Niravam

SIDE EFFECTS

Clinical Trial Experience

The most commonly reported ( ≥ 5% and ~ twice the rate of placebo) adverse reactions with NIRAVAM treatment are: sedation, impaired coordination, dysarthria, and increased libido.

The data cited in the two tables below are estimates of adverse reactions occurring in patients who participated in clinical trials under the following conditions: relatively short duration (four weeks) placebo-controlled clinical studies with dosages up to 4 mg per day of (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg per day of in patients with panic disorder, with or without agoraphobia.

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.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce dry mouth in others.)

Table 1: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Generalized Anxiety Disorder ( > 2% and at a rate greater than placebo)

GENERALIZED ANXIETY DISORDER
Body System/Adverse Reaction Treatment-Emergent Symptom Incidencea
ALPRAZOLAM (%)
N = 565
PLACEBO (%)
N = 505
Central Nervous System
  Sedation 41 22
  Lightheadedness 21 19
  Dizziness 2 1
  Akathisia 2 1
Gastrointestinal
  Dry Mouth 15 13
  Increased Salivation 4 2
Cardiovascular
  Hypotension 5 2
Cutaneous
  Dermatitis/Allergy 4 3
a) Events reported by 1% or more of alprazolam patients are included.
b) None reported

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

Table 2: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Panic Disorder ( > 2% and greater than placebo)

PANIC DISORDER
Body System/Adverse Reaction Treatment-Emergent Symptom Incidencea
ALPRAZOLAM (%)
N = 1388
PLACEBO (%)
N = 1231
Central Nervous System
  Sedation 77 43
  Fatigue and Tiredness 49 42
  Impaired Coordination 40 18
  Irritability 33 30
  Memory Impairment 33 22
  Cognitive Disorder 29 21
  Dysarthria 23 6
  Decreased Libido 14 8
  Confusional State 10 8
  Increased Libido 8 4
  Change in Libido (Not Specified) 7 6
  Disinhibition 3 2
  Talkativeness 2 1
  Derealization 2 1
Gastrointestinal
  Constipation 26 15
  Increased Salivation 6 4
Cutaneous
  Rash 11 8
Other
  Increased Appetite 33 23
  Decreased Appetite 28 24
  Weight Gain 27 18
  Weight Loss 23 17
  Micturition Difficulties 12 9
  Menstrual Disorders 10 9
  Sexual Dysfunction 7 4
  Incontinence 2 1
a) Events reported by 1% or more of alprazolam patients are included.

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, the following adverse reactions have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of NIVARAM. 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. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia, and galactorrhea.

Read the Niravam (alprazolam) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Use with Other CNS Depressants

If NIRAVAM is coadministered with other psychotropic agents or anticonvulsant drugs, carefully consider the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including NIRAVAM, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs which themselves produce CNS depression.

Drugs Effecting Salivary Flow and Stomach pH

Because NIRAVAM disintegrates in the presence of saliva, and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption.

Use with Imipramine and Desipramine

The steady state plasma concentrations of imipramine and desipramine can increase by approximately 30% and 20%, respectively, when administered concomitantly with NIRAVAM in doses up to 4 mg per day. The clinical significance of these changes is unknown.

Drugs that Inhibit NIRAVAM Metabolism via Cytochrome P450 3A

The initial step in NIRAVAM metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway can have a profound effect on the clearance of NIRAVAM [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Drugs Demonstrated to be CYP3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam

Use caution during coadministration NIRAVAM and the following drugs:

Fluoxetine — Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.

Propoxyphene — Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.

Oral Contraceptives — Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.

Drugs and Other Substances Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Benzodiazepines Metabolized Similarly to Alprazolam or on the Basis of In Vitro Studies with Alprazolam or Other Benzodiazepines

Use caution during the coadministration of NIRAVAM and the following:

Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction between alprazolam and the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction between alprazolam and the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction between benzodiazepines and the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. [see WARNINGS AND PRECAUTIONS].

Inducers of CYP3A

Carbamazepine can increase NIRAVAM metabolism and therefore can decrease plasma levels of NIRAVAM.

Drug Abuse And Dependence

Controlled Substance

NIRAVAM is a Schedule IV controlled substance.

Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including NIRAVAM. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of NIRAVAM sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal from recurrence of anxiety symptoms, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (eg, 0.75 mg to 4 mg per day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg per day [see WARNINGS AND PRECAUTIONS].

Avoid abrupt discontinuation of NIRAVAM, especially in individuals with a history of seizures or epilepsy. It is recommended that all patients on NIRAVAM who require a dosage reduction be gradually tapered under close supervision [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Psychological dependence is a risk with all benzodiazepines, including NIRAVAM. The risk of psychological dependence may also be increased at doses greater than 4 mg per day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from NIRAVAM, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving NIRAVAM. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

Read the Niravam Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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