A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Xanax Warnings, Precautions, Pregnancy, Nursing, Abuse - Alprazolam
Xanax Warnings, Precautions, Pregnancy, Nursing, Abuse - Alprazolam
WARNINGS
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical
events, some life-threatening, are a direct consequence of physical
dependence to alprazolam.
These include a spectrum of withdrawal
symptoms; the most important is seizure
(see DRUG ABUSE AND DEPENDENCE).
Even after relatively short-term use at the doses recommended for the
treatment of transient
anxiety and anxiety disorder (i.e., 0.75-4.0 mg
per day), there is some risk
of 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/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/day had more difficulty tapering
to zero dose
than those treated with less than 4 mg/day.
The Importance of Dose and the Risks of Alprazolam as a Treatment
for Panic Disorder
Because the management of panic
disorder often requires the
use of average daily doses of alprazolam 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 a larger database comprised of both controlled and uncontrolled studies
in which 641 patients received alprazolam, discontinuation-emergent symptoms
which occurred at a rate of over
5% in patients treated with alprazolam and at a greater rate
than the placebo treated group
were as follows:
Discontinuation-Emergent Symptom Incidence: Percentage
of 641 Alprazolam-Treated Panic Disorder Patients Reporting Events.
- Neurologic: Insomnia (29.5), light-headedness
(19.3), abnormal involuntary movement
(17.3), headache (17.0),
muscular twitching (6.9),
impaired coordination
(6.6), muscle tone
disorders (5.9), weakness (5.8).
- Psychiatric: Anxiety (19.2), fatigue
and tiredness (18.4), irritability (10.5), cognitive disorder
(10.3), memory impairment
(5.5), depression (5.1), confusional state
(5.0).
- Gastrointestinal: Nausea/vomiting (16.5), diarrhea
(13.6), decreased salivation
(10.6).
- Metabolic-Nutritional: Weight loss
(13.3), decreased appetite (12.8).
- Dermatological: Sweating (14.4).
- Cardiovascular: Tachycardia (12.2).
- Special Senses: Blurred vision
(10.0).
From the studies cited, it has not been determined whether these symptoms
are clearly related to the dose
and duration of therapy with
alprazolam in patients with panic
disorder.
In two controlled trials of 6 to 8 weeks duration
where the ability of patients to discontinue medication
was measured, 71%-93% of alprazolam treated patients 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
daily for over 3 months were permitted. Five of these cases clearly occurred
during abrupt dose reduction,
or discontinuation from daily doses of 2 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 for recommended tapering and discontinuation
schedule).
Status Epilepticus and its Treatment
The medical event voluntary
reporting system shows that
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. Ordinarily, the treatment of status
epilepticus of any etiology involves use of intravenous
benzodiazepines plus phenytoin
or barbiturates, maintenance of a patent
airway and adequate hydration. For additional details regarding therapy,
consultation with an
appropriate specialist
may be considered.
Interdose Symptoms
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, etc.). Therefore, the dosage
of alprazolam should be reduced or discontinued gradually (see DOSAGE
AND ADMINISTRATION).
Alprazolam tablets are not of value
in the treatment of psychotic
patients and should not be employed in lieu of appropriate
treatment for psychosis.
Because of its CNS depressant
effects, patients receiving alprazolam should be cautioned against engaging
in hazardous occupations or activities requiring complete mental
alertness such as operating machinery or driving a motor vehicle. For
the same reason, patients should be cautioned about the simultaneous ingestion
of alcohol and other CNS
depressant drugs during
treatment with alprazolam.
Benzodiazepines can potentially cause
fetal harm when administered
to pregnant women. If alprazolam 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, alprazolam 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.
Alprazolam Interaction with Drugs that Inhibit Metabolism Via Cytochrome
P450 3A
The initial step
in alprazolam metabolism
is hydroxylation catalyzed by cytochrome
P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a
profound effect on the clearance
of alprazolam. Consequently, alprazolam should be avoided in patients
receiving very potent inhibitors
in CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant
degree, alprazolam should be used only with caution and consideration
of appropriate dosage reduction.
For some drugs, an interaction with alprazolam 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
alpraxzolam and/or related benzodiazepines, presumably through inhibition
of CYP 3A.
Potent CYP 3A Inhibitors: Azole Antifungal Agents:
Although in vivo interaction data with alprazolam are not available,
ketoconazole and itraconazole are potent
CYP 3A inhibitors and the coadministration of alprazolam with them is
not recommended. Other azole-type antifungal agents should also be considered
potent CYP 3A inhibitors and
the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis
of clinical studies involving alprazolam (caution and consideration of
appropriate alprazolam dose reduction
are recommended during coadministration
with the following drugs):
- Nefazodone: Coadministration of nefazodone increased
alprazolam concentration
twofold.
- 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
by inhibition of CYP 3A
are discussed in DRUG INTERACTIONS.
PRECAUTIONS
General
If alprazolam tablets are to be combined with other psychotropic agents
or anticonvulsant drugs,
careful consideration should be given to the pharmacology of the agents
to be employed, particularly with compounds which might potentiate the
action of benzodiazepines (see
DRUG INTERACTIONS).
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.
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 (e.g., increased
plasma half-life) has been
observed in both alcoholic
liver disease
patients and obese patients
receiving alprazolam (see CLINICAL PHARMACOLOGY).
Episodes of hypomania and
mania have been reported in
association with the use
of alprazolam in patients with depression.
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 alprazolam.
Information for the Patient
See PATIENT INFORMATION section.
Laboratory Tests
Laboratory tests are not ordinarily required in otherwise healthy patients.
Drug/Laboratory Test Interactions
Although interactions between benzodiazepines and commonly employed clinical
laboratory tests have occasionally been reported, there is no consistent
pattern for a specific
drug or specific
test.
Carcinogenesis, Mutagenesis, and 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/day
(150 times the maximum recommended daily human
dose of 10 mg/day) and in mice
at doses up to 10 mg/kg/day (50 times the maximum
recommended daily human dose).
Alprazolam was not mutagenic in the rat
micronucleus test
at doses up to 100 mg/kg, which is 500 times the maximum
recommended daily human dose
of 10 mg/day. Alprazolam also was not mutagenic in vitro in the
DNA Damage/Alkaline Elution Assay or the Ames Assay.
Alprazolam produced no impairment
of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the
maximum recommended daily
human dose of 10 mg/day.
Pregnancy Category D
Teratogenic Effects: See WARNINGS
.
Nonteratogenic Effects: 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
Alprazolam has no established use in labor
or delivery.
Nursing Mothers
Benzodiazepines are known to be excreted in human
milk. It should be assumed that alprazolam is as well. Chronic administration
of diazepam to nursing mothers
has been reported to cause their
infants to become lethargic and to lose weight. As
a general rule, nursing should
not be undertaken by mothers who must use alprazolam.
Pediatric Use
Safety and effectiveness
of alprazolam in individuals below 18 years of age
have not been established.
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