Rivotril

Clonazepam.

Tablets: Active ingredient: clonazepam 0.5 mg or 2 mg.

Therapeutic / Pharmacologic Class of Drug: Antiepileptic agent.
Pharmacology: Pharmacodynamics: Mechanism of Action: Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle-relaxing and anxiolytic effects. As with other benzodiazepines, these effects are thought to be mediated mainly by post-synaptic GABA-mediated inhibition, although there are animal data showing in addition an effect of clonazepam on serotonin. 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.
Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings, clonazepam has beneficial effects in generalized and focal epilepsies.
Pharmacokinetics: Absorption: Clonazepam is rapidly and almost completely absorbed after oral administration of Rivotril tablets. Peak plasma concentrations of clonazepam are reached in 1-4 hours. The absorption half-life is around 25 mins. The absolute bioavailability is 90%. 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 tablet.
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. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged 55 ng/ml. The plasma concentration-dose relationship of clonazepam is linear. The target anticonvulsant plasma concentrations of clonazepam range from 20 to 70 ng/ml. The threshold plasma concentration of clonazepam in patients with panic disorders is about 17 ng/ml.
Distribution: Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures.
The distribution half-life is approximately 0.5-1 hour. The volume of distribution is 3 l/kg. The plasma protein binding is 82-86%.
Metabolism: Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.
The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.
Elimination: The mean elimination half-life is 30-40 hours. The clearance is 55 ml/min.
50-70% of the dose is excreted in the urine and 10-30% in faeces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
The elimination kinetics in children are similar to those observed in adults.
Pharmacokinetics in Special Populations: Renal Failure: Renal disease does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal disease.
Hepatic Failure: The influence of hepatic disease on clonazepam pharmacokinetics has not been investigated.
Elderly: The pharmacokinetics of clonazepam in the old age has not been established.
Neonates: The elimination half-life and clearance values in neonates are of the same order of magnitude of those reported in adults.
Toxicology: Preclinical Safety: Carcinogenicity: No 2-year carcinogenicity studies have been conducted with clonazepam. 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.
Mutagenicity: Genotoxicity tests using bacterial systems with in vitro or host-mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
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.
Teratogenicity: No adverse maternal or embryo-fetal 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.
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 Pregnancy under Use in Pregnancy & Lactation).

Most clinical forms of epilepsy in infants and children, in particular typical and atypical absences (Lennox syndrome), nodding spasms, primary or secondary generalized tonic-clonic spasms.
Rivotril may also be used in adult epilepsy and focal seizures.

Standard dosage: The dosage of Rivotril must be individually adjusted according to the patient's clinical response, tolerance of the drug, and the patient's age. To ensure optimum dosage adjustment, infants should be given the drops and children the 0.5 mg tablets. The single break-mark 0.5 mg tablets facilitate the administration of lower daily doses to adults in the initial stages of treatment.
As a general rule, Rivotril is given as low-dose, single-drug therapy in new, non-therapy-resistant cases.
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.
To avoid adverse reactions at the beginning of therapy, it is essential to 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. For children over 10 years (or over 30 kg) and for adults, the recommended initial dose is 1-2 mg daily.
The maintenance dose for infants and children up to the age of 10 years (or up to 30 kg bodyweight) is 0.05-0.1 mg/kg daily. For children 10-16 years (or over 30 kg), a dose of 1.5-3 mg daily, and for adults, a dose of 2-4 mg daily is recommended.
Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening. Should several doses be necessary, the largest should be taken in the evening. The maintenance dose level is best attained after 1-3 weeks of treatment. To ensure optimum dosage adjustment, infants should be given the drops and children the 0.5 mg tablets.
The single break-mark 0.5 mg tablets facilitate the administration of lower daily doses to adults in the initial stages of treatment.
The maximum therapeutic dose for adults is 20 mg daily.
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.
Special dosage instructions: 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.
As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion (see Adverse Reactions).

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Rivotril is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it 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.
Treatment: Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.
Further absorption should be prevented using an appropriate method, e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used, airway protection is imperative for drowsy patients. In case of mixed ingestion, gastric lavage may be considered, however not as a routine measure.
If CNS depression is severe, consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil (Anexate) for further information on the correct use of this drug.
Warning: The benzodiazepine antagonist Anexate (active ingredient: 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.

Rivotril must not be used in patients with known hypersensitivity to benzodiazepines or any of the drug's excipients, or those with severe respiratory insufficiency or severe hepatic insufficiency.

