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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
MARINOL (NDA-018651)
(DRONABINOL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
01/17/2023 (SUPPL-33)
8 Use in Specific Populations
8.1 PregnancyAdditions and revisions underlined:
Risk Summary
. . .
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.
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 AlDS, and up to the MRHD for patients with cancer (see Data).
In a pre- and postnatal development study, female rats were administered dronabinol by oral gavage at doses of 0.5, 5, or 15 mg/kg /day (equivalent to 0.2, 2, and 6 times the MRHD for patients with AIDS and 0.03, 0.33, and 1.0 times the MRHD for patients with cancer, respectively, based on body surface area) from gestation day 6 (implantation) through lactation day 20 (weaning). Maternal toxicity including adverse clinical signs (i.e., decreased motor activity, low carriage, abnormal gait, hunched posture, vocalization to touch, ungroomed coat, mild dehydration, piloerection, and splayed hindlimbs), reduced body weight and body weight gain, and decreased food consumption were observed during the gestation period at 2 and 6 times the MRHD for patients with AIDS and 0.33 and 1.0 times the MRHD for patients with cancer, respectively. At the same doses, reduced pup bodyweight, increased stillbirths, and mortality of offspring were observed. No neurodevelopmental adverse effects (i.e., neurobehavioral function, sensory function, motor activity, learning and memory) were observed in pups at maternal doses up 15 mg/kg/day (6 times the MRHD in patients with AIDS or 1.0 times the MRI-ID in patients with cancer).
Newly added information:
In rat offspring exposed to dronabinol in utero and during lactation, reduced bodyweight was observed during the preweaning (lactation) stage with maternal administration of dronabinol at 2 times and less than the MRHD for patients with AIDS and cancer, respectively.
Breastfeeding infants should have their weight monitored. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MARlNOL and any potential adverse effects on the breastfed infant from MARINOL or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and revisions underlined:
If you are being treated for nausea and vomiting caused by anti-cancer medicine and you breastfeed while taking MARINOL, your doctor should check the weight of your baby regularly.
Always take your dose at the same time in relation to your mealtimes for each chemotherapy treatment.
08/28/2017 (SUPPL-29)
4 Contraindications
PLR conversion, revised as below:
MARINOL is 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.
5 Warnings and Precautions
5.1 Neuropsychiatric Adverse Reactions
Psychiatric Adverse Reactions
Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Significant CNS symptoms followed oral doses of 0.4 mg/kg (28 mg per 70 kg patient) of MARINOL in antiemetic studies.
Prior to initiating treatment with MARINOL, 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 MARINOL has been associated with cognitive impairment and altered mental state. Reduce the dose of MARINOL or discontinue use of MARINOL if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of MARINOL.
Hazardous Activities
MARINOL 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, ethanol, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that MARINOL does not affect them adversely.
Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking MARINOL. 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 MARINOL.
Seizure and seizure-like activity have been reported in patients receiving dronabinol.
Weigh this potential risk against the benefits before prescribing MARINOL 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 MARINOL therapy.
If a seizure occurs, advise patients to discontinue MARINOL and contact a healthcare provider immediately.
Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse MARINOL as well.
Assess each patient’s risk for abuse or misuse prior to prescribing MARINOL and monitor patients with a history of substance abuse during treatment with MARINOL for the development of these behaviors or conditions.
5.5 Paradoxical Nausea, Vomiting, or Abdominal Pain
Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9- tetrahydrocannabinol (delta-9-THC), the active ingredient in MARINOL. 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 MARINOL. Consider dose reduction or discontinuing MARINOL if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.
6 Adverse Reactions
PLR conversion, revised as below:
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
Hemodynamic Instability
Seizures
Paradoxical Nausea, Vomiting, and Abdominal Pain
Studies of AIDS-related weight loss included 157 patients receiving MARINOL 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 MARINOL and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to MARINOL in studies.
A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving MARINOL 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 MARINOL. 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 replaces PROBABLY CAUSALLY RELATED: Incidence greater than 1%, and is now in table form; please refer to label.
Less Common Adverse Reactions replaces PROBABLY CAUSALLY RELATED: Incidence less than 1% and CASUAL RELATIONSHIP UNKNOWN: Incidence less than 1%, and is now in table form; please refer to label.
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
Injury, poisoning and procedural complications: Fall
Nervous system disorders: Seizures disorientation, movement disorder, loss of consciousness
Psychiatric disorders: Delirium, insomnia, panic attack
Vascular disorders: Syncope
7 Drug Interactions
PLR conversion, revised as below:
7.1 Additive CNS Effects
Additive CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants.
7.2 Additive Cardiac Effects
Additive cardiac effects (e.g., hypotension, hypertension, syncope, tachycardia) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the cardiovascular system.
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 MARINOL.
Monitor for potentially increased dronabinol-related adverse reactions when MARINOL 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).
7.4 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 MARINOL.
8 Use in Specific Populations
8.1 PregnancyPLLR conversion; revised as below:
Risk Summary
MARINOL, a synthetic cannabinoid, may cause fetal harm. Avoid use of MARINOL 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. 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 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 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.
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.
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.
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/m2, equivalent to 1 to 30 times the MRHD of 15 mg/m2/day in AIDS patients or 0.2 to 5 times the MRHD of 90 mg/m2/day 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.
PLLR conversion; revised as below:
Risk Summary
For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommends 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 MARINOL.
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 MARINOL on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with MARINOL and for 9 days after the last dose.
PLR conversion; addition of the following:
The safety and effectiveness of MARINOL have not been established in pediatric patients. Pediatric patients may be more sensitive to neurological and psychoactive effects of MARINOL.
PLR conversion; revised as below:
Clinical studies of MARINOL in AIDS and cancer patients did not include the 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 MARINOL.
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 MARINOL. These patients should be monitored closely and placed on fall precautions prior to initiating MARINOL 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.
.PLR conversion; addition of the following:
Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in the presence of CYP2C9 genetic polymorphism. Monitoring for potentially increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONPLR conversion; newly added section; please refer to label.
PLR conversion; newly added section; please refer to label.
Other
PLR and PLLR conversion.