SYNDROS (Page 3 of 6)

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 [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)].

7 DRUG INTERACTIONS

7.1 Disulfiram and Metronidazole

SYNDROS 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 SYNDROS and do not administer these products within 7 days of completing treatment with SYNDROS [see Contraindications ( 4), Warnings and Precautions ( 5.3)].

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.

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 SYNDROS.

Monitor for increased dronabinol-related adverse reactions when SYNDROS 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 SYNDROS.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.2 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.

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