Included as part of the PRECAUTIONS section.
Suicide and Overdose
As with other psychotropic medications, the usual precautions with respect
to administration of the drug and size of the prescription are indicated for
severely depressed patients or those in whom there is reason to expect concealed
suicidal ideation or plans. Panic disorder has been associated with primary
and secondary major depressive disorders and increased reports of suicide among
Withdrawal seizures have been reported in association with the discontinuation
of alprazolam. In most cases, only a single seizure was reported; however, multiple
seizures and status epilepticus were reported as well.
Dependence and Withdrawal Reactions, Including Seizures
NIRAVAM is a Schedule IV controlled substance. The use of benzodiazepines,
including NIRAVAM, may lead to physical and psychological dependence. In general,
benzodiazepines should be prescribed for short periods. Even after relatively
short-term use at the recommended doses, there is some risk of dependence and
withdrawal symptoms [see Dependence].
Certain adverse clinical events, some life-threatening, are a direct consequence
of physical dependence to NIRAVAM. These include a spectrum of withdrawal symptoms;
the most important is seizure [see Drug Abuse and Dependence]. Spontaneous
reporting system data suggest that the risk of dependence and its severity appear
to be greater in patients treated with doses greater than 4 mg per day and for
long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation
study of panic disorder patients, the duration of treatment (3 months compared
to 6 months) had no effect on the ability of patients to taper to zero dose.
In contrast, patients treated with doses of alprazolam greater than 4 mg per
day had more difficulty tapering to zero dose than those treated with less than
4 mg per day.
The importance of dose and the risks of NIRAVAM as a treatment for panic disorder
Because the management of panic disorder often requires the use of average
daily doses of NIRAVAM above 4 mg, the risk of dependence among panic disorder
patients may be higher than that among those treated for less severe anxiety.
Experience in randomized placebo-controlled discontinuation studies of patients
with panic disorder showed a high rate of rebound and withdrawal symptoms in
patients treated with alprazolam compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic
of panic disorder (primarily panic attacks) to levels approximately equal to
those seen at baseline before active treatment was initiated. Rebound refers
to a return of symptoms of panic disorder to a level substantially greater in
frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms
were identified as those which were generally not characteristic of panic disorder
and which occurred for the first time more frequently during discontinuation
than at baseline.
In a controlled clinical trial in which 63 patients were randomized to alprazolam
and where withdrawal symptoms were specifically sought, the following were identified
as symptoms of withdrawal: heightened sensory perception, impaired concentration,
dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea,
blurred vision, appetite decrease, and weight loss. Other symptoms, such as
anxiety and insomnia, were frequently seen during discontinuation, but it could
not be determined if they were due to return of illness, rebound, or withdrawal.
In two controlled trials of 6 to 8 weeks duration where the ability of patients
to discontinue medication was measured, 71% - 93% of patients treated with alprazolam
tapered completely off therapy compared to 89% - 96% of placebo-treated patients.
In a controlled postmarketing discontinuation study of panic disorder patients,
the duration of treatment (3 months compared to 6 months) had no effect on the
ability of patients to taper to zero dose.
Seizures attributable to alprazolam were seen after drug discontinuance or
dose reduction in 8 of 1980 patients with panic disorder or in patients participating
in clinical trials where doses of alprazolam greater than 4 mg/day for over
3 months were permitted. Five of these cases clearly occurred during abrupt
dose reduction, or discontinuation from daily doses of 2 mg to 10 mg. Three
cases occurred in situations where there was not a clear relationship to abrupt
dose reduction or discontinuation. In one instance, seizure occurred after discontinuation
from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from
6 mg daily. In two other instances, the relationship to taper is indeterminate;
in both of these cases the patients had been receiving doses of 3 mg daily prior
to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks.
There have been occasional voluntary reports of patients developing seizures
while apparently tapering gradually from alprazolam. The risk of seizure seems
to be greatest 24 - 72 hours after discontinuation [see DOSAGE AND ADMINISTRATION].
To discontinue treatment in patients taking NIRAVAM, the dosage should be reduced
gradually. Decrease the daily dosage of NIRAVAM by no more than 0.5 mg every
three days [see DOSAGE AND ADMINISTRATION]. Some patients may benefit
from an even slower dosage reduction. In a controlled postmarketing discontinuation
study of panic disorder patients which compared this recommended taper schedule
with a slower taper schedule, no difference was observed between the groups
in the proportion of patients who tapered to zero dose; however, the slower
schedule was associated with a reduction in symptoms associated with a withdrawal
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant
women. If NIRAVAM is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard
to the fetus. Because of experience with other members of the benzodiazepine
class, NIRAVAM is assumed to be capable of causing an increased risk of congenital
abnormalities when administered to a pregnant woman during the first trimester.
Because use of these drugs is rarely a matter of urgency, their use during the
first trimester should almost always be avoided. The possibility that a woman
of childbearing potential may be pregnant at the time of institution of therapy
should be considered. Patients should be advised that if they become pregnant
during therapy or intend to become pregnant they should communicate with their
physicians about the desirability of discontinuing the drug.
CNS Depression and Impaired Performance
Because NIRAVAM has CNS depressant effects and has the potential to impair
judgment, cognition, and motor performance, caution patients against engaging
in hazardous occupations or activities requiring complete mental alertness such
as operating machinery or driving a motor vehicle, until they are reasonably
certain that NIRAVAM treatment does not affect them adversely. Caution patients
about the simultaneous ingestion of alcohol and other CNS depressant drugs during
treatment with NIRAVAM.
Episodes of hypomania and mania have been reported in association with the
use of alprazolam in patients with depression.
