Teratogenicity No adverse maternal or embryo-foetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies. Peak plasma concentrations of clonazepam are reached in 1-4 hours. PHARMACOLOGICAL PROPERTIES AND EFFECTS Pharmacodynamic Properties Mechanism of Action: Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Preclinical Safety Carcinogenicity: No 2-year carcinogenicity studies have been conducted with clonazepam. In several rabbit studies following doses of clonazepam of up to 20 mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused sternebrae and limb defects) was observed (see 2.5.1 Pregnancy). In patients with panic disorders; effective concentrations of clonazepam for reducing the frequency of panic attacks were around 20 ng/ml. Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. 50-70% of the dose is excreted in the urine and 10-30% in faeces as metabolites. In children clearance values of 0.42+/- 0.32 ml/min/kg (ages 2-18 years ) and 0.88 +/- 0.4 ml/min/kg (ages 7-12 years ) were reported; these values decreased with increasing body weight. Mutagenicity: Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam. In neonates 0.10 mg/kg doses led to concentrations between 28-117 ng/ml at the end of a short infusion, dropping to 18 – 60 ng/ml 30 minutes later; these were tolerated with no appreciable side effects. Pharmacokinetics in Special Populations Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Elimination: The mean elimination half-life is 30-40 hours and is independent of the dose. The distribution half-life is approximay 0.5-1 hour. Elimination half-life values in neonates are of the same magnitude as those reported in adults. Severe toxic effects including increased frequency of seizures developed in the majority of patients with steady state plasma concentrations above 100 ng/ml. In neonates clearance values are dependent on post-natal age. The target anticonvulsant plasma concentrations of clonazepam range from 20 to 70 ng/ml. Distribution Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures. Hydroxylation at the C-3 position also occurs. Plasma concentrations of clonazepam at steady state for a once-daily dosage regimen are 3-fold higher than those after a single oral dose; the predicted accumulation ratios for two times and three times daily regimens are 5 and 7, respectively. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux. The plasma concentration-dose relationship of clonazepam is linear. Clinical / Efficacy Studies: No text. Ketogenic diet in children does not affect clonazepam concentrations. Pediatric Patients: Overall the elimination kinetics in children are similar to those observed in adults. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment. The plasma protein binding is 82- 86%. Rivotril tablets are bioequivalent to an oral solution with respect to the extent of clonazepam absorption, whereas the rate of absorption is slightly slower for the tablets. The absolute bioavailability is around 90% with large differences between individuals. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day. Other: No text. The clearance is close to 55 ml/min irrespective of gender, but weight-normalized values declined with increasing body weight. Elderly Patients: The pharmacokinetics of clonazepam in old age has not been established. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. The volume of distribution is 3l/kg. Impairment of Fertility: Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day. Metabolism: Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamido-clonazepam. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive or weakly active metabolites. After therapeutic doses to children (0.03-0.11 mg/kg) the serum concentrations were in the same range (13-72 ng/ml) as effective concentrations in adults. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis. Pharmacokinetic Properties Absorption Clonazepam is rapidly and almost compley absorbed after oral administration of Rivotril tablets. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged 55 ng/ml. The absorption half-life is around 25 min. The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds. There are also animal data showing an effect of clonazepam on serotonin.
