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2008 ‫ ספטמבר‬:‫ עלון מאושר‬."‫"פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר‬
“This leaflet format has been determined by the Ministry of Health and the content thereof has been
checked and approved.” Date of approval: September 2008.
LENITIN
TABLETS
Composition
Each tablet contains:
Active Ingredient
Bromazepam
3 mg
Other Ingredients
Lactose, microcrystalline cellulose, magnesium stearate, silicon dioxide, sodium
starch glycolate, FD&C Red No.3 lake 15%, FD&C Blue No.1 lake 12%.
Lactose content: 105.50 mg per tablet.
Sodium content: 0.045-0.067 mg per tablet.
Mechanism of Action
Lenitin is a pyridyl-benzodiazepine possessing anxiolytic properties. It produces less
sedation than many other benzodiazepine compounds, and possesses mood
elevation properties.
The precise site and mechanism of action have not been completely established,
but it is believed that Lenitin's anxiolytic and sedative properties arise from enhanced
inhibition by gamma-aminobutyric acid (GABA) in the ascending reticular activating
system, blocking both cortical and limb arousal. The muscle relaxant activity may be
due to an enhancement of presynaptic inhibition in the central nervous system, as
well as to a direct peripheral action in the contractile process of the muscle.
Indications
Anxiety and tension states.
Sedation, as a minor hypnotic and premedicant.
Contraindications
Known hypersensitivity to benzodiazepines or to any other ingredient of the
preparation.
First trimester of pregnancy and in breastfeeding.
Labor.
Acute pulmonary insufficiency or severe respiratory insufficiency.
Psychoses and in those suffering from mental depression or suicidal tendencies
unless there is a marked component of anxiety in their illness.
Acute narrow-angle glaucoma (benzodiazepines may be used in patients with openangle glaucoma who are receiving appropriate therapy).
Myasthenia gravis.
Severe hepatic insufficiency (it may cause encephalopathy).
Sleep apnea syndrome.
Warnings
(See also Precautions).
Patients should be checked regularly at the start of treatment in order to minimize
the dosage and/or the frequency of administration, and to prevent overdose due to
accumulation of bromazepam.
Prolonged use may cause dependence.
LENITIN , 4. 9. 2008, RH
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This drug is not recommended for use in patients with a history of drug abuse or
dependence.
Large quantities of benzodiazepines should not be prescribed for patients with
suicidal tendencies, or whose history indicates that they may increase dosage on their
own initiative.
Patients should avoid ingesting alcohol while under treatment with this medicine.
Such concomitant use has the potential to increase the clinical effects of bromazepam
possibly including severe sedation, clinically relevant respiratory and/or
cardiovascular depression (see Drug Interactions).
Withdrawal symptoms similar in character to those noted with barbiturates and
alcohol have occurred following abrupt discontinuation of benzodiazepine drugs.
These symptoms include convulsions, tremor, abdominal and muscle cramps,
vomiting and sweating.
When discontinuing therapy in patients who have used these agents for prolonged
periods, dosage should be decreased gradually to avoid the possibility of withdrawal
symptoms.
Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations,
increased muscle spasticity, rage, insomnia, sleep disturbances and stimulation have
been reported. Should these occur, use of the drug should be discontinued.
Duration of Treatment
In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to
4 weeks). Continuous long-term use of bromazepam is not recommended. There is
evidence that tolerance develops to the sedative effects of benzodiazepines. After as
little as one week of therapy, withdrawal symptoms can appear following the
cessation of recommended doses (eg. rebound insomnia following cessation of a
hypnotic benzodiazepine). The patient should be checked regularly at the start of
treatment in order to minimize the dosage and/or the frequency of administration and
to prevent overdose due to accumulation.
Hypotension
Although hypotension has occurred rarely, bromazepam should be administered with
caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral
complications. This is particularly important in elderly patients.
Amnesia
Transient amnesia or memory impairment has been reported in association with the
use of benzodiazepines. Anterograde amnesia may occur using higher therapeutic
dosages, the risk increasing at higher dosages. Amnesiac effects may be associated
with inappropriate behavior.
