Adverse reactions : תופעות לוואי

Adverse Reactions
Adverse reactions with different benzodiazepines vary in type and frequency. Some are dose-related, while others involve individual patient sensitivity. Although not all of the following adverse reactions have been attributed specifically to each benzodiazepine drug, the potential for their occurrence exists. This should be borne in mind when drugs of this class are administered.
Side effects most commonly reported have been drowsiness, fatigue and ataxia, especially in elderly or debilitated patients.
Infrequently reported side effects are as follows:

Central Nervous System
Sedation and sleepiness, hangover, tiredness, drowsiness during the day, ataxia, tremor, amnesia, excitation, daytime sedation, disorientation, hallucinations, agitation, anxiety, depression, lethargy, apathy, hypoactivity, lightheadedness, disorientation, restlessness, confusion, delirium, headache, slurred speech, dysarthria, syncope, vertigo, dizziness, nervousness, vivid dreams, psychomotor retardation.
Occasionally, prolonged use with this medicine may cause behavioral changes and paranoid symptoms.

Gastrointestinal
Constipation, diarrhea, dry mouth, nausea, vomiting, increased salivation, hiccups.

Genitourinary
Incontinence, dysuria, enuresis, changes in libido, urinary retention, menstrual irregularities.

Cardiovascular
Bradycardia, tachycardia, hypertension, hypotension, palpitations, cardiac failure including cardiac arrest .

Ophthalmological
Visual disturbances, diplopia.

Dermatological
Urticaria, pruritus, skin rash, dermatitis, sweating, angioedema.
Musculoskeletal and Connective Tissue Disorders
Muscle weakness. This phenomenon occurs predominantly at the start of therapy and usually disappears with prolonged administration.

Immune System Disorders:
Hypersensitivity reactions, including rash, angioedema and hypotension, may occur.

Respiratory Disorders
Respiratory depression.


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Other
Hepatic dysfunction (including hepatitis and jaundice), blood dyscrasias including agranulocytosis, anemia, thrombocytopenia, eosinophilia.
More frequent adverse reactions indicative of possible withdrawal synptoms following abrupt discontinuation, and necessitating medical attention (if they occur within 2-3 days with short to intermediate half-life benzodiazepines, and 10-20 days with long half-life benzodiazepines) include: irritability, nervousness, and trouble in sleeping.

Other adverse reactions: falling, asthenia, collapse, unsteadiness, muscle weakness.

Injury, Poisoning and Procedural Complications: An increased risk for falls and fractures has been reported in elderly benzodiazepine users

Postmarketing experience
Paradoxical reactions
Restlessness, irritability, nightmares, inappropriate behaviour, delusions, aggressiveness and psychoses.

Special senses
Double vision.

Urogenital system
Changes in libido.
Central nervous system
Pre-existing depression may be unmasked during benzodiazepine use.

Precautions
In elderly or debilitated patients and in children, the initial dose should be low and dosage increments made gradually, in accordance with the response of the patient, to preclude ataxia or excessive sedation.
Although hypotension has rarely occurred, administer with caution to patients in whom a drop in blood pressure might lead to cardiac complications.
Caution should be exercised in patients with chronic pulmonary insufficiency, and in patients with impaired renal or hepatic function.
Flunitrazepam clearance is increased in cigarette smokers, probably due to enzyme induction.
Patients who experience drowsiness during treatment should be warned that their ability to perform potentially-hazardous tasks requiring mental alertness or physical coordination , such as driving a vehicle or operating machinery, may be impaired.
Because of a possible muscular relaxant effect, caution should be exercised when administering this drug in patients with myasthenia gravis.
Liver and kidney function tests and blood counts should be performed regularly during long-term therapy.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Drug Interactions
Flunitrazepam/Estrogen-Containing Oral Contraceptives/Cimetidine/Disulfiram: Concurrent administration of estrogen-containing oral contraceptives, disulfiram or cimetidine with flunitrazepam, which is metabolized primarily by nitro-reduction, may result in inhibition of hepatic metabolism of the benzodiazepine leading to delayed elimination and increased plasma concentrations of the benzodiazepine. Dosage reduction of fllunitrazepam may be required in some patients.

