5.1 Neuropsychiatric
Adverse Reactions replaces
Neurological Adverse Reactions
Hazardous Activities
Additions and/or
revisions underlined:
… 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) …
5.2 Hemodynamic
Instability
Additions and/or
revisions underlined:
… 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) …
6.1 Clinical Trials Experience
Additions and/or revisions underlined in
bulleted line listing:
6.2 Postmarketing Experience
Newly added category of adverse reactions:
General disorders and
administration site conditions: fatigue.
Risk Summary
Additions and/or revisions underlined:
… 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 (delta-9-THC) 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 … 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 rats, maternal administration of
dronabinol from pregnancy (implantation) through weaning was associated with
maternal toxicity, including mortality of pups, and adverse developmental and neurodevelopmental
effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less
than and up to 3.3 times the MRHD for patients with cancer. (see Data).
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 …
… Animal
Data
The recommended dose ranges for SYNDROS in
patients with AIDS and patients with cancer are designed to
achieve the same systemic exposure ranges to delta-9-THC as with the
recommended dose ranges for dronabinol capsules …
These studies have revealed no evidence of
teratogenicity due to delta-9-THC. At these dronabinol dosages in mice and
rats, delta-9-THC 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 …
… 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 delta-9-THC has resulted in significant and long-term changes in brain development, cognition,
and behavior in rat offspring.
In a pre- and post-natal developmental study,
female rats administered dronabinol by oral gavage in a vehicle of medium chain
triglycerides at doses of 5, 25 and 50 mg/kg/day (equivalent to 1.7, 10, and 20
times the MRHD for patients with AIDS and 0.33, 1.7, and 3.3 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
caused mortality of pups at and above 10 times the MRHD for patients with AIDS and
1.7 times the MRHD for patients with cancer. At 20 times the MRHD for patients
with AIDS and 3.3 times the MRHD for patients with cancer, treatment with
dronabinol was associated with an increase in the number of dams with 100% pup
mortality on lactation days 1 to 4. At 2 and 10 times the MRHD for patients
with AIDS and 0.33 and 1.7 times the MRHD for patients with cancer, dronabinol
produced adverse effects on the offspring including delays in developmental
landmark parameters (e.g., surface righting reflex, negative geotaxis, and air
righting reflex), decreased fertility and pregnancy index, reduced ovary and
uterus weights, decreased implantations and viable embryos, and increased
post-implantation loss.
Neurological adverse effects such as piloerection,
landing foot splay and an increase in the number of rears in open field were observed
in offspring at 10 and 20 times the MRHD for patients with AIDS and 0.33 and
1.7 times the MRHD for patients with cancer.
Administration of dronabinol in 50%
ethanol (used in the vehicle for SYNDOS), was poorly tolerated in maternal
animals. Serious adverse signs of toxicity were observed in the control group (vehicle
only) and in dronabinol-containing dose groups at 10 and 20 times the MRHD for
patients with AIDS and 1.7 and 3.3 times the MRHD for patients with cancer,
resulting in termination of all animals at the 50 mg/kg dose level prior to
delivery of litters. These animal findings are difficult to interpret due to effects
of alcohol in the vehicle.
Additions and or revisions underlined:
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. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for SYNDROS and any
potential adverse effects on the breastfed infant from SYNDROS or
from the underlying maternal condition.
‘Neuropsychiatric Adverse Reactions’ replaces ‘Neurological
Adverse Reactions’
Additions and/or revisions underlined:
Pregnancy
Advise a pregnant woman of the potential risk
to a fetus and to avoid use of SYNDROS during pregnancy. [see Use in Specific Populations (8.1)]
Lactation
Advise HIV infected women with anorexia associated
with weight loss, not to breastfeed because HIV can be passed to the baby
through the breast milk [see Use in
Specific Population (8.2)].
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