Myasthenia Gravis
Bromazepam could increase the muscle weakness in myasthenia gravis and should
not be used in patients with this condition (see Contraindications ).
Impaired Respiratory Function
Respiratory depression may occur following administration of bromazepam. This
effect may be aggravated by pre-existing airway obstruction or brain damage or if
other medications which depress respiration have been given. As a rule, this effect
can be avoided by careful adjustment of the dose to individual requirements.
Acute Narrow-angle Glaucoma
(See Contraindications.)
Caution should be used in the treatment of patients with acute narrow-angle
glaucoma because of atropine-like side effects.
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Depression, Psychosis and Schizophrenia
Bromazepam is not recommended as primary therapy in patients with depression,
anxiety and/or psychosis. In such conditions, psychiatric assessment and supervision
are necessary if benzodiazepines are indicated. Benzodiazepines may increase
depression in some patients and may contribute to deterioration in severely disturbed
schizophrenics with confusion and withdrawal. Preexisting depression may be
unmasked during benzodiazepine use. Suicidal tendencies may be present or
uncovered and protective measures may be required.
Since excitement and other paradoxical reactions can result from the use of
anxiolytic sedatives in psychotic patients, bromazepam should not be used in
ambulatory patients suspected of having psychotic tendencies.
As with other benzodiazepines, bromazepam should not be used in individuals with
physiological anxiety or normal stresses of daily living, but only in the presence of
disabling manifestations of an appropriate pathological anxiety disorder.
These drugs are not effective in patients with characterological and personality
disorders or those with obsessive-compulsive disorders. Bromazepam is also not
recommended for management of depressive or psychotic disorders.
Benzodiazepines should not be used to treat anxiety associated with depression, as
suicide may be precipitated in these patients.
Paradoxical Reactions
Paradoxical reactions such as restlessness, agitation, irritability, rages,
hallucinations, aggressiveness, delusion, nightmares, psychoses, inappropriate
behavior and other adverse behavioral effects, acute rage, stimulation or excitement
may occur; should such reactions occur, bromazepam should be discontinued.
Epilepsy
When bromazepam is administered to persons with convulsive disorders, an
increase in the frequency and/or severity of grand mal seizures may occur,
necessitating increased anticonvulsant medication. Abrupt withdrawal of
benzodiazepines in persons with convulsive disorders may be associated with a
temporary increase in the frequency and/or severity of seizures.
Hereditary Problems
As Lenitin contains lactose, patients with rare hereditary problems such as galactose
intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not
take this drug.
Abuse
Caution must be exercised in administering bromazepam to individuals known to be
addiction prone or those whose history suggests they may increase the dosage on
their own initiative. It is desirable to limit repeat prescription without adequate medical
supervision.
Dependence
The use of benzodiazepines may lead to dependence, as defined by the presence of
a withdrawal syndrome on discontinuation of the medicine. The risk of dependence
increases with dose and duration of treatment; it is also greater in patients with a
history of alcohol or drug abuse.
Tolerance, as defined by a need to increase the dose in order to achieve the same
therapeutic effect, seldom occurs in patients receiving recommended doses under
medical supervision. Tolerance to sedation may occur with benzodiazepines,
especially in those with drug seeking behavior.
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Withdrawal symptoms similar in character to those noted with barbiturates and
alcohol have occurred following abrupt discontinuation of benzodiazepines or
changing to a benzodiazepine with a considerably shorter elimination half-life. These
symptoms range from headaches, muscle pain, insomnia, tension, restlessness,
confusion, irritability, anxiety, dysphoria, palpitations, panic attacks, vertigo,
myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body
sensations (eg. feeling of motion, metallic taste), hyperacusis, numbness and tingling
of the extremities, epileptic seizures, depersonalisation, derealisation, delusional
beliefs, hyperreflexia and loss of short term memory, to a major syndrome which may
include convulsions, tremor, abdominal and muscle cramps, confusional state,
delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating.
Such manifestations of withdrawal, especially the more serious ones, are more
common in patients who have received excessive doses over a prolonged period.
