Nitrazadon Product Monograph

INDICATIONS AND CLINICAL USE

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.

NITRAZADON (nitrazepam) is indicated for the short-term treatment and symptomatic relief of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Treatment with NITRAZADON should usually not exceed 7-10 consecutive days. Use for more than 2-3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for NITRAZADON should be written for short-term use (7-10 days) and it should not be prescribed in quantities exceeding a 1-month supply.

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

NITRAZADON is also useful for the management of myoclonic seizures.

CONTRAINDICATIONS

NITRAZADON (nitrazepam) is contraindicated in patients with known hypersensitivity to benzodiazepines, any component to its formulation, and in those with severe impairment of respiratory function, e.g., significant sleep apnea syndrome.

NITRAZADON is contraindicated in patients who have myasthenia gravis or severe hepatic insufficiency. NITRAZADON is contraindicated in children when used as a hypnotic.

WARNINGS

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 7-10 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 behaviour 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. NITRAZADON should be used with caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

Pregnancy: The use of NITRAZADON (nitrazepam) 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 NITRAZADON 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 NITRAZADON. 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 NITRAZADON 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 NITRAZADON, 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 behaviour and a history of unusual reactions to sedatives including alcohol and the benzodiazepines. Psychotic behavioural changes that have been reported with benzodiazepines include bizarre behaviour, hallucinations, and depersonalization. Abnormal behaviours 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 behaviours listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioural sign or symptom of concern requires careful and immediate evaluation.

Confusion: The benzodiazepines affect mental efficiency, 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 has 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. Nitrazepam has an intermediate half-life.

Depression: Caution should be exercised if NITRAZADON 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.

Complex Sleep-related Behaviours: Complex sleep-related behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken NITRAZADON. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events. The use of alcohol and other CNS-depressants with NITRAZADON appears to increase the risk of such behaviours, as does the use of NITRAZADON at doses exceeding the maximum recommended dose. NITRAZADON is not to be taken with alcohol. Caution is needed with concomitant use of other CNS depressant drugs. Due to the risk to the patient and the community, discontinuation of NITRAZADON should be strongly considered for patients who report any such sleep-related behaviours.

Severe Anaphylactic and 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 NITRAZADON. 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 throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with NITRAZADON should not be rechallenged with the drug.

PRECAUTIONS

Drug Interactions: NITRAZADON (nitrazepam) may produce additive CNS depressant effects when co-administered with alcohol, sedative antihistamines, narcotic analgesics, anticonvulsants, antipsychotics (neuroleptics), anesthetics, or antidepressant agents or psychotropic medications which themselves can produce CNS depression. In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychological dependence.

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

Tolerance: Some tolerance to the hypnotic effects of benzodiazepines may develop after repeated use.

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, headache, extreme anxiety, tension, restlessness, confusion and irritability) have occurred following abrupt discontinuation of benzodiazepines, and may follow the discontinuation of NITRAZADON. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations and epileptic seizures. The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1-2 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 if it is at all necessary to administer NITRAZADON to these individuals.

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

It may be useful to inform the patient when treatment is started that it will be of limited duration

and to explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimizing anxiety over such symptoms should they occur while the medicinal product is being discontinued.

Rebound Insomnia: A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness.

Patients with Specific Conditions: NITRAZADON should be given with caution to patients with impaired hepatic or renal function, and is contraindicated in patients with severe impairment of hepatic or respiratory function. Respiratory depression has been reported in patients with compromised respiratory function. A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are not recommended for the primary treatment of psychotic illnesses.

Patients Requiring Mental Alertness: Because of NITRAZADON'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 NITRAZADON and alcohol or CNS depressant drugs.

Bronchial Hypersecretion, Excessive Salivation: In infants and young children, as well as elderly, bed-ridden patients, bronchial hypersecretion and excessive salivation leading to aspiration/pneumonia may occur on rare occasions.

Use in Pregnancy: NITRAZADON is not recommended for use during pregnancy. For teratogenic effects see WARNINGS. Non-teratogenic 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.

Use in Nursing Mothers: Since nitrazepam is excreted in maternal milk, nursing should not be undertaken while the patient is taking NITRAZADON.

Use in Children: The safety and effectiveness of NITRAZADON as a hypnotic in children below the age of 18 have not been established. (See Contraindications Section)

Use in the Elderly: 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 should be used in these subjects.