Niravam Interaction with Drugs that Inhibit Metabolism via Cytochrome P450
The initial step in NIRAVAM metabolism is hydroxylation catalyzed by cytochrome
P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound
effect on the clearance of NIRAVAM. Consequently, NIRAVAM should be avoided
in patients receiving potent inhibitors of CYP3A. With drugs inhibiting CYP3A
to a lesser but still significant degree, NIRAVAM should be used only with caution
and consideration of appropriate dosage reduction. For some drugs, an interaction
with NIRAVAM has been quantified with clinical data; for other drugs, interactions
are predicted from in vitro data and/or experience with similar drugs
in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of NIRAVAM
and/or related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents— Ketoconazole and itraconazole are potent CYP3A inhibitors
and have been shown in vivo to increase plasma alprazolam concentrations 3.98
fold and 2.70 fold, respectively. The coadministration of alprazolam with these
agents is not recommended. Other azole-type antifungal agents should also be
considered potent CYP3A inhibitors and the coadministration of alprazolam with
them is not recommended [see CONTRAINDICATIONS].
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies
Consider dose reduction of NIRAVAM during coadministration with the following
- Nefazodone — Coadministration of nefazodone increased alprazolam concentration
- Fluvoxamine — Coadministration of fluvoxamine approximately doubled the
maximum plasma concentration of alprazolam, decreased clearance by 49%, increased
half-life by 71%, and decreased measured psychomotor performance.
- Cimetidine — Coadministration of cimetidine increased the maximum plasma
concentration of alprazolam by 86%, decreased clearance by 42%, and increased
half-life by 16%.
Other drugs possibly affecting alprazolam metabolism
Other drugs possibly affect alprazolam metabolism by inhibition of CYP3A [see
Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam
have been reported in patients with panic disorder taking prescribed maintenance
doses of alprazolam. These symptoms may reflect the development of tolerance
or a time interval between doses which is longer than the duration of clinical
action of the administered dose. In either case, it is presumed that the prescribed
dose is not sufficient to maintain plasma levels above those needed to prevent
relapse, rebound or withdrawal symptoms over the entire course of the interdosing
interval. In these situations, it is recommended that the same total daily dose
be given divided as more frequent administrations [see DOSAGE AND ADMINISTRATION].
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason.
This includes purposeful tapering, but also inadvertent reduction of dose (e.g.,
the patient forgets, the patient is admitted to a hospital). Therefore, the
dosage of NIRAVAM should be reduced or discontinued gradually [see DOSAGE
Alprazolam has a weak uricosuric effect. Although other medications with weak
uricosuric effect have been reported to cause acute renal failure, there have
been no reported instances of acute renal failure attributable to therapy with
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose
to preclude the development of ataxia or oversedation which may be a particular
problem in elderly or debilitated patients. [see DOSAGE AND ADMINISTRATION].
The usual precautions in treating patients with impaired renal, hepatic or pulmonary
function should be observed. There have been rare reports of death in patients
with severe pulmonary disease shortly after the initiation of treatment with
alprazolam. A decreased systemic alprazolam elimination rate (eg, increased
plasma half-life) has been observed in both alcoholic liver disease patients
and obese patients receiving alprazolam [see CLINICAL PHARMACOLOGY].
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies
of alprazolam in rats at doses up to 30 mg/kg per day (30 times the maximum
recommended human dose of 10 mg per day on a mg/m² basis) and in mice at
doses up to 10 mg/kg per day (5 times the maximum recommended human dose on
Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline
Elution Assay or the Ames Assay, and was negative in the rat micronucleus test.
Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg
per day, which is 5 times the maximum recommended human dose of 10 mg per day
on a mg/m² basis.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category D.
Benzodiazepines can potentially cause fetal harm when administered to a pregnant
woman. The possibility that a woman of childbearing potential may be pregnant
at the time of institution of therapy should be considered. If NIRAVAM is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus. Because
of experience with other members of the benzodiazepine class, NIRAVAM is assumed
to be capable of causing an increased risk of congenital abnormalities when
administered to a pregnant woman during the first trimester. Because use of
these drugs is rarely a matter of urgency, their use during the first trimester
should almost always be avoided [see WARNINGS AND PRECAUTIONS].
It should be considered that the child born of a mother who is receiving benzodiazepines
may be at some risk for withdrawal symptoms from the drug during the postnatal
period. Also, neonatal flaccidity and respiratory problems have been reported
in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery
The potential effect of NIRAVAM in labor and delivery in humans has not been
studied. However, perinatal complications have been reported in neonates exposed
to benzodiazepines late in pregnancy. The findings are suggestive of excess
benzodiazepine exposure or withdrawal phenomena.
Benzodiazepines are excreted in human milk. It should be assumed that NIRAVAM
is excreted in human milk. Chronic administration of diazepam to nursing mothers
has been reported to cause their infants to become lethargic and to lose weight.
Because of the potential for serious adverse reactions in nursing infants from
NIRAVAM, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother. As a
general rule, nursing should not be undertaken by mothers who must use NIRAVAM.
Safety and effectiveness of NIRAVAM in individuals below 18 years of age have
not been studied.
The elderly may be more sensitive to the effects of benzodiazepines. They exhibit
higher plasma alprazolam concentrations due to reduced clearance of the drug,
compared with a younger population receiving the same doses. The smallest effective
dose of NIRAVAM should be used in the elderly to preclude the development of
ataxia and oversedation [see CLINICAL PHARMACOLOGY and DOSAGE AND
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines
have been demonstrated in geriatric patients. A mean half-life of NIRAVAM of
16.3 hours has been observed in healthy elderly subjects (range: 9.0 - 26.9
hours, n=16) compared to 11.0 hours (range: 6.3 - 15.8 hours, n=16) in healthy