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Benzodiazepines/Centrally-Acting Drugs/Alcohol: Benzodiazepines may have a potentiating effect on centrally-acting drugs such as barbiturates, neuroleptics, tranquilizers, antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, hypnotics, antiepileptics, sedatives, analgesics (including narcotic analgesics), skeletal muscle relaxants, antihistamines, and anesthetics. When these drugs are administered concomitantly with benzodiazepines, their dosage should be reduced.
In case of narcotic analgesics, enhancement of euphoria may also occur, leading to an increase in psychological dependence.
Benzodiazepines may also intensify the response to alcohol. Patients should be advised to avoid drinking alcoholic beverages while under treatment with this drug.
Benzodiazepines/Anticholinergics: The anticholinergic effects of other drugs, including atropine and similar drugs, antihistamines and antidepressants may be potentiated.
Benzodiazepines/Anticonvulsants: Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently.
Benzodiazepines/Cisapride: Cisapride may lead to a temporary increase in the serum levels, and thus sedative effects, of orally administered benzodiazepines due to faster absorption.
Benzodiazepines/Anticoagulants/Antidiabetics: There appears to be no interaction with coumarin anticoagulants or oral diabetic agents.
Benzodiazepines/Levodopa: Rare reports indicate that patients treated with levodopa experienced diminished control of parkinsonian symptoms when chlordiazepoxide or diazepam was added to their therapeutic regimen, For this reason, benzodiazepines should be administered with caution to patients receiving levodopa.
Benzodiazepines/Digoxin: Limited evidence suggests that some benzodiazepines, namely diazepam and alprazolam, may reduce the renal excretion of digoxin, resulting in an increased plasma half-life of the cardiac glycoside and possibe digoxin toxicity.
Although the exact mechanism for the effect of benzodiazepines on the renal excretion of digoxin has not been clearly elucidated, serum digoxin concentrations should be monitored and patients should be carefully observed for signs and/or symptoms of digoxin toxicity during concomitant therapy. Dosage reduction of digoxin may be necessary in some patients receiving concomitant therapy.
Benzodiazepines/Rifampin/Isoniazid: Concurrent use may enhance the elimination of diazepam, resulting in decreased plasma concentrations; dosage adjustment of the benzodiazepine may be necessary. Data as to whether this effect applies to other benzodiazepines are not available.

Known Inhibitors of Hepatic Enzymes: e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action, and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines 
Diagnostic Interference: Minor EEG changes, usually low voltage fast activity, of no known clinical significance, have been reported with benzodiazepine administration.

Information for Patients
(see also Dosage and Administration)

Treatment is usually intended for short periods only. Patients should be instructed to consult their physician after 2-4 weeks of the treatment.
Since benzodiazepines may produce psychologic and physical dependence, patients should be advised to consult their physician before increasing the dose of, or abruptly discontinuing, benzodiazepine therapy.

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Patients should be advised to exercise caution if drowsiness, dizziness, lightheadedness, or clumsiness or unsteadiness occurs, especially in the elderly, who are more sensitive to the CNS effects of benzodiazepines.

Dosage and Administration
Treatment should be as short as possible and should be started with the lowest recommended dose. The maximum dose should not be exceeded. Generally the duration of treatment varies from a few days to two weeks with a maximum of four weeks, including the tapering off process. Patients who have taken benzodiazepines for a prolonged time may require a longer period during which doses are reduced. Specialist help may be appropriate. Little is known regarding the efficacy or safety of benzodiazepines in long-term use.

In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status. Long-term chronic use is not recommended.

The product should be taken just before going to bed.

The dosage should be carefully adapted to the age and the general condition of the patient and to the nosological classification of the sleep disturbance.
Adults: Half a tablet at bedtime. In severe insomnia, 1 tablet at bedtime.
Elderly Patients: One quarter of a tablet at bedtime. In severe insomnia, half a tablet at bedtime.