ADVERSE REACTIONS

The most common adverse reactions are fatigue, dizziness, light-headedness, drowsiness, lethargy, mental confusion, staggering, ataxia and falling. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.

Depressed dreaming and nightmares have also been reported.

Sedative effects can often be decreased by a reduction in dosage. Children, the elderly and/or debilitated patients are more susceptible to sedative effects and paradoxical reactions. Therefore, these patients should be carefully screened before they are given hypnotics and the lowest effective dose should be used. Paradoxical reactions such as agitation, hyperactivity, excitement, hallucinations, increased muscle spasticity, aggressiveness, irritability, rages, psychoses and violent behaviour have been reported in rare instances when using drugs that act at the benzodiazepine receptors. Should these occur, the drug should be discontinued.

Hangover, disorientation, severe sedation, hypotension, signs and symptoms of withdrawal including delirium tremens, and cutaneous reactions have been reported. Headache, heartburn, upset stomach, diarrhea, constipation, nausea, vomiting, weakness, faintness, palpitations, blurred vision, dyspnea, nervousness, apprehension, depression, numbed emotions, changes in libido, inappropriate behaviour, altered hepatic function tests and, in rare instances, leucopenia and granulocytopenia have been reported with this drug or other drugs of this class.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms: The cardinal manifestations are drowsiness, confusion, reduced reflexes, increasing sedation, and coma. Effects on respiration, pulse and blood pressure are noticed with large overdoses. Patients exhibit some jitteriness and over stimulation usually when the effects of the drug begin to wear off.

Treatment: In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken. Following overdose with NITRAZADON vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. If respiratory depression and/or coma are observed, the presence of other central nervous system depressants should be suspected. Respiration, pulse and blood pressure should be monitored. General supportive measures aimed at maintaining cardiopulmonary function should be instituted and administration of intravenous fluids started. Hypotension and CNS depression are managed by the usual means. Dialysis is usually of little value.

Use of Reversal Agent: The benzodiazepine antagonist, flumazenil (Anexate) is a specific antidote in known or suspected benzodiazepine overdose. (For conditions of use see Anexate Product Monograph.)

The use of Anexate is not recommended in epileptic patients who have been treated with NITRAZADON (or any other benzodiazepine). The reversal of the benzodiazepine effect could induce convulsions in such patients.

DOSAGE AND ADMINISTRATION

The lowest effective dose of NITRAZADON (nitrazepam) should be used. Treatment with NITRAZADON should be as short as possible, and should usually not exceed 7-10 consecutive days. Use for more than 2-3 consecutive weeks requires complete re-evaluation of the patient. NITRAZADON should be withdrawn for a treatment-free period at regular intervals to ascertain whether the therapy needs to be continued.

Dosage of NITRAZADON should be individualized for maximal beneficial effect.

NITRAZADON tablets may be swallowed whole, chewed or dissolved in liquid.

Insomnia

Adults: The usual adult dose is 5 or 10 mg before retiring.

Elderly and/or Debilitated Patients: It is recommended that in these patients therapy be initiated with 2.5 mg until individual responses are determined. Doses higher than 5 mg are usually not recommended in the elderly.

Myoclonic Seizures

Children: The usual dose for children (up to 30 kg of body weight) is between 0.3 and 1.0 mg/kg/day given in three divided doses. Treatment should be initiated with a lower dose than the usual recommended dosage range in order to determine tolerance and response. If a dose within the recommended dosage range does not control the condition, a higher dosage may be gradually attempted. Higher doses may cause excessive drowsiness, and may cause bronchial hypersecretion in infants with epilepsy. The use of NITRAZADON in infants with epilepsy must be examined before treatment is started in order to determine whether the upper airways are clear. Whenever possible the daily dosage should be divided into three equal doses. If doses are not equally divided, the larger dose should be given before retiring. In some patients tolerance develops to the effects of nitrazepam.

The use of multiple anticonvulsants may result in an increase of central nervous system depressant adverse effects. This should be borne in mind whenever NITRAZADON is added to an already existing anticonvulsant regimen.