General: Rivotril may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver).
Concomitant use of alcohol / CNS depressants: The concomitant use of Rivotril with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Rivotril possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see Interactions).
Medical history of alcohol or drug abuse: Rivotril should be used with extreme caution in patients with a history of alcohol or drug abuse.
For warnings related to the use in infants and small children, see Use in Children as follows.
The dosage of Rivotril must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system (e.g. chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally-acting medications or anticonvulsant (antiepileptic) agents (see Interactions).
Like all drugs of this type, Rivotril may, depending on dosage, administration and individual susceptibility, modify the patient's reactions (e.g. driving ability, behaviour in traffic) (see Ability to Drive and Use Machines as follows).
Anticonvulsant drugs including Rivotril should not be discontinued abruptly in epileptic patients as this may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction or discontinuation arises, this should be done gradually.
Patients with a history of depression and/or suicide attempts should be kept under close supervision.
Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including Rivotril, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Porphyria: In patients with porphyria, clonazepam has to be used with care because it may have a porphyrogenic effect.
Drug Abuse and Dependence: Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see Adverse Reactions). The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop after a lengthy period of use, especially with high doses or if the daily dose is reduced rapidly or abruptly discontinued. The symptoms include tremor, sweating, agitation, sleep disturbances and anxiety, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability and epileptic seizures which may be associated with the underlying disease. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact or hallucinations. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should therefore be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose.
Renal Impairment: See Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic Impairment: See General as previously mentioned.
Ability to Drive and Use Machines: Even if taken as directed, clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This effect is aggravated by consumption of alcohol.
Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient's physician and should be based on the patient's response to treatment and the dosage involved (see Adverse Reactions).
Use in Children: In infants and small children, Rivotril may cause increased production of saliva and bronchial secretion. Therefore, special attention must be paid to maintaining patency of the airways. See General as previously mentioned.

Pregnancy: From preclinical studies, it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations, there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors, e.g. genetic factors, or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the fetus.
During pregnancy, Rivotril may be administered only if there is a compelling indication. 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. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy.
Labor and Delivery: See Pregnancy as previously mentioned.
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. If there is a compelling indication for Rivotril, breastfeeding should be discontinued.

Clinical Trials: Panic Disorder: Data from 3 placebo-controlled clinical trials including 477 patients on active treatment in total are presented in the following table. Adverse events occurring in ≥5% of patients in at least one of the active treatment groups are included. (See table.)

Click on icon to see table/diagram/image

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 premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.
Psychiatric Disorders: Impaired concentration, restlessness, confusional state, disorientation have been observed. Depression may occur in patients treated with Rivotril, but it may be also associated with the underlying disease.
The following paradoxical reactions have been observed: excitability, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams.
In rare cases, loss of libido may occur.
Dependence and withdrawal (see Drug Abuse and Dependence under Precautions).
Nervous System Disorders: Somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia. 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. They can be partially prevented by increasing the dose slowly at the start of treatment.
Headache was observed in rare cases.
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.
Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.
With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.
Eye Disorders: Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur.
Cardiac Disorders: Cardiac failure including cardiac arrest has been reported.
Respiratory, Thoracic and Mediastinal System Disorders: Respiratory depression may occur. This effect may be aggravated by pre-existing airways 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.
In infants and young children, Rivotril may cause increased production of saliva or of bronchial secretion. Particular attention should therefore be paid to maintaining patency of the airways.
Gastrointestinal Disorders: The following effects have been reported in rare cases: nausea and epigastric symptoms.
Skin and Subcutaneous Tissue Disorders: The following effects may occur in rare cases: urticaria, pruritus, rash, transient hair loss, pigmentation changes.
Musculoskeletal and Connecting 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. It can be partially prevented by increasing the dose slowly at the start of treatment.
Renal and Urinary Disorders: In rare cases, urinary incontinence may occur.
Reproductive System and Breast Disorders: In rare cases, erectile dysfunction may occur.
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. It can be partially prevented by increasing the dose slowly at the start of treatment.
Paradoxical reactions including irritability have been observed (see also Psychiatric Disorders as previously mentioned). If the injection is rapid or the caliber of the vein insufficient, there is a risk of thrombophlebitis, which may in turn lead to thrombosis.
Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Investigations: In rare cases, decreased platelet count may occur.

Rivotril can be administered concurrently with one or more antiepileptic agents. But 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. In such cases, the dosage of each drug must be adjusted to achieve the optimum desired effect.
Pharmacokinetic Drug-Drug Interactions (DDI): The antiepileptic drugs phenytoin, phenobarbital, carbamazepine, and valproate may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.
Clonazepam itself does not induce the enzymes responsible for its own metabolism.
The selective serotonin reuptake inhibitors sertraline and fluoxetine do not affect the pharmacokinetics of clonazepam when administered concomitantly.
Pharmacodynamic Drug-Drug Interactions (DDI): The combination of clonazepam with valproic acid may occasionally cause petit mal status epilepticus.
Enhanced effects on sedation, respiration and hemodynamics may occur when Rivotril is co-administered with any centrally-acting depressants, including alcohol.
Alcohol should be avoided in patients receiving Rivotril (see General under Precautions).
See Overdosage for warning of other central nervous system depressants, including alcohol.
In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.

Store in the original package in order to protect from light.

Anticonvulsants

N03AE01 - clonazepam ; Belongs to the class of benzodiazepine derivatives antiepileptic.

DD, P₁S₁S₃