patients with AIDS
The recommended adult starting dosage of Syndros 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 Syndros at 2.1 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 Central Nervous System (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 2.1 mg once daily one hour before dinner or in the evening at bedtime.
- 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 Syndros 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.
Nausea and Vomiting Associated with Cancer Chemotherapy in Adult Patients Who Failed Conventional Antiemetics
The recommended starting dosage of Syndros is 4.2 mg/m2 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 m2 multiplied by 4.2 mg/m2
- Round dose to the nearest 0.1 mg increment
- 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 Syndros at 2.1 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)].
Because food delays the absorption of Syndros, 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.
- 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/m2.
- Maximum Dosage: 12.6 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 2.1 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.
Warnings and Precautions
Neuropsychiatric Adverse Reactions
Psychiatric Adverse Reactions
Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Prior to initiating treatment with Syndros, 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 Syndros has been associated with cognitive impairment and altered mental state. Reduce the dose of Syndros or discontinue use of Syndros if signs or symptoms of cognitive impairment develop. Elderly and pediatric patients may be more sensitive to the neurological and psychoactive effects of Syndros [see Use in Specific Populations (8.4, 8.5)].
Syndros 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 Syndros does not affect them adversely.
Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking Syndros [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 Syndros.
Interaction with Disulfiram and Metronidazole
Syndros contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Use of Syndros 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 Syndros and do not administer these products within 7 days of completing treatment with Syndros [see Contraindications (4), Drug Interactions (7.3)].
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 Syndros is unknown.
Seizures and seizure-like activity have been reported in patients receiving dronabinol.
Weigh this potential risk against the benefits before prescribing Syndros 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 Syndros therapy.
If a seizure occurs, advise patients to discontinue Syndros and contact a healthcare provider immediately.
Multiple Substance Abuse
Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse Syndros as well. Syndros contains 50% (w/w) dehydrated alcohol.
Assess each patient’s risk for abuse or misuse prior to prescribing Syndros and monitor patients with a history of substance abuse during treatment with Syndros for the development of these behaviors or conditions.
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 Syndros. 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 Syndros. Consider dose reduction or discontinuing Syndros if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.
Toxicity in Preterm Neonates
Syndros 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 Syndros have not been established in pediatric patients. Avoid Syndros 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.