Flurazepam Hydrochloride

Mylan Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use safely and effectively. See full prescribing information for .  Initial U.S. Approval: 1970RECENT MAJOR CHANGESDosage and Administration (2)     04/2014Warnings and Precautions (5)     04/2014INDICATIONS AND USAGEFlurazepam, a gamma-aminobutyric (GABAA) agonist, is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. (1)DOSAGE AND ADMINISTRATION •Use the lowest dose effective for the patient. •Recommended initial dose is 15 mg for women and 15 mg or 30 mg for men. (2.1) •Elderly or debilitated patients: recommended dose is 15 mg. (2.2) DOSAGE FORMS AND STRENGTHS •15 mg and 30 mg capsules. (3) CONTRAINDICATIONS •Pregnancy (4) •Hypersensitivity to flurazepam or other benzodiazepines. (4) WARNINGS AND PRECAUTIONS •CNS depressant effects: Impaired alertness and motor coordination, including risk of falling. Daytime impairment. Caution patients against driving and other activities requiring complete mental alertness. (5.1) •When discontinued, benzodiazepine withdrawal syndrome can occur. (5.2) •The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. (5.3) •Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4) •Sleep driving and other complex behaviors while not fully awake: Risk increases with dose and concomitant CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. (5.5) •Worsening of depression or suicidal thinking may occur: Prescribe the least number of capsules feasible to avoid intentional overdose. (5.6) Side EffectsAdverse reactions: dizziness, drowsiness, light-headedness, staggering, ataxia, falling. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3769 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •CNS Depressants: Downward dose adjustment may be necessary due to additive effects. (7) USE IN SPECIFIC POPULATIONS •Pregnancy: Based on animal data, may cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 FLURAZEPAM HYDROCHLORIDE INDICATIONS AND USAGE
• 2 FLURAZEPAM HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 Dosage in Adults
  • 2.2 Dosage in Elderly or Debilitated Patients
• 3 DOSAGE FORMS AND STRENGTHS
• 4 FLURAZEPAM HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 CNS-Depressant Effects and Daytime Impairment
  • 5.2 Benzodiazepine Withdrawal Syndrome
  • 5.3 Need to Evaluate for Co-morbid Disorders
  • 5.4 Severe Anaphylactic or Anaphylactoid Reactions
  • 5.5 Abnormal Thinking and Behavior Changes
  • 5.6 Worsening of Depression
• 6 FLURAZEPAM HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Pediatric Use
  • 8.3 Geriatric Use
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse and Dependence
• 10 OVERDOSAGE
• 11 FLURAZEPAM HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Flurazepam hydrochloride capsules are indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings [see Clinical Studies (14)].

Since insomnia is often transient and intermittent, short-term use is usually sufficient. Prolonged use of hypnotics is usually not indicated and should only be undertaken concomitantly with appropriate evaluation of the patient.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults

Use the lowest dose effective for the patient, as important adverse effects of flurazepam hydrochloride capsules are dose related.

The recommended initial dose is 15 mg for women and either 15 mg or 30 mg for men. The 15 mg dose can be increased to 30 mg if necessary for efficacy.

The recommended initial doses for women and men are different because flurazepam clearance is lower in women [see Pharmacokinetics (12.3)].

2.2 Dosage in Elderly or Debilitated Patients

Elderly or debilitated patients may be especially sensitive to flurazepam. Since the risk of the development of oversedation, dizziness, confusion and/or ataxia increases substantially with larger doses in elderly or debilitated patients, it is recommended that in such patients the dosage be limited to 15 mg. Staggering and falling have also been reported, particularly in geriatric patients [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Flurazepam Hydrochloride Capsules, USP are available containing either 15 mg or 30 mg of flurazepam hydrochloride, USP.

The 15 mg capsule is a hard-shell gelatin capsule with a white opaque cap and a powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4415 in black ink on both the cap and body.

The 30 mg capsule is a hard-shell gelatin capsule with a powder blue opaque cap and a powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4430 in black ink on both the cap and body.

4 CONTRAINDICATIONS

Flurazepam hydrochloride capsules are contraindicated in patients with known hypersensitivity to flurazepam or other benzodiazepines. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of flurazepam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Patients who develop such reactions should not be rechallenged with flurazepam.

5 WARNINGS AND PRECAUTIONS

5.1 CNS-Depressant Effects and Daytime Impairment

Dizziness, drowsiness, light-headedness, staggering, ataxia and falling can occur, particularly in elderly or debilitated persons. Severe sedation, lethargy, disorientation and coma, probably indicative of drug intolerance or overdosage, have been reported.

