ALPRAZOLAM ER (Page 4 of 6)

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, 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

Teratogenic Effects: Pregnancy Category D: (see WARNINGS section).

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.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Adverse Reactions to ALPRAZOLAM ER

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Alprazolam Extended-Release Tablets

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received alprazolam extended-release tablets in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the patients treated with alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in the following table.

Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials
System Organ Class/Adverse Event Percentage of Patients DiscontinuingDue to Adverse Events
AlprazolamExtended-ReleaseTablets (n=531) Placebo(n=349)
Nervous system disorders
Sedation 7.5 0.6
Somnolence 3.2 0.3
Dysarthria 2.1 0
Coordination abnormal 1.9 0.3
Memory impairment 1.5 0.3
General disorders/administration site conditions
Fatigue 1.7 0.6
Psychiatric disorders
Depression 2.5 1.2

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with alprazolam extended-release tablets (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table).

Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Alprazolam Extended-Release Tablets
System Organ Class/Adverse Event Percentage of PatientsReporting Adverse Event
AlprazolamExtended-ReleaseTablets(n=531) Placebo(n=349)
Nervous system disorders
Sedation 45.2 22.6
Somnolence 23.0 6.0
Memory impairment 15.4 6.9
Dysarthria 10.9 2.6
Coordination abnormal 9.4 0.9
Mental impairment 7.2 5.7
Ataxia 7.2 3.2
Disturbance in attention 3.2 0.6
Balance impaired 3.2 0.6
Paresthesia 2.4 1.7
Dyskinesia 1.7 1.4
Hypoesthesia 1.3 0.3
Hypersomnia 1.3 0
General disorders/administration site conditions
Fatigue 13.9 9.2
Lethargy 1.7 0.6
Infections and infestations
Influenza 2.4 2.3
Upper respiratory tract infections 1.9 1.7
Psychiatric disorders
Depression 12.1 9.2
Libido decreased 6.0 2.3
Disorientation 1.5 0
Confusion 1.5 0.9
Depressed mood 1.3 0.3
Anxiety 1.1 0.6
Metabolism and nutrition disorders
Appetite decreased 7.3 7.2
Appetite increased 7.0 6.0
Anorexia 1.5 0
Gastrointestinal disorders
Dry mouth 10.2 9.7
Constipation 8.1 4.3
Nausea 6.0 3.2
Pharyngolaryngeal pain 3.2 2.6
Investigations
Weight increased 5.1 4.3
Weight decreased 4.3 3.7
Injury, poisoning, and procedural complications
Road traffic accident 1.5 0
Reproductive system and breast disorders
Dysmenorrhea 3.6 2.9
Sexual dysfunction 2.4 1.1
Premenstrual syndrome 1.7 0.6
Musculoskeletal and connective tissue disorders
Arthralgia 2.4 0.6
Myalgia 1.5 1.1
Pain in limb 1.1 0.3
Vascular disorders
Hot flushes 1.5 1.4
Respiratory, thoracic, and mediastinal disorders
Dyspnea 1.5 0.3
Rhinitis allergic 1.1 0.6
Skin and subcutaneous tissue disorders
Pruritis 1.1 0.9

Other Adverse Events Observed During the Premarketing Evaluation of Alprazoalam Extended-Release Tablets
Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with alprazolam extended-release tablets. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with alprazolam extended-release tablets, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/l00 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Cardiac disorders:Frequent: palpitation; Infrequent: sinus tachycardia
Ear and Labyrinth disorders:Frequent: Vertigo; Infrequent: tinnitus, ear pain
Eye disorders:Frequent: blurred vision; Infrequent: mydriasis, photophobia
Gastrointestinal disorders:Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion
General disorders and administration site conditions:Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors
Musculoskeletal and connective tissue disorders:Frequent: back pain, muscle cramps, muscle twitching
Nervous system disorders:Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor
Psychiatric system disorders:Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation
Renal and urinary disorders:Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence
Respiratory, thoracic, and mediastinal disorders:Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea
Skin and subcutaneous tissue disorders:Frequent: sweating increased; Infrequent: clamminess, rash, urticaria
Vascular disorders:Infrequent: hypotension

The categories of adverse events reported in the clinical development program for alprazoalam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam extended-release tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam Extended-Release TabletsThe following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was two times greater than the incidence in placebo-treated patients.

Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with Alprazolam Extended-Release Tablets
System Organ Class/Adverse Event Percentage of Patients ReportingAdverse Event
AlprazolamExtended-ReleaseTablets(n=422) Placebo(n=261)
Nervous system disorders
Tremor 28.2 10.7
Headache 26.5 12.6
Hypoesthesia 7.8 2.3
Paresthesia 7.1 2.7
Psychiatric disorders
Insomnia 24.2 9.6
Nervousness 21.8 8.8
Depression 10.9 5.0
Derealization 8.0 3.8
Anxiety 7.8 2.7
Depersonalization 5.7 1.9
Gastrointestinal disorders
Diarrhea 12.1 3.1
Respiratory, thoracic and mediastinaldisorders
Hyperventilation 8.5 2.7
Metabolism and nutrition disorders
Appetite decreased 9.5 3.8
Musculoskeletal and connective tissuedisorders
Muscle twitching 7.4 2.7
Vascular disorders
Hot flushes 5.9 2.7

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see WARNINGS).

To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam extended-release tablets be decreased 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 syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

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