However, withdrawal symptoms have been reported following abrupt discontinuation
of benzodiazepines taken continuously at therapeutic levels. Accordingly,
bromazepam should be terminated by tapering the dose to minimize occurrence of
withdrawal symptoms. Patients should be advised to consult with their physician
before either increasing the dose or abruptly discontinuing the medication.
Rebound phenomena have been described in the context of benzodiazepine use.
Rebound insomnia and anxiety mean an increase in the severity of these symptoms
beyond pre-treatment levels following cessation of benzodiazepines. Rebound
phenomena in general possibly reflect reemergence of pre-existing symptoms
combined with withdrawal symptoms. Some patients prescribed benzodiazepines with
very short half-lives (in the order of 2 to 4 hours) may experience relatively mild
rebound symptoms in between their regular doses. Withdrawal/rebound symptoms
may follow high doses for relatively short periods.
Use in Pregnancy
Benzodiazepines have the potential to cause fetal harm when administered to
pregnant women. If this drug is used during pregnancy or the patient becomes
pregnant while taking this drug, she should be informed of the potential hazard to the
fetus.
Benzodiazepines are assumed to be capable of causing an increased risk of
congenital abnormalities when administered to pregnant women during the first
trimester. Since use of these drugs is rarely a matter of urgency, their use during the
first trimester of pregnancy should almost always be avoided (see Contraindications).
The possibility that women of child-bearing potential may be pregnant when therapy
is instituted should be considered. Patients should be advised that if they become
pregnant during therapy or intend to become pregnant, they should refer to their
physician about the desirability of discontinuing the drug.
Use in Breastfeeding
Benzodiazepines are excreted in breast milk. Since neonates metabolize this drug
more slowly than adults, and accumulation of the drug and its metabolites to toxic
levels is possible, it should not be administered to nursing mothers (see
Contraindications).
Use in Patients with Impairment of Hepatic or Renal Function
In patients with impaired hepatic or renal function, it is recommended to initiate
therapy, if necessary, at a very low dose and to increase the dosage only to the extent
that such an increase is compatible with the degree of residual function of these
organs. Such patients should be followed closely and have periodic laboratory
assessments.
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Use in Pediatrics
Benzodiazepines may impair mental alertness in children. Because of the lack of
sufficient clinical evidence of safety and efficacy, bromazepam is not recommended
for use in this age group.
Use in the Elderly
Elderly and debilitated patients, or those with organic brain syndrome, have been
found to be prone to CNS depression after even low doses of benzodiazepines.
Therefore, medication should be initiated in these patients with very low initial doses,
and increments should be made gradually, depending on the response of the patient,
in order to avoid oversedation or neurological impairment.
An increased risk of falls and fractures has been recorded in elderly benzodiazepine
users.
Adverse Reactions
Adverse Reactions Reported with Bromazepam
Most adverse effects encountered with bromazepam have been referable to the
central nervous system. At mean daily doses of 24 mg, drowsiness (32%), ataxia
(13%) and dizziness (7.6%) have been most frequently reported.
Also reported were behavior disorders (4%), speech disorders (2%), sleep disorders,
confusion, headache, depression, nausea, vomiting, gastrointestinal disturbances
(each 1%), fatigue, numbed emotions and reduced alertness.
Other adverse effects less frequently reported were blurred vision, diplopia, seizures,
restlessness, agitation, aggression, delusion, anger, nightmares, hallucinations,
psychosis, respiratory depression, dry mouth, gastrointestinal disorders, rash,
pruritus, amnesia, tremor, irritability, nervousness, muscle spasm, muscle weakness,
anorexia, incontinence, hypotension, tachycardia, cardiac failure including cardiac
arrest, palpitations, euphoria and decreased libido.
Anterograde amnesia may occur using therapeutic dosages with the risk increasing
at higher dosages. Amnesic effects may be associated with inappropriate behavior.
Minor elevations of bilirubin, AST, ALT, SAP and BUN occurred in about 3% of
patients. There were some instances of decreased haemoglobin and increased white
cell counts.
