Lexotanil is used for the treatment of emotional disorders: anxiety and tension states, as adjuvant therapy for anxiety in depression, nervous tension, restlessness, and anxiety- and tension-related insomnia.
Lexotanil can also be used for the treatment of functional or psychosomatic impairments of various organs caused or exacerbated by anxiety and tension, and possibly as an adjuvant to treatment of underlying disease of the
− cardiovascular and respiratory systems (e.g. pseudoangina, precordial anxiety, tachycardia, hypertension of emotional origin, dyspnea, hyperventilation);
− gastrointestinal tract (e.g. adjuvant treatment of irritable bowel syndrome, ulcerative colitis, epigastric pain, spasm, abdominal distension, diarrhea);
− urogenital system (e.g. irritable bladder, urinary frequency, adjuvant treatment of dysmenorrhea);
− other psychosomatic disorders (e.g. adjuvant treatment of psychogenic headache, psychogenic dermatoses).
Lexotanil is also suitable for treatment of anxiety and tension states due to chronic organic disease and as an adjuvant to psychotherapy in psychoneuroses.

Standard dosage
Average dose for outpatient treatment: 1.5 – 3 mg up to three times daily.
In severe cases, especially for inpatients: 6 – 12 mg two to three times daily.
The doses indicated represent general guidelines and must be individually tailored in each case. Treatment of outpatients should begin with low doses, which should be gradually titrated to the optimum level.
Duration of treatment
The duration of treatment should be as short as possible. The patient’s condition should be reassessed at regular intervals and the need for continuation of treatment determined, especially when the patient’s symptoms have resolved. As a general rule, the total duration of treatment should not exceed 8 – 12 weeks, including a tapering-off period. In certain cases, treatment may need to be continued beyond the maximum recommended duration, but only after careful reassessment of the patient’s condition and the indication.
Patients should be examined regularly at the start of treatment in order to minimize the dose and/or frequency of administration and to avoid the risk of overdose of the product due to accumulation.
At the outset it may be useful to inform the patient that the duration of treatment will be for a limited time only and that the dose will be gradually reduced at the end of the treatment period. It is important for the patient to be aware that rebound effects and withdrawal symptoms may occur when treatment is discontinued.
Special dosage instructions Use in pediatric patients
As with other benzodiazepines, Lexotanil should only be given to children and adolescents after careful consideration of the relative risks and benefits. If treatment with Lexotanil is considered by a doctor to be indicated, the dose should be adjusted to the child’s lower body weight.
Use in elderly patients
Elderly patients require lower doses due to potentially increased sensitivity and different pharmacokinetics.
Impaired hepatic function
Patients with severe hepatic impairment should not be treated with Lexotanil tablets. Patients with mild or moderate hepatic impairment should receive the lowest possible dose.

Lexotanil is contraindicated in patients with hypersensitivity to benzodiazepines or any of the excipients, severe respiratory insufficiency, sleep apnea syndrome, myasthenia gravis or severe hepatic impairment (benzodiazepines may exacerbate hepatic encephalopathy). Patients known or suspected to be dependent on CNS depressants, including alcohol, must not take benzodiazepines.

Caution should be exercised in patients with chronic respiratory insufficiency, in view of the risk of respiratory depression.
Benzodiazepines are not suitable for the primary treatment of a psychotic disorder.
Benzodiazepines should not be used alone to treat depression or anxiety states associated with depression.
Amnesia
Benzodiazepines can cause anterograde amnesia. This means that things may happen (usually a few hours) after taking the medication that the patient cannot later remember. This risk increases with the dose.
Dependence
The use of benzodiazepines may cause physical and psychological dependence. This risk is increased with prolonged use, at high dosages and in predisposed patients in whom abuse of alcohol, medicinal products, or illegal drugs has previously been diagnosed. Abuse of the medicinal product has been reported more frequently in cases of multiple substance use.
Withdrawal
Once physical dependence has developed, discontinuation of treatment will be accompanied by withdrawal symptoms. These may comprise headache, diarrhea, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or convulsions.
Withdrawal symptoms may also occur when switching from one benzodiazepine to another drug in the same class with a substantially shorter elimination half-life.
Depending on the duration of action of the substance, the onset of withdrawal symptoms can vary from a few hours to a week or more after discontinuation of treatment.
To keep the risk of dependence to a minimum, benzodiazepines should be prescribed only after careful assessment of the indication and should be used for the shortest possible period (e.g. as a hypnotic they should not generally be used for longer than 4 weeks). The need for continued treatment must be reviewed periodically. Longer-term treatment is only indicated in certain patients (e.g. for panic attacks), the benefits being less clear in relation to the risks.
Rebound phenomenon
Rebound phenomenon is a transient syndrome in which the symptoms that led to treatment with Lexotanil occur in more severe form on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness.

