Syndros

Pregnancy

May cause fetal harm; avoid use during pregnancy

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

Contains alcohol; alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development

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

Effects of delta-9-THC on the fetus are not known

Lactation

Women with HIF: Advise HIV infected women not to breastfeed

Women with CINV: Do not breastfeed during treatment with dronabinol and for 9 days after the last dose

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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

C21H30O2 (molecular weight=314.46)

Dronabinol is a clear colorless to amber oil. Dronabinol is insoluble in water. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

SYNDROS (dronabinol) oral solution, 5 mg/mL is a clear, pale yellow to brown solution. Each mL of SYNDROS contains 5 mg of dronabinol as an active ingredient and the following inactive ingredients: 50 % (w/w) dehydrated alcohol, polyethylene glycol 400, propylene glycol, sucralose, methyl paraben, propyl paraben, butylated hydroxyanisole, and water.

Included as part of the PRECAUTIONS section.

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.

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

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

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 [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].

Read the entire FDA prescribing information for Syndros ( C-X Dronabinol Oral Solution)

This section provides information on the proper use of a number of products that contain dronabinol. It may not be specific to Syndros. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much is taken, it may lead to medical problems because of an overdose.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Swallow the capsule whole. Do not crush, break, or chew it.

If you are using the oral liquid:

• Measure the oral liquid with the marked oral dosing syringe that comes with the package. The average household teaspoon may not hold the right amount of liquid.
• Take each dose with a full glass of water.
• If you are taking this medicine for treatment of nausea and vomiting caused by cancer medicines, take the first dose on an empty stomach, at least 30 minutes before a meal. After your first dose, you can take it with or without food.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For increasing appetite in patients with AIDS:
    • Adults and teenagers—At first, 2.5 milligrams (mg) two times a day, taken before lunch and supper. Your doctor may change your dose depending on your condition. However, the dose is usually not more than 20 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For nausea and vomiting caused by cancer medicines:
    • Adults and teenagers—Dose is based on body surface area and must be determined by your doctor. Your doctor will tell you how much medicine to take and when to take it.
    • Children—Dose is based on body surface area and must be determined by your doctor.
• For oral dosage form (solution):
  • For increasing appetite in patients with AIDS:
    • Adults—At first, 2.1 milligrams (mg) two times a day, taken 1 hour before lunch and 1 hour before dinner. Your doctor may gradually increase your dose as needed and tolerated. However, the dose is usually not more than 8.4 mg two times a day.
    • Older adults—At first, 2.1 mg once a day, taken 1 hour before dinner or at bedtime. Your doctor may gradually increase your dose as needed and tolerated.
    • Children—Use and dose must be determined by your doctor.
  • For treatment of nausea and vomiting caused by cancer medicines:
    • Adults—Dose is based on body surface area and must be determined by your doctor. The dose is usually 4.2 milligrams (mg) per square meter (m[2]) taken 1 to 3 hours before chemotherapy and then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses per day. Your doctor may gradually increase your dose as needed and tolerated. However, the dose is usually not more than 12.6 mg/m[2] per dose for 4 to 6 doses per day.
    • Older adults—Dose is based on body surface area and must be determined by your doctor. The dose is usually 2.1 milligrams (mg) per square meter (m[2]) taken 1 to 3 hours before chemotherapy.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store in the refrigerator. Do not freeze.

You may keep the opened bottle of oral liquid at room temperature. Throw away any unused medicine 28 days after opening the bottle.

Oral Solution: 5 mg/mL, a clear, pale yellow to brown solution.

Syndros 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)]. Syndros contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol.

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 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%.

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%.

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 [see Contraindications (4)].

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

Nervous system disorders: seizures [see Warnings and Precautions (5.4)], disorientation, movement disorder, loss of consciousness.

Psychiatric disorders: delirium, insomnia, panic attack.

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

Pregnancy

Risk Summary

Syndros, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid use of Syndros in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) and use of alcohol during pregnancy have 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 doses) 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. 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.

Syndros contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Avoid use of Syndros in pregnant women.

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

The recommended dose ranges for Syndros in AIDS and cancer patients are designed to achieve the same systemic exposure ranges as with the recommended dose ranges for dronabinol capsules. Therefore, animal to human dose multiples, as shown below, are based on the MRHDs (maximum recommended human doses) for dronabinol capsules, instead of the MRHDs for Syndros, which are 15% lower. This approach for dose comparison between animals and humans is supported by the demonstrated difference in dronabinol bioavailability between Syndros and dronabinol capsules.

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 (dronabinol capsules) in AIDS patients or 0.2 to 5 times the MRHD of 90 mg/m2/day (dronabinol capsules) 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.

Lactation

Risk Summary

For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommend 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 Syndros.

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 Syndros on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with Syndros and for 9 days after the last dose.

Pediatric Use

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

Pediatric patients may be more sensitive to neurological and psychoactive effects of Syndros [see Warnings and Precautions (5.1)]. Syndros contains the excipients 50% (w/w) dehydrated alcohol and 5.5% (w/w) 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 events due to diminished ability to metabolize propylene glycol, thereby, leading to accumulation [see Warnings and Precautions (5.7)].

Geriatric Use

Clinical studies of dronabinol capsules in AIDS and cancer patients did not include 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 Syndros [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 Syndros [see Warnings and Precautions (5.1)]. These patients should be monitored closely and placed on fall precautions prior to initiating Syndros 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 (2.2, 2.3)].

Effect of CYP2C9 Polymorphism

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

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.