Adverse Reactions Reported with Benzodiazepines
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, dizziness, and
ataxia, especially in elderly or debilitated patients.
Infrequently reported side effects are as follows:
Central Nervous System
Sedation
and
sleepiness,
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.
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Gastrointestinal
Constipation, diarrhea, dry mouth, nausea, vomiting, increased salivation.
Genitourinary
Incontinence, dysuria, enuresis, changes in libido, urinary retention, menstrual
irregularities.
Cardiovascular
Bradycardia, tachycardia, hypertension, hypotension, palpitations.
Ophthalmological
Visual disturbances, diplopia.
Dermatological
Urticaria, pruritus, skin rash, dermatitis.
Other
Hepatic dysfunction (including hepatitis and jaundice), blood dyscrasias including
agranulocytosis, anemia, thrombocytopenia, eosinophilia, seizures, difficulty in depth
perception, muscle spasm, muscle weakness, increased and decreased blood sugar
levels.
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.
An increased risk for falls and fractures has been reported in elderly users of
benzodiazepines.
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.
Bromazepam 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.
Abilities may be impaired on the day following use.
Liver and kidney function tests and blood counts should be performed regularly
during long-term therapy.
Drug Interactions
Bromazepam/Disulfiram: Concurrent administration of disulfiram with bromazepam,
which is metabolized by hepatic mircosomal oxidation, may result in inhibition of
metabolism of the benzodiazepine, leading to delayed elimination and increased
plasma concentrations of bromazepam.
Patients should be closely observed for evidence of enhanced bromazepam
response during concomitant therapy with disulfiram; some patients may require
reduction in bromazepam dosage.
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Bromazepam/Cimetidine: Concurrent administration of cimetidine with bromazepam,
which undergoes metabolism through hepatic mircosomal oxidation, may result in
inhibition of metabolism of the benzodiazepine, leading to its delayed elimination and
increased plasma concentrations. Dosage reduction of bromazepam may be
necessary in patients receiving concomitant therapy with cimetidine.
Bromazepam/Erythromycin: Concurrent administration of erythromycin with
bromazepam, which is metabolized by hepatic microsomal oxidation, may result in
inhibition of metabolism of the benzodiazepine leading to delayed elimination and
increased plasma concentrations of the benzodiazepine. Dosage reduction of
bromazepam may be required in some patients.
Bromazepam/Drugs that Inhibit P450 liver enzymes: Bromazepam undergoes hepatic
microsomal oxidation via the cytochrome P450 liver enzymes. Therefore, caution
should be taken in patients taking medicines that inhibit the P450 liver enzymes
(e.g. azole antifungals, macrolide antibiotics, HIV protease inhibitors, calcium channel
blocking agents).
Bromazepam/Atropine and Similar Medicines/Antihistamines/Antidepressants: The
anticholinergic effects of atropine and similar medicines, antihistamines and
antidepressants may be potentiated
Bromazepam/Estrogen-Containing Oral Contraceptives: Concurrent administration of
estrogen-containing oral contraceptives with bromazepam, which is metabolized by
hepatic microsomal oxidation, may result in inhibition of metabolism of the
benzodiazepine leading to delayed elimination and increased plasma concentrations
of the benzodiazepine. Dosage reduction of bromazepam may be required in some
patients.
Benzodiazepines/Centrally-Acting Drugs: Benzodiazepines may have a potentiating
effect on centrally-acting drugs such as neuroleptics, tranquilizers, antidepressants,
sedatives, anxiolytics, phenothiazines and other antipsychotics, hypnotics,
barbiturates, antiepileptics, analgesics (including narcotic analgesics, in which case
enhancement of euphoria may also occur leading to an increase in psychological
dependence), skeletal muscle relaxants, antihistamines, and anesthetics. When these
drugs are administered concomitantly with benzodiazepines, their dosage should be
reduced.
Benzodiazepines may also intensify the response to alcohol. Patients should be
advised to avoid drinking alcoholic beverages while under treatment with this drug.
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/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.
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Diagnostic Interference: Minor EEG changes, usually low voltage fast activity, of no
known clinical significance, has been reported with benzodiazepine administration.