To prevent withdrawal symptoms or rebound phenomena, tapering off is recommended as the standard method of discontinuation, i.e. the dose should be gradually reduced. Should withdrawal symptoms or rebound phenomena occur, the patient will require close medical supervision and support.
General precautions
Concomitant use of alcohol/CNS depressants
The concomitant use of Lexotanil with alcohol and/or CNS depressants should be avoided. Such concomitant use can potentially intensify the clinical action of Lexotanil, possibly with heavy sedation and clinically relevant respiratory and/or cardiovascular depression, which may result in coma or death (see Interactions and Overdose).
Lexotanil should be used with extreme caution by patients in whom abuse of alcohol, medicinal products, or illegal drugs has previously been diagnosed.
Tolerance
Repeated use of Lexotanil for long periods can lead to a reduction in the response to the action of benzodiazepines.
Lexotanil tablets contain lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take Lexotanil tablets.
Impaired hepatic function
Benzodiazepines may play a contributory role in precipitating episodes of hepatic encephalopathy in patients with severe hepatic impairment (see “Contraindications”). Particular caution is required when administering Lexotanil to patients with mild to moderate hepatic impairment.
Psychiatric and “paradoxical” reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, anxiety, delusion, fits of rage, nightmares, hallucinations, psychosis, inappropriate behavior and other adverse behavioral effects are known to occur with the use of benzodiazepines. If such reactions occur, use of the drug should be discontinued. They are more likely to occur in children and elderly patients than in other patients.
Elderly patients
The pharmacological effects of benzodiazepines appear to be greater in elderly patients than in younger patients, even at similar plasma concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms and organ function. Dose reduction is recommended in patients over 50 years old.

Pharmacodynamic drug-drug interaction (DDI)
Increased adverse reactions such as sedation and cardiorespiratory depression may occur when bromazepam is used in combination with CNS depressants, including alcohol.
Alcohol should be avoided by patients taking bromazepam (see also General precautions). Advice on other CNS depressants, including alcohol, is also given under Overdose.
In the case of narcotic analgesics intensification of euphoria can occur, which can lead to increased dependence.
In patients receiving muscle relaxants, the increased risk of muscular weakness should be borne in mind.
There is an increased risk of respiratory depression.
Pharmacokinetic drug-drug interaction (DDI)
There is a possibility that compounds which inhibit key oxidative hepatic enzymes may enhance the activity of benzodiazepines. Coadministration of cimetidine, an inhibitor of several CYP enzymes, and possibly propranolol may prolong the elimination half-life of bromazepam through a substantially reduced clearance (with cimetidine: reduction by 50%). Combined administration with fluvoxamine, an inhibitor of CYP1A2, results in significantly increased bromazepam exposure (2.4-fold higher AUC) and elimination half-life (1.9-fold higher).
Bromazepam had no effect on phenazone metabolism, a surrogate marker for CYP1A2, CYP2B6,
CYP2C and CYP3A activity. Moreover, bromazepam did not induce major CYP450 isozymes in vitro at the level of mRNA; nor did it activate nuclear hormone receptors. Therefore, bromazepam is unlikely to cause pharmacokinetic drug-drug interactions based on CYP450 induction.

Lexotanil should not be used during pregnancy unless it is clearly necessary and there is no safer alternative available.
If the drug is prescribed to a woman of child-bearing age, she should be advised to tell her doctor if she plans to become or suspects that she is pregnant, so that treatment may be discontinued.
The safety of bromazepam in pregnant women has not been established. There is no evidence from spontaneously reported adverse drug reactions that the incidence is any higher than would be expected in a similar, untreated group of patients. Several studies have reported an increased risk of congenital malformations when tranquillizers (diazepam, meprobamate or chlordiazepoxide) are taken during the first trimester of pregnancy.
In humans, the risk of malformation associated with the use of therapeutic doses of benzodiazepines in early pregnancy appears to be low, although some epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of malformations and mental retardation in children exposed prenatally after overdose and intoxication.