PHARMACEUTICAL INFORMATION

1. i)

   Drug Substance

   Proper Name: Nitrazepam

   Chemical Name: 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one

   Structural Formula:

Molecular Formula: C₁₅H₁₁N₃O₃

Molecular Weight: 281.3

Description: Nitrazepam is a yellow, crystalline powder. It is practically insoluble in water; slightly soluble in ethanol (96%) and in ether; sparingly soluble in chloroform.

ii) Composition

Each NITRAZADON tablet contains either 5 or 10 mg of nitrazepam, BP, crosscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose.

iii) Stability and Storage Recommendations

Store at controlled room temperature at 15-30°C. Protect from light. The medicine should not be used after the expiry date (EXP) shown on the pack.

DOSAGE FORMS

Availability

Each white, round, scored NITRAZADON tablet contains 5 mg nitrazepam, BP. Bottles of 100’s and 500’s.

Each white, round, scored NITRAZADON tablet contains 10 mg nitrazepam, BP. Bottles of 100’s and 500’s.

PHARMACOLOGY

In animal tests, nitrazepam produces sedative, hypnotic, taming, muscle relaxant and anticonvulsant effects. It selectively suppresses metrazole-induced seizures. After I.V. administration of doses of 1 to 8 mg/kg to dogs and cats, nitrazepam did not significantly modify the systolic or diastolic blood pressure. However, in both species, there was a significant reduction in heart rate, particularly evident at the highest dose. Blood pressure response to norepinephrine and serotonin was inhibited while the response to histamine was somewhat prolonged. Nitrazepam had a depressant effect on both the spontaneous and the activated EEG after relatively high intravenous doses, i.e., 1 to 10 mg. The same doses produced a marked reduction in the response to hypothalamic as well as reticular activating system (RAS) stimulations, whereas there was an increase in the threshold upon stimulation of the limbic system.

TOXICOLOGY

Acute Toxicity: LD₅₀'s

SPECIES

ROUTE

DOSE

Mouse i.p.

p.o.

275 mg/kg at 72 hours

1,800 mg/kg

Rat i.p.

p.o.

>2,000 mg/kg at 24 hours

950 mg/kg at 10 days >2,000 at 24 hours

1,000 at 10 days

In dogs, doses of 1,200 mg/kg produced a three-day sleep and all animals survived.

Subacute and Chronic Toxicity Studies: Oral doses of nitrazepam 10, 20, 80, 100, 240 and 320 mg/kg/day were administered to rats in a series of studies lasting from 6 to 78 weeks. At doses of 10, 20, 80 and 100 mg/kg/day no serious side effects were encountered, with the exception of an initial hyperexcitability followed by ataxia, and reduction in weight and food intake in the 100 mg/kg group. At doses of 240 and 320 mg/kg/day a marked reduction in weight and food consumption was observed and most animals presented an unhealthy appearance. At these doses in males, testicular tubular degeneration and aspermiogenesis were produced. Deaths occurred caused either by diarrhea, convulsive seizures of brief duration or other acute toxic effects.

Oral doses of nitrazepam of 10, 20, 40 and 80 mg/kg/day were administered for 6 weeks to dogs. A significant sedative effect was observed at all dose levels. Histopathological examination revealed evidence of liver involvement in the dogs treated with 40 and 80 mg/kg/day (liver enlargement, cloudy swelling of liver). The six-month oral chronic toxicity study in the dog was performed with the same doses as the previous study. Lower doses were well tolerated. There was loss of weight in the 40 and 80 mg/kg groups. Three dogs out of 6 in the 80 mg/kg group died during epileptiform seizures. There was increase weight of livers in the 40 and 80 mg/kg groups. Oral doses of 2.5, 10 and 40 mg/kg/day were administered to dogs in a study, lasting 55 to 56 weeks. At the highest dose elevated leucocyte counts, elevated sedimentation rates, slight increase in liver weights, and edematous swelling of the forepaws were observed. No unusual histopathology was noted.

Reproductive Studies: Reproductive studies in the rat, rabbit, mouse and dog, were performed using doses ranging from 2 to 100 mg/kg/day. At the 100 mg/kg/day dosage in the rat and rabbit, multiple skeletal defects and fetal resorption were produced. Nitrazepam may produce dose-related teratogenic effects in the rat. Changes in fertility and general reproductive performance may be related to its pharmacological action (sedative and hypnotic effect) in the animal species studied.

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