Renal and Urinary Disorder: In rare cases urinary incontinence may occur. Paradoxical reactions are more likely to occur in children and in the elderly. Panic Disorder Data from 3 placebo-controlled clinical trials including 477 patients on active treatment in total are presented in the table below. Investigations: In rare cases decreased plaet count may occur. administration of clonazepam. Post Marketing Immune system Disorders: Allergic reactions and very few cases of anaphylaxis have been reported to occur with benzodiazepines. Endocrine Disorders: Isolated cases of reversible development of prematuresecondary sex characteristics in children (incomplete precocious puberty) have been reported. Particularly in long-term or high-dose treatment, reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia) and nystagmus may occur. Adverse Events occurring in 5% of patients in at least one of the Active Treatment Groups are included. Amnestic effects may be associated with inappropriate behaviour. Undesirable Effects Clinical Trials Epilepsy No text. It can be partially prevented by increasing the dose slowly at the start of treatment. This effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk increasing at higher dosages. They can be partially prevented by increasing the dose slowly at the start of treatment. In infants and young children, Rivotril may cause increased production of saliva or of bronchial secretion. It can be partially prevented by increasing the dose slowly at the start of treatment. If the injection is rapid or the calibre of the vein insufficient, there is a risk of thrombophlebitis, which may in turn lead to thrombosis. Musculoskeletal and Connective Tissue Disorders: muscle weakness, this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. General Disorders and Administration Site Conditions: Fatigue (tiredness, lassitude), this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. Dependence and withdrawal, see section Drug Abuse and Dependence. Cardiac disorders: Cardiac failure including cardiac arrest has been reported. Particular attention should therefore be paid to maintaining patency of the airways. Nervous system Disorders: impaired concentration, somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia. Headache was observed in rare cases. Depression may occur in patients treated with Rivotril, but it may be also associated with the underlying disease. With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible. The following paradoxical reactions have been observed: restlessness, agitation, irritability, aggressiveness, nervousness, hostility, anxiety, sleep disturbances, delusion, anger, nightmares, abnormal dreams, hallucinations, psychoses, hyperactivity, inappropriate behavior and other adverse behavioral effects are known to occur. Reproductive System and Breast Disorder: In rare cases erectile dysfunction may occur. Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements. In rare cases changes in libido may occur. Eye Disorder: Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur. Should this occur, the use of the drug should be discontinued. These undesirable effects occur relatively frequently and are usually transient and generally disappear spontaneously in the course of the treatment or on reduction of the dosage. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly. Psychiatric Disorders: Emotional and mood disturbances, confusional state,disorientation have been observed. Skin and Subcutaneous Tissue Disorders: The following effects may occur in rare cases: urticaria, pruritus, rash, transient hairloss, pigmentation changes. Gastrointestinal Disorders: The following effects have been reported in rare cases: nausea and epigastric symptoms. Respiratory Thoracic and Mediastinal System Disorders: Respiratory depression may occur, particularly on i.v. Paradoxical reactions including irritability have been observed (see also psychiatric disorders).
An increase to 0.5 mg twice daily (1 mg/day) may be made after 3 days. The dose may be increased in increments of 0.5 mg every three days until either seizures are adequay controlled or undesired effects preclude any further increase. The daily dose should be divided into 3 equal doses. Rivotril tablets 2 mg can be divided into equal halves or quarters to facilitate dosing. The usual maintenance dose is 1 mg twice daily (2 mg/day). Standard dosage in Epilepsy :Before adding Rivotril to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesired effects. The 0.5mg tablets facilitate the administration of lower daily doses to adults in the initial stages of treatment. Subsequent up-titration should be made at intervals of 3 days until Panic Disorder is controlled or until limited by side effects. A maximum dose of 2mg twice daily (4 mg/day) may be prescribed in exceptional cases. Tablets are scored to allow administration of lower doses. Relapsing patients should begin taking medication again. The maintenance dose level is best attained after 1-3 weeks of treatment. Once a stable dose is achieved, patients may switch to a once daily dose, usually taken at bedtime. The dose may be increased by 0.25-0.5 mg every third day until the individual maintenance dose (usually 3-6 mg/day) is reached. A single oral dose of Rivotril begins to take effect within 30-60 minutes and remains effective for 6-8 hours in children and 8-12 hours in adults. Dosage and Administration The dosage of Rivotril must be individually adjusted according to the patient’s clinical response and tolerance. To break the tablet, hold it with the score facing up and apply downward pressure. The dose should be increased by no more than 0.25-0.5 mg every third day until either a daily maintenance dose of approximay 0.1 mg/kg of bodyweight daily has been reached or seizures are controlled or undesired effects preclude further increase. The maintenance dose must be individualized for each patient depending upon response. Special Dosage Instructions Elderly Patients: The lowest possible dose should be used in the elderly (see 2.5.5 Use in Special Populations; Geriatric Use) and particular care should be taken during up-titration. Dosage in Panic Disorder Adults: The initial dose for adults with Panic Disorder is 0.25 mg twice daily (0.5 mg/day). The initial dose for adults should not exceed 1.5 mg/day divided into 3 doses. Oral treatment To avoid adverse reactions at the beginning of therapy, it is essential to start treatment with Rivotril at a low dose and increase the daily dose progressively until the maintenance dose suited to the individual patient has been reached.The initial dose for infants and children up to the age of 10 years (or up to 30 kg bodyweight) is 0.01-0.03 mg/kg daily given in 2-3 divided doses. The daily maximum dose in children is 0.2 mg/kg of bodyweight and should not be exceeded. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening. As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion (see Undesirable effects). Patients with mild to moderate hepatic impairment should be given the lowest dose possible. Based on established dosages for children up to 10 years (see above) and those for adults (see below) the following can be recommended for children between 10 and 16 years: The initial dose is 1-1.5 mg/day given in 2-3 divided doses. Hepatic Impairment: Patients with severe hepatic impairment should not be treated with Rivotril (see section 2.3 Contraindications). To ensure optimum dosage adjustment, infants should be given the drops. After at least 1 year of response gradual discontinuation should be attempted, with down-titration of 0.25 mg every 3 days, until the drug is compley withdrawn and close follow-up of the patient. Duration of treatment: Maintenance treatment is recommended for at least 12-24months, and in some cases, indefiniy. Usually a maintenance dose of 3-6 mg per day is sufficient. Rivotril tablets 0.5 mg can be divided into equal halves to facilitate dosing. The maximum therapeutic dose for adults is 20 mg daily and should not be exceeded. Panic disorder Pediatric Patients: The safety and efficacy of clonazepam for the treatment of Panic Disorder in children has not been studied. Renal Impairment: The safety and efficacy of clonazepam in patients with renal impairment has not been studied, however based on pharmacokinetic considerations no dose adjustment is required in these patients (see 3.2.5 Pharmacokinetics in Special Populations). Epilepsy Rivotril can be administered concurrently with one or several other antiepileptic agents, in which case the dosage of each drug must be adjusted to achieve the optimum effect. If doses are not equally divided, the largest dose should be given before retiring.
From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines. See 2.4.1 General (Warnings and Precautions). Therefore special attention must be paid to maintaining patency of the airways. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus.During pregnancy, Rivotril may be administered only if there is a compelling indication. Use in Special Populations Pregnancy From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Pediatric Use In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Labour and Delivery See Pregnancy. Nursing Mothers Although the active ingredient of Rivotril has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. Geriatric Use Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function. If there is a compelling indication for Rivotril, breastfeeding should be discontinued. Hepatic Impairment See Special Dosage Instructions and General (Warnings and Precautions). The possibility also exists that other factors e.g. Renal Impairment See Pharmacokinetics in Special Populations. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects.
Contraindications Rivotril is contraindicated in patients with known hypersensitivity to clonazepam or any of the drug’s excipients, and in patients with severe respiratory insufficiency or severe hepatic impairment as benzodiazepines may precipitate hepatic encephalopathy. Rivotril tablets are contraindicated in patients with a medical history of sleep apnoea for the treatment of panic disorders.
Interactions with other Medicinal Products and other Forms of Interaction: Rivotril can be administered concurrently with one or more antiepileptic agents. The probability of pharmacokinetic interactions with these other drugs is low. Inhibitors of CYP3A4 (e.g., fluconazole) may impair the metabolism of clonazepam and lead to exaggerated concentrations and effects. Due to the bi-directional nature of the clonazepam-phenytoin interaction, phenytoin levels have been found to be unchanged, increased or decreased upon coadministration with clonazepam depending on dosing and patient factors. Clonazepam has the potential to influence concentrations of phenytoin. Pharmacokinetic Drug-Drug Interactions (DDI) The antiepileptic drugs phenytoin, phenobarbital, carbamazepine, lamotrigine and to a lesser extent valproate may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter by up to 38% during combined treatment. The enzymes involved in the metabolism of Rivotril have not been clearly identified but include CYP3A4. Pharmacodynamic Drug-Drug Interactions (DDI) The combination of clonazepam with valproic acid may occasionally cause petit mal status epilepticus. In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect. The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) fluoxetine (CYP2D6 inhibitor) and the anti-epileptic drug felbamate (CYP2C19 inhibitor; CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam when administered concomitantly. See section Overdose for warning of other central nervous system depressants, including alcohol. Clonazepam itself does not induce the enzymes responsible for its own metabolism. Nevertheless, adding an extra drug to the patient’s regimen should involve a careful evaluation of the response to the treatment, because unwanted effects, such as sedation and apathy are more likely to occur. Alcohol should be avoided in patients receiving Rivotril (see General Warnings and Precautions). In such cases, the dosage of each drug must be adjusted to achieve the optimum desired effect. Enhanced side effects such as sedation and cardio-respiratory depression may also occur when Rivotril is co-administered with any centrally acting depressants including alcohol.
Tablets: 0.5 mg and 2 mg.Rivotril