Information for Patients
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.
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
Dosage must be adjusted on an individual basis. Usual doses are as follows:
Mild to Moderate Anxiety
3-6 mg, 3 times daily.
Severe Anxiety States
6-12 mg, 3 times daily.
Some patients may be more sensitive to the effects of bromazepam and may
respond to 1.5mg, 3 times daily.
In exceptionally-severe anxiety states in hospitalized patients, up to 60 mg/day may
be administered, in divided doses.
Elderly patients are more sensitive to the actions of Lenitin. Therefore, doses should
not exceed half those normally recommended.
Overdosage
Manifestations
Overdosage of benzodiazepines is usually manifested by degrees of central nervous
system depression ranging from drowsiness to coma. In mild cases, symptoms
include drowsiness, mental confusion and lethargy. In more serious cases, symptoms
may include ataxia, hypotonia, hypotension, respiratory depression, coma and very
rarely death. Coma may be more protracted and cyclical, particularly in elderly
patients. Benzodiazepine respiratory depressant effects are more serious in patients
with respiratory disease.
Benzodiazepines increase the effects of other central nervous system depressants,
including alcohol. When combined with other CNS depressants, the effects of
overdosage are likely to be severe and may prove fatal.
Treatment
In managing overdosage the possibility of multiple drug involvement may be
considered.
The patient’s vital signs should be monitored and isupportive measures should be
instituted as indicated by the patient’s clinical state. In particular, patients may require
symptomatic treatment for cardiorespiratory effects or central nervous system effects.
If the patient is conscious, vomiting should be induced either mechanically or with
emetics. Also, activated charcoal may be administered orally (within 1-2 hours) to
increase clearance, as well as decrease absorption of the benzodiazepine.
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If the patient is unconscious, immediate gastric lavage utilizing a cuffed endotracheal
tube, to prevent aspiration and pulmonary complications, should be employed.
General supportive measures should be employed along with intravenous fluids. An
adequate airway should be maintained.
Hypotension may be combated by the administration of noradrenaline or
metaraminol
If excitation occurs, barbiturates should not be used.
Hemoperfusion and hemodialysis are of limited value.
If CNS depression is severe the use of Flumazenil injection (Anexate), a specific
benzodiazepine-receptor antagonist, should be considered for the complete or partial
reversal of the sedative effects of benzodiazepines, and may be used in situations
when an overdose with a benzodiazepine is known or suspected.
The following should be kept in mind when flumazenil is used in the treatment of
benzodiazepine overdosage:
• Flumazenil should only be administered under closely monitored conditions. In
view of the short half life (about 1 hour)and duration of action of flumazenil, and the
possible need for repeat doses, the patient should be closely monitored until all
possible central benzodiazepine effects (e.g., resedation) have subsided.
• Particular caution is necessary when using flumazenil in cases of multiple drug
overdosage, since the toxic effects (cardiac arrhythmias and/or convulsions) of
other psychotropic drugs, especially cyclic antidepressants, may increase as the
effects of benzodiazepines subside. Flumazenil is contraindicated in patients who
are showing signs of serious cyclic antidepressant overdose.
Warning: The benzodiazepine receptor antagonist flumazenil is not indicated in
patients with epilepsy who have been treated with benzodiazepines. Antagonism of
the benzodiazepine effect in such patients may provoke seizures.
Prior to the administration of flumazenil, the complete package insert of the
product should be consulted, and necessary measures should be instituted to
secure airway, ventilation, and intravenous access.
Flumazenil is intended as an adjunct to, not a substitute for, proper management of
benzodiazepine overdosage. Patients treated with flumazenil should be monitored for
resedation, respiratory depression, and other residual benzodiazepine effects, for an
appropriate period after treatment. Awareness is required regarding a risk of
seizure in association with flumazenil treatment, particularly in long-term
benzodiazepine users and in cyclic antidepressant overdose.
Drug Registration Number:
032 34 22423 00
Manufacturer
Teva Pharmaceutical Industries Ltd
P.O.Box 3190, Petach Tikva 49131
LENITIN , 4. 9. 2008, RH
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