Dalmane (Flurazepam HCl)

DALMANE®

Roche

Flurazepam HCl

Hypnotic

Action And Clinical Pharmacology: Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Flurazepam decreases sleep latency and number of awakenings for a consequent increase in total sleep time.

The duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) and beta (elimination) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. However, during nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e., in relation to the receptor site) may occur at some point in the interval between each night’s use. This sequence of events may account for 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night; and 2) the appearance of increased daytime anxiety (see Warnings).

Flurazepam is a benzodiazepine with a long half-life.

Rebound Insomnia: A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of hypnotic treatment.

Pharmacokinetics: Following oral administration of 15 mg flurazepam to male and female volunteers, measurable concentrations for the parent compound were not detectable. Flurazepam undergoes rapid and pronounced metabolism to 2 pharmacologically active metabolites, namely hydroxyethyl flurazepam and flurazepam aldehyde. In healthy volunteers, Cmax values for the 2 metabolites were 8.6 and 2.5 ng/mL, respectively. They were reached in an average of 1.0 and 1.2 hours, respectively. The mean elimination half-lives for these 2 metabolites were less than 2.5 hours.

The final active and principal metabolite, desalkyl flurazepam (DAFLZ), appears in the systemic circulation more slowly, with a mean Cmax of 14 ng/mL attained an average of 10.6 hours after dosing. The mean elimination half-life of DAFLZ is approximately 75 hours (range 50 to 100 hours). Therefore, multiple-dose therapy with flurazepam leads to the accumulation of DAFLZ.

Following 15 days of treatment with 15 mg flurazepam once daily, mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/mL, p
More than 50% of the total dose of flurazepam appears in the urine in 24 hours, with eventual urinary excretion accounting for 80% or more of the total dose. The major urinary metabolite is conjugated hydroxyethyl flurazepam. Less than 1% of the dose is excreted in the urine as DAFLZ. Approximately 10% of the total dose of flurazepam appears in the feces.

Indications And Clinical Uses: Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.

Flurazepam is indicated for the symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.

Treatment with flurazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for flurazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a one-month supply.

The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning.

Contra-Indications: In patients with known hypersensitivity to the drug, any component of its formulation, or to other benzodiazepines; myasthenia gravis; sleep apnea syndrome. Flurazepam is contraindicated in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

Manufacturers’ Warnings In Clinical States: General: Benzodiazepines should be used with extreme caution in patients with a history of substance or alcohol abuse.

The smallest possible effective dose should be prescribed for elderly patients. Inappropriate, heavy sedation in the elderly, may result in accidental events/falls.

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 or the presence of sleep-state misperception.

Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of drugs that act at the benzodiazepine receptors.

Pregnancy: The use of flurazepam during pregnancy is not recommended. Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines. During the last weeks of pregnancy, ingestion of therapeutic doses of a benzodiazepine hypnotic has resulted in neonatal CNS depression due to transplacental distribution. If flurazepam is prescribed to women of childbearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant or suspects that she might be pregnant.

Memory Disturbance: Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines. The event is rare with flurazepam. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk.

Cases of transient global amnesia and “traveller’s amnesia” have also been reported in association with benzodiazepines, the latter in individuals who have taken benzodiazepines, often in the middle of the night, to induce sleep while travelling. Transient global amnesia and traveller’s amnesia are unpredictable and not necessarily dose-related phenomena. Patients should be warned not to take flurazepam under circumstances in which a full night’s sleep and clearance of the drug from the body are not possible before they need again to resume full activity.

Abnormal thinking and psychotic behavioral changes have been reported to occur in association with the use of benzodiazepines including flurazepam, although rarely. Some of the changes may be characterized by decreased inhibition, e.g., aggressiveness or extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behavior and a history of unusual reactions to sedatives including alcohol and the benzodiazepines. Psychotic behavioral changes that have been reported with benzodiazepines include bizarre behavior, hallucinations, and depersonalization. Abnormal behaviors associated with the use of benzodiazepines have been reported more with chronic use and/or high doses but they may occur during the acute, maintenance or withdrawal phases of treatment.

It can rarely be determined with certainty whether a particular instance of abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Confusion: The benzodiazepines affect mental efficency, e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.

Anxiety, Restlessness: An increase in daytime anxiety and/or restlessness have been observed during treatment with short half-life benzodiazepines although the syndrome can apply on occasion to drugs with longer elimination half-lives as well. Flurazepam has a long half-life.

Depression: Caution should be exercised if flurazepam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug that is feasible should be available to them at any one time.

Precautions: Drug Interactions : Flurazepam may produce additive CNS depressant effects when coadministered with alcohol, sedative antihistamines, narcotic analgesics, anticonvulsants, or psychotropic medications which themselves can produce CNS depression.

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. Examples include cimetidine or erythromycin.

Drug Abuse, Dependence and Withdrawal: Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia) have occurred following abrupt discontinuations of benzodiazepines, and may follow the discontinuation of flurazepam. The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1 to 2 weeks can also have withdrawal symptoms including daytime anxiety between nightly doses. Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks. The recommendation for tapering is particularly important in patients with a history of seizures.

The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders. Caution must be exercised in administering flurazepam to these individuals.

As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.

Patients with Specific Conditions: Flurazepam should be given with caution to patients with impaired hepatic or renal function, or severe pulmonary insufficiency. Respiratory depression has been reported in patients with compromised respiratory function.

Occupational Hazards: Because of flurazepam’s CNS depressant effect, patients receiving the drug should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be warned against the concomitant ingestion of flurazepam and alcohol or CNS-depressant drugs.

Pregnancy: For teratogenic effects see Warnings. Nonteratogenic effects: a child born to a mother who is on benzodiazepines may be at risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity has been reported in an infant born to a mother who had been receiving benzodiazepines.

Lactation: The safety of flurazepam during lactation has not been established. Therefore, its use during nursing is not recommended.

Children: The safety and effectiveness of flurazepam in children below the age of 15 have not been established.

Geriatrics: Elderly patients are especially susceptible to dose-related adverse effects, such as drowsiness, dizziness, or impaired coordination. Inappropriate, heavy sedation may result in accidental events/falls. Therefore, the lowest possible dose (15 mg) should be used in these subjects.

Laboratory Tests: Should flurazepam be used repeatedly, periodic blood counts, liver, and kidney function tests should be performed.

Adverse Reactions: The most common adverse effects reported with flurazepam are dizziness, drowsiness, lightheadedness and ataxia. These adverse effects are particularly common in elderly and debilitated patients (see Precautions). Severe sedation, lethargy, disorientation, and coma, probably indicative of drug intolerance or overdosage, have been reported.

Isolated instances of headache, heartburn, upset stomach, nausea, vomiting, amnesia, constipation, diarrhea, gastrointestinal pain, nervousness, apprehension, irritability, weakness, palpitations, chest pains, and genitourinary complaints have been reported. However, in controlled studies, these appeared as often or more often with placebo than with the active drug.

There have also been rare occurrences of leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations, nightmares, numbed emotions, reduced alertness, changes in libido, inappropriate behavior and elevated AST, ALT, total and direct bilirubins, and alkaline phosphatase. Paradoxical reactions such as excitement, stimulation, agitation, aggressiveness, rages, psychoses and hyperactivity have also been reported in rare instances when using drugs that act at the benzodiazepine receptors.

Symptoms And Treatment Of Overdose: Symptoms: Somnolence, confusion, coma.

Treatment: 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. I.V. 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 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. The benzodiazepine antagonist, flumazenil is a specific antidote in known or suspected benzodiazepine overdose. (For conditions of use see flumazenil product monograph.)

Dosage And Administration: The lowest effective dose should be used. Treatment should be as short as possible, and should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient.

Dosage should be individualized for maximal beneficial effects.

Adults: The usual adult dosage is 30 mg before retiring. In some patients, 15 mg may suffice.

Elderly and/or Debilitated Patients: It is recommended that therapy be initiated with 15 mg until individual responses are determined.

Availability And Storage: 15 mg: Each orange and ivory No. 2 hard gelatin capsule imprinted† (black ink) on both body and the cap contains: flurazepam HCl 15 mg. Nonmedicinal ingredients: allura red AC, brilliant blue FCF sodium salt, cornstarch, erythrosine, gelatin, lactose, magnesium stearate, methylparaben, potassium sorbate, propylparaben, quinoline yellow WS, sunset yellow FCF and talc. Also contains lactose 276 mg. Energy: 5.0 kJ (1.2 kcal). Gluten-, sodium-, sulfite- and tartrazine-free. Bottles of 100.

30 mg: Each red and ivory No. 2 hard gelatin capsule imprinted (black ink) on both body and cap contains: flurazepam HCl 30 mg. Nonmedicinal ingredients: allura red AC, brilliant blue FCF sodium salt, cornstarch, erythrosine, gelatin, lactose, magnesium stearate, methylparaben, quinoline yellow WS, potassium sorbate, propylparaben, sunset yellow FCF and talc. Also contains lactose 263 mg. Energy: 5.0 kJ (1.2 kcal). Gluten-, sodium-, sulfite- and tartrazine-free. Bottles of 100.

Keep in a tightly closed, light-resistant container. Store at 15 to 30°C.

DALMANE® Roche Flurazepam HCl Hypnotic

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