Flurazepam is a central nervous system (CNS) depressant and can impair daytime function even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of flurazepam may develop, patients using flurazepam should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness.

Additive effects occur with concomitant use of other CNS depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants, alcohol). Downward dose adjustment of flurazepam and concomitant CNS depressants should be considered. The potential for adverse drug interactions continues for several days following discontinuation of flurazepam, until serum levels of psychoactive metabolites decline.

Use of flurazepam with other sedative-hypnotics is not recommended. Alcohol generally should not be used during treatment with flurazepam. The risk of next-day psychomotor impairment is increased if flurazepam is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants [see Dosage and Administration (2)].

5.2 Benzodiazepine Withdrawal Syndrome

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines.

5.3 Need to Evaluate for Co-morbid Disorders

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs.

5.4 Severe Anaphylactic or Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including flurazepam. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis.

Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with flurazepam should not be rechallenged with the drug.

5.5 Abnormal Thinking and Behavior Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including flurazepam. Some of these changes include decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, and depersonalization. Visual and auditory hallucinations have also been reported. Amnesia, and other neuro-psychiatric symptoms, may occur.

Paradoxical reactions such as stimulation, agitation, increased muscle spasticity, and sleep disturbances may occur unpredictably.

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake, with amnesia for the event) have been reported with use of sedative-hypnotics. These behaviors can occur with initial treatment or in patients previously tolerant of flurazepam or other sedative-hypnotics. Although these behaviors can occur with use at therapeutic doses, risk is increased by higher doses or concomitant use of alcohol or other CNS depressants. Due to risk to the patient and community, flurazepam should be discontinued if “sleep-driving” occurs.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

5.6 Worsening of Depression

Benzodiazepines may worsen depression. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• •CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]
• •Benzodiazepine Withdrawal Syndrome [see Warnings and Precautions (5.2)]
• •Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.3)]
• •Abnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions (5.4)]
• •Worsening of depression [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Reported were headache, heartburn, upset stomach, nausea, vomiting, diarrhea, constipation, gastrointestinal pain, nervousness, talkativeness, apprehension, irritability, weakness, palpitations, chest pains, body and joint pains, and genitourinary complaints. There have also been rare occurrences of leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, burning eyes, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations and elevated SGOT, SGPT, total and direct bilirubin elevations, and elevated alkaline phosphatase.

7 DRUG INTERACTIONS

Benzodiazepines, including flurazepam, produce additive CNS depressant effects when co-administered with ethanol or other CNS depressants (e.g., psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of flurazepam and/or concomitant CNS depressants may be necessary because of additive effects.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Available human data on the risk of teratogenicity for benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy or neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Administration of flurazepam to pregnant animals did not indicate a risk for adverse effects on morphological development at clinically relevant doses; however, animal data for other benzodiazepines suggest that possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) following prenatal exposure. Flurazepam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Registry

To provide information regarding the effects of in utero exposure to flurazepam, physicians are advised to recommend that pregnant patients taking flurazepam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

8.2 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.3 Geriatric Use

Flurazepam may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a low dose of flurazepam and observed closely.

Elderly or debilitated patients may be more sensitive to benzodiazepines, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Flurazepam is classified as a Schedule IV controlled substance by federal regulation.

9.2 Abuse and Dependence

Addiction-prone individuals (e.g., history of drug addiction or alcoholism) should be under careful surveillance when receiving flurazepam because of increased risk of abuse and dependence. Benzodiazepine withdrawal symptoms can occur following discontinuation of flurazepam [see Warnings and Precautions (5.2)].

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

10 OVERDOSAGE

Manifestations of flurazepam hydrochloride overdosage include somnolence, confusion and coma. Respiration, pulse and blood pressure should be monitored as in all cases of drug overdosage. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension and CNS depression may be combated by judicious use of appropriate therapeutic agents. The value of dialysis has not been determined. If excitation occurs in patients following flurazepam hydrochloride overdosage, barbiturates should not be used. As with the management of intentional overdosage with any drug, it should be borne in mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be useful in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.

11 DESCRIPTION

Flurazepam hydrochloride is chemically 7-chloro-1-[2-(diethylamino)ethyl]-5-(o-fluoro-phenyl)-1,3dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride. It is a pale yellow, crystalline compound, freely soluble in alcohol and very soluble in water. It has a molecular weight of 460.81 and the following structural formula: