CORE DATA SHEET 6.0 RIVOTRIL (INTERNATIONAL …Epilepsy Rivotril can be administered concurrently with one or several other antiepileptic agents, in which case the dosage of each drug

Rivotril® (Ro 05-4023) Core Data Sheet Version 6.0

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CORE DATA SHEET 6.0

RIVOTRIL® (INTERNATIONAL TRADENAME) RAVOTRIL®, RIVATRIL®, IKTORIVIL®, KLONOPIN® (OTHER TRADENAMES) Clonazepam

September 2012

Caution: Never administer Rivotril drops directly into the mouth from the bottle.

After each opening, make sure the dropper is secured within the neck of the bottle.

1. DESCRIPTION 1.1 Therapeutic / Pharmacologic Class of Drug Antiepileptic agent

Antipanic agent

ATC code: N03AE01

1.2 Type of Dosage Form • Drops

• Tablets

• Ampoules for injection

1.3 Route of Administration • Oral:

o Tablets

o Drops

• Intravenous (Ampoules): o Injection

o Infusion

• Intramuscular (Ampoules):


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o Injection

1.4 Sterile / Radioactive Statement Drops: Not applicable.

Tablets: Not applicable.

Ampoules: Sterile product.

1.5 Qualitative and Quantitative Composition Active ingredient: clonazepam.

Drops:

2.5 mg/ml (1 drop = 0.1 mg active ingredient).

Excipients: Described as per local requirements.

Tablets:

0.5 mg and 2 mg.

Excipients: Described as per local requirements (Rivotril tablets contain lactose. For warning related to lactose, see 2.4.1 General (Warnings and Precautions)).

Ampoules:

One Pack: 5 ampoules containing 1 mg active ingredient in 1 ml solution and 5 ampoules (1 ml) sterile water for injections as diluent, to be mixed before i.v. or i.m. injection.

Excipients: Described as per local requirements (Rivotril ampoules contain benzyl alcohol. For warning related to benzyl alcohol, see 2.3 Contraindications).

Diluent: sterile water for injections.

2. CLINICAL PARTICULARS 2.1 Therapeutic Indication(s) Rivotril is indicated as a first-line drug in typical absences (petit mal), atypical absences (Lennox-Gastaut syndrome), myoclonic seizures and atonic seizures (drop syndrome).

Rivotril is indicated as a second-line agent in infantile spasms (West-Syndrome).

In tonic-clonic seizures (grand mal), simple and complex partial seizures and in secondary generalized tonic-clonic seizures Rivotril is indicated as a third-line drug.

After i.v. administration Rivotril has been shown to be effective in controlling different types of status epilepticus.

Rivotril is indicated for the treatment of Panic Disorder, with or without agoraphobia [1, 2].


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2.2 Dosage and Administration Standard dosage in Epilepsy

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. The 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. An i.v. dose has an immediate effect which lasts for 2-3 hours.

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 dose should be increased by no more than 0.25-0.5 mg every third day until either a daily maintenance dose of approximately 0.1 mg/kg of bodyweight daily has been reached or seizures are controlled or undesired effects preclude further increase. The daily maximum dose in children is 0.2 mg/kg of bodyweight and should not be exceeded.

If Rivotril is prescribed as drops they should be given with a spoon and may be mixed with water, tea or fruit juice.

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. 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.

The initial dose for adults should not exceed 1.5 mg/day divided into 3 doses. The dose may be increased in increments of 0.5 mg every three days until either seizures are adequately controlled or undesired effects preclude any further increase. The maintenance dose must be individualized for each patient depending upon response. Usually a maintenance dose of 3-6 mg per day is sufficient. The maximum therapeutic dose for adults is 20 mg daily and should not be exceeded.

The daily dose should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before retiring. The maintenance dose level is best attained after 1-3 weeks of treatment. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.


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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.

Parenteral treatment

Intravenous administration:

The i.v. administration is mainly used for treatment of status epilepticus:

Infants and children: half an ampoule (0.5 mg) by slow intravenous injection or by intravenous infusion.

Adults: 1 ampoule (1 mg) by slow intravenous injection or by intravenous infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25-0.5 mg (0.5-1.0 ml of the prepared solution) per minute and a total dose of 10 mg should not be exceeded.

Intramuscular administration:

The intramuscular route should be used only in exceptional cases or if i.v. administration is not feasible (after i.m. application Tmax is 3 hours).

Slow intravenous injection

The solution of the ampoule containing 1 mg active substance may be employed only after addition of 1 ml diluent in order to avoid local irritation of the veins. The injection solution should be prepared immediately before use. Intravenous injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion

Rivotril (only the ampoule with the active substance) can be diluted for infusion (see section 4.2 Special Instructions for Use, Handling and Disposal).

Dosage in Panic Disorder [1]

Adults: The initial dose for adults with Panic Disorder is 0.25 mg twice daily (0.5 mg/day).

An increase to 0.5 mg twice daily (1 mg/day) may be made after 3 days. Subsequent up-titration should be made at intervals of 3 days until Panic Disorder is controlled or until limited by side effects.

The usual maintenance dose is 1 mg twice daily (2 mg/day). A maximum dose of 2 mg twice daily (4 mg/day) may be prescribed in exceptional cases.

Once a stable dose is achieved, patients may switch to a once daily dose, usually taken at bedtime.

Duration of treatment: Maintenance treatment is recommended for at least 12-24 months, and in some cases, indefinitely [3].


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After at least 1 year of response gradual discontinuation should be attempted, with close follow-up of the patient. Relapsing patients should then begin taking medication again [4].