Use of bromazepam during the last trimester of pregnancy or during labour is allowed only if the clinical indication has been rigorously established, as the pharmacological action of the product means that effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression can be expected.
Moreover, infants born to mothers who took benzodiazepines regularly during the later stages of pregnancy may have developed physical dependence and may therefore be at risk of developing withdrawal symptoms in the postnatal period.
Lactation
As benzodiazepines pass into breast milk, Lexotanil should not be taken by nursing mothers or else breastfeeding should be discontinued.

As a consequence of the action and possible side effects of the drug, the ability to drive, operate machinery or undertake any other hazardous activities may be impaired. Patients should therefore abstain from such activities entirely or at the very least for the first few days of treatment. The decision in each individual case must be made by the doctor in charge of the patient’s treatment on the basis of individual reaction and the administered dose. The patient must also be warned to abstain from alcohol while on the drug, as this combination can potentiate the undesirable effects of both substances.

Post-marketing experience
During treatment with bromazepam, the following adverse effects can be expected to occur with the greatest frequency: sedation, dizziness, drowsiness, hypotension, poor concentration and slow reactions. There have been frequent reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Psychiatric disorders
Confusional state, disorientation, emotional and mood disturbances. These effects occur primarily at the start of treatment and generally disappear with continued use.
Pre-existing depression may be unmasked during treatment with benzodiazepines.
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, fits of rage, nightmares, hallucinations, psychosis, inappropriate behavior, nervousness, anxiety, abnormal dreams, hyperactivity and other adverse behavioral effects are known to occur. Such reactions are more common in children and elderly patients than in other patients.
Nervous system disorders
Common: Fatigue, drowsiness, headache, poor concentration, dizziness, slow reactions.
Rare: Ataxia, anterograde amnesia.
These effects occur primarily at the start of treatment and generally disappear with continued use.
Anterograde amnesia may occur at therapeutic doses, with the risk increasing at higher doses. This means that things may happen (usually a few hours) after taking the medication that the patient cannot later remember.

Eye disorders
Double vision
This effect occurs primarily at the start of treatment and generally disappears with continued use.
Ear and labyrinth disorders
Common: Dizziness
This effect occurs primarily at the start of treatment and generally disappears with continued use.
Cardiac disorders
Heart failure, including cardiac arrest.
Respiratory, thoracic and mediastinal disorders
Respiratory depression.
Gastrointestinal disorders
Uncommon: Gastrointestinal disturbances
Rare: Nausea, dry mouth, increased appetite.
Skin and subcutaneous tissue disorders
Uncommon: Dermatological reactions
Musculoskeletal and connective tissue disorders
Rare: Muscle weakness
This effect occurs primarily at the start of treatment and generally disappears with continued use.
Reproductive system and breast disorders
Uncommon: Changes in libido
Dependence
Long-term use (even at therapeutic doses) can lead to physical and psychological dependence: withdrawal symptoms or rebound effects may occur when the drug is discontinued (see Warnings and precautions). Abuse of benzodiazepines is more common in multiple substance use.
To report any side effect(s):
• Saudi Arabia:
− The National Pharmacovigilance Centre (NPC)
• SFDA Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/

• Other GCC States:

− Please contact the relevant competent authority.

Symptoms
Overdosage with benzodiazepines commonly leads to stupor, ataxia, dysarthria, and nystagmus.
Although overdosage with Lexotanil is rarely life-threatening when the product has been taken on its own, it can lead to areflexia, apnea, hypotension, cardiorespiratory depression, and coma. If coma develops, it generally lasts only a few hours, but can sometimes be protracted and cyclic, particularly in the elderly. Respiratory depression caused by benzodiazepines is more severe in patients with respiratory illnesses.
Benzodiazepines potentiate the effects of other CNS depressants, including alcohol.
Treatment
Monitor the patient’s vital functions and instigate whatever supportive measures are indicated by his/her clinical state. Patients may, in particular, require symptomatic treatment of cardiorespiratory or CNS effects.
Further absorption should be prevented by appropriate means, e.g. by treatment with activated charcoal within 1–2 h. In drowsy patients, airway protection is essential if activated charcoal is administered. If more than one substance has been ingested, gastric lavage may be considered, but is not a routine countermeasure.
In patients with serious CNS depression, administration of the benzodiazepine antagonist flumazenil (Anexate®) should be considered. This product must, however, be administered under close supervision and, because it only has a short half-life (about one hour), patients administered flumazenil must be kept under supervision once its effects have worn off. Flumazenil must be used with extreme caution after ingestion of substances that lower the seizure threshold (e.g. tricyclic antidepressants). For further information on the correct use of flumazenil (Anexate®), refer to the prescribing information for the product.

