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MOGADON®
Roche
Nitrazepam
Hypnotic - Anticonvulsant
 
Action And Clinical Pharmacology: Nitrazepam is a benzodiazepine with hypnotic and anticonvulsant properties.

In sleep laboratory studies, nitrazepam decreased sleep latency, increased total sleep time and decreased awake time. There is delay in the onset, and decrease in the duration of REM sleep. Nitrazepam is reported to significantly decrease stage 1, 3 and 4 sleep and to increase stage 2. Following discontinuation of the drug, REM sleep rebound has been reported in some studies.

Nitrazepam has been shown to raise the seizure threshold.

General Benzodiazepine: 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 two 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).

Nitrazepam has an intermediate 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: Nitrazepam is rapidly absorbed from the gastrointestinal tract. Bioavailability after an oral dose averages about 80%. Peak blood concentrations after oral administration are observed in approximately 3 hours.

Following the administration of single oral doses of 5 or 10 mg nitrazepam to healthy volunteers, mean peak plasma concentrations ranged between 23 to 66 ng/mL and 55 to 107 ng/mL, respectively. In elderly patients suffering from various debilitating diseases, a mean peak plasma concentration of 22 ng/mL was observed after a single dose of 5 mg nitrazepam. Steady-state plasma concentrations following administration of 5 mg nitrazepam once daily were reached after approximately 4 days. Steady-state plasma concentrations of nitrazepam were approximately 40 ng/mL.

Nitrazepam is a lipophilic drug and crosses the membrane barriers of the body readily. The concentrations in cerebrospinal fluid, about 10% of the total plasma level, are similar to the protein free fraction of plasma. Following oral administration, mean volumes of distribution were greater in elderly patients than in young volunteers (4.8±1.7 vs 2.4±0.8 L/kg, respectively). Total clearance was not significantly different in the two groups (78±25 and 68±33 mL/min, respectively).

Nitrazepam has no clinically active metabolites. The drug is excreted in human urine mainly as conjugated and non-conjugated aminonitrazepam and aceta-midonitrazepam. When given orally, 65 to 71% of the dose eventually appears in the urine and 14 to 20% in the feces. Only about 1% of the administered dose is excreted in the urine as unchanged nitrazepam. The major pathway involves hepatic nitroreduction.

The half-life of nitrazepam in healthy young volunteers is approximately 30 hours (range 18 to 57 hours). Elderly, ill patients showed a prolonged half-life of approximately 40 hours. Due to its slow elimination, nitrazepam accumulates when taken every night.

Approximately 87% of unchanged nitrazepam is bound to plasma proteins. In patients with liver cirrhosis, protein binding was significantly less than in healthy subjects (19 vs 14% unbound). In patients with mild to moderate renal insufficiency, protein binding was somewhat less than in healthy volunteers (16.8 vs 15.0% unbound).

Nitrazepam crosses the placental barrier and is excreted in maternal milk. Milk nitrazepam concentrations increased significantly from the first (30 nmol/L) to the fifth morning (48 nmol/L) in nursing mothers receiving 5 mg nitrazepam at night. The milk to plasma ratio of nitrazepam was 0.27 after 7 hours and did not vary from day 1 to day 5.

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.

Nitrazepam 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 awakenings.

Treatment with nitrazepam 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 nitrazepam should be written for short-term use (7 to 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.

Nitrazepam is also useful for the management of myoclonic seizures.

Contra-Indications: In patients with known hypersensitivity to the drug, any component to its formulation, or to other benzodiazepines; myasthenia gravis; sleep apnea syndrome.

Nitrazepam 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.

Geriatrics: 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 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 ditribution. If nitrazepam 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 nitrazepam. 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 nitrazepam 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 nitrazepam, 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 behavior 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 behavior 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 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 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. Nitrazepam has an intermediate half-life.

Depression: Caution should be exercised if nitrazepam 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 : Nitrazepam 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 discontinuation of benzodiazepines, and may follow the discontinuation of nitrazepam. 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 if it is at all necessary to administer nitrazepam to these individuals.

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

Patients with Specific Conditions: Nitrazepam 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 nitrazepam 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 nitrazepam and alcohol or CNS depressant drugs.

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

Pregnancy: Nitrazepam is not recommended for use during 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: Since nitrazepam is excreted in maternal milk, nursing should not be undertaken while the patient is taking nitrazepam.

Children: The safety and effectiveness of nitrazepam as a hypnotic in children below the age of 18 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 should be used in these subjects.

Adverse Reactions: The most common adverse reactions are fatigue, dizziness, lightheadedness, drowsiness, lethargy, mental confusion, staggering, ataxia and falling.

Depressed dreaming and nightmares have also been reported.

Sedative effects can often be decreased by a reduction in dosage. 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 behavior 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 behavior, altered hepatic function tests and, in rare instances, leukopenia and granulocytopenia have been reported with this drug or other drugs of this class.

Symptoms And Treatment Of Overdose: 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 overstimulation usually when the effects of the drug begin to wear off. tag_Treatment

Treatment: Immediate gastric lavage may be beneficial if performed soon after ingestion of nitrazepam. If respiratory depression and/or coma are observed, the presence of other CNS depressants should be suspected. Respirations, pulse and blood pressure should be monitored. General supportive measures aimed at maintaining cardiopulmonary function should be instituted and administration of i.v. fluids started. Hypotension and CNS depression are managed by the usual means. Dialysis is usually of little value.

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

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

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 effect.

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 not usually recommended in the elderly.

Myoclonic seizures: Children: (up to 30 kg of body weight) between 0.3 and 1.0 mg/kg/day given in 3 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. Whenever possible the daily dosage should be divided into 3 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 CNS depressant adverse effects. This should be borne in mind whenever nitrazepam is added to an already existing anticonvulsant regimen.



Availability And Storage: 5 mg: Each white cylindrical, bi-plane scored tablet, contains: nitrazepam 5 mg. Energy: 1.68 kJ (0.4 kcal). Nonmedicinal ingredients: cornstarch, lactose and magnesium stearate. Bottles of 100 and 500.

10 mg: Each white, cylindrical, bi-plane, scored tablet, contains: nitrazepam 10 mg. Energy: 3.2 kJ (0.8 kcal). Nonmedicinal ingredients: cornstarch, lactose and magnesium stearate. Bottles of 100 and 500.

Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Protect from light. Store at 15 to 30°C. (Shown in Product Recognition Section)