Pharmacotherapeutic group: benzodiazepines (GABA receptor inhibitor), ATC code: N05BA08.
Mechanism of action/pharmacodynamics
The central effect of benzodiazepines is mediated by potentiation of GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines, the affinity of the GABA receptor for the neurotransmitter is increased by positive allosteric modulation, resulting in an enhanced effect of released GABA on chloride ion influx through the postsynaptic membrane.
At low doses, Lexotanil relieves anxiety, tension and nervousness. At high doses, it has sedative and muscle relaxant effects.

Clinical efficacy
Clinical efficacy has been demonstrated in various clinical studies.

 

Absorption
After oral administration of bromazepam, peak plasma concentrations are reached within 2 h. The absolute bioavailability from the tablet (relative to the i.v. solution) is 60%. Food may decrease the bioavailability of bromazepam, although it has not been demonstrated that this is clinically relevant. The degree of absorption remains constant after ingestion of multiple bromazepam doses; steady-state concentrations are calculable and confirm the linear kinetics of the active substance. Steady-state plasma concentrations are reached in about five to nine days. Following multiple oral doses of 3 mg three times daily, the average maximum steady-state concentration of bromazepam was 120 ng/ml, which is three- to four-fold higher than that observed after a single 3 mg dose.
Distribution
Bromazepam is rapidly distributed in the body after absorption. On average, 70% of bromazepam is bound to plasma proteins by hydrophobic interaction; binding partners are albumin and α1-acid glycoprotein. The volume of distribution is about 50 litres.
Metabolism
Bromazepam is extensively metabolized in the liver. No metabolites are formed that have a longer half-life than the parent compound. Quantitatively, two metabolites predominate: 3-hydroxybromazepam (less active than bromazepam) and 2-(2-amino-5-bromo-3- hydroxybenzoyl)-pyridine (inactive).
Bromazepam is metabolized, at least in part, through cytochrome P450 (CYP450). However, it is still unclear exactly which CYP isozymes are involved in this process. Nevertheless, the observations that a strong CYP3A4 inhibitor (itraconazole) and a moderate CYP2C9 inhibitor (fluconazole) have no effect on the pharmacokinetics of bromazepam suggest that these isozymes are not involved to a major extent. However, the pronounced interaction with fluvoxamine (see Interactions) points to involvement of CYP1A2.
Elimination
Bromazepam has an elimination half-life of about 20 hours and an elimination clearance of about 40 ml/min.
The drug is mainly eliminated by metabolism. Only about 2% of bromazepam is excreted unchanged in the urine, while the glucuronide conjugates of 3-hydroxybromazepam and 2-(2- amino-5-bromo-3-hydroxybenzoyl)-pyridine account, respectively, for 27% and 40% of the administered dose.
Pharmacokinetics in special populations
Elderly patients
Elderly patients may have significantly higher peak concentrations, a smaller volume of distribution, a greater unbound serum fraction, lower clearance and hence also a prolonged elimination half-life. This indicates that steady-state concentrations of bromazepam at any dosing rate will be on average nearly twice as high in elderly patients as in younger patients (see Dosage and administration, Special dosage instructions).
Impaired renal function
No special pharmacokinetic study has been conducted and no population pharmacokinetic data have been collected in patients with renal impairment.
Impaired hepatic function
No special pharmacokinetic study has been conducted and no population pharmacokinetic data have been collected in patients with hepatic impairment.

Carcinogenicity
Carcinogenicity studies in rats have not brought to light evidence of any carcinogenic potential for bromazepam.
Genotoxicity
In-vitro and in-vivo tests have not brought to light evidence of any mutagenic potential for bromazepam.
Impairment of fertility
Daily oral administration of bromazepam in rats had no effect on the animals’ fertility and general reproductive ability.
Reproductive toxicity
An increase in fetal mortality and in the number of stillbirths and a reduction in the survival rate of the offspring was observed after administration of bromazepam to pregnant rats. In embryotoxicity/teratogenicity studies, no teratogenic effects were observed at dosages of up to 125 mg/kg/day.
After oral doses of up to 50 mg/kg/day in pregnant rabbits, reduced maternal weight gain, lower fetal weight, and increased occurrence of fetal reabsorption were observed.

microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate, red iron oxide.

NA

60 months.

Do not store above 30°C. Keep out of reach of children.

PVC blister, contains 100 of 30mg tablet.3 mg tablets (scored; light red) 30, 100
*Not all pack sizes may be marketed.

No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.