Treatment should be discontinued gradually, with down-titration of 0.25 mg every 3 days, until the drug is completely withdrawn.

2.2.1 Special Dosage Instructions Intravenous Administration

There is evidence that clonazepam can be adsorbed within plastic infusion bags and infusion sets containing PVC and leading to a reduction in clonazepam concentration by up to 50%, especially where prepared bags are stored for 24 hours or more, in warm ambient conditions, or where long tubing sets or slow rates of infusion are used. PVC-containing bags and infusion sets should be avoided when infusing clonazepam. When infusing clonazepam, caution should be exercised when switching between PVC and non-PVC-containing bags and infusion sets [89, 90].

Epilepsy and Panic Disorder

Rivotril tablets 0.5 mg can be divided into equal halves to facilitate dosing. Rivotril tablets 2 mg can be divided into equal halves or quarters to facilitate dosing [9].

Elderly Patients:

Particular care should be taken during up-titration in elderly patients [5, 6, 7, 8].

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).

Hepatic Impairment:

The safety and efficacy of clonazepam in patients with hepatic impairment has not been studied. No data are available on the influence of hepatic disease on clonazepam pharmacokinetics (see 2.4.1 General (Warnings and Precautions)).

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.

As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion (see 2.6 Undesirable effects).

Panic disorder

Paediatric Patients:


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The safety and efficacy of clonazepam for the treatment of Panic Disorder in children has not been studied.

2.3 Contraindications 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 [70, 71, 72, 73, 74, 75].

Rivotril ampoules contain benzyl alcohol. Since there have been reports of permanent neuropsychiatric deficits and multiple system organ failure associated with benzyl alcohol, administration to neonates, and especially to premature infants, must be avoided.

2.4 Warnings and Precautions

2.4.1 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 cardio-vascular depression [76, 77, 78] (see 2.4.5 Interactions with other Medicinal Products and other Forms of 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 [27].

For warnings related to the use in infants and small children see 2.5.4 Paediatric Use.

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 2.4.5 Interactions with other Medicinal Products and other Forms of Interaction).

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 2.4.3 Ability to Drive and Use Machines).

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.


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During i.v. administration, a vein of sufficient calibre must be chosen and the injection administered very slowly, with continuous monitoring of respiration and blood pressure. If the injection is rapid or the calibre of the vein is insufficient, there is a risk of thrombophlebitis, which may in turn lead to thrombosis.

Patients with a history of depression and/or suicide attempts should be kept under close supervision.

In adults, the rate of injection must not exceed 0.25-0.5 mg (0.5-1 ml of the prepared solution) per minute (see 2.2 Dosage and administration).

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine [79].

Porphyria

In patients with porphyria, clonazepam has to be used with care because it may have a porphyrogenic effect [80, 81, 82, 83].

2.4.2 Drug Abuse and Dependence Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see 2.6 Undesirable Effects). 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 [27, 84].

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: derealisation, depersonalisation, 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.

2.4.3 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 2.6 Undesirable Effects).


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2.4.4 Laboratory Tests No text.

2.4.5 Interactions with other Medicinal Products and other Forms of Interaction

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 [10, 12, 13], phenobarbital [12, 14, 15], carbamazepine [16, 17], and valproate [85] 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 [48].

The selective serotonine reuptake inhibitors sertraline [18] and fluoxetine [19] 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 haemodynamics may occur when Rivotril is co-administered with any centrally acting depressants including alcohol [76, 77, 78].

Alcohol should be avoided in patients receiving Rivotril (see 2.4.1 General (Warnings and Precautions)).

See section 2.7 Overdose 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.

2.5 Use in Special Populations

2.5.1 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 foetus.


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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.

2.5.2 Labour and Delivery See 2.5.1 Pregnancy.

2.5.3 Nursing Mothers Although the active ingredient of Rivotril has been found to pass into the maternal milk in small amounts only [20], mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Rivotril, breastfeeding should be discontinued.

2.5.4 Paediatric Use 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 2.4.1 General (Warnings and Precautions).

2.5.5 Geriatric Use No text.

2.5.6 Renal Impairment See 3.2.5 Pharmacokinetics in Special Populations.

2.5.7 Hepatic Impairment See 2.4.1 General (Warnings and Precautions).

2.6 Undesirable Effects

2.6.1 Clinical Trials Epilepsy

No text.

Panic Disorder

Data from 3 placebo-controlled clinical trials including 477 patients on active treatment in total are presented in the table below [1, 2, 21]. Adverse Events occurring in ≥ 5% of patients in at least one of the Active Treatment Groups are included.

Table 1 Adverse Events Occurring in ≥ 5% of Patients in at least one of the Active Treatment Groups.

Adverse Event Placebo 1 to <2 mg/day 2 to <3 mg/day >3 mg/day


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(%) (n = 294)

(%) (n = 129)

(%) (n = 113)

(%) (n = 235)

Somnolence 15.6 42.6 58.4 54.9 Headache 24.8 13.2 15.9 21.3

Upper Respiratory Infection 9.5 11.6 12.4 11.9 Fatigue 5.8 10.1 8.8 9.8

Influenza 7.1 4.7 7.1 9.4 Depression 2.7 10.1 8.8 9.4 Dizziness 5.4 5.4 12.4 8.9 Irritability 2.7 7.8 5.3 8.5 Insomnia 5.1 3.9 8.8 8.1

Ataxia 0.3 0.8 4.4 8.1 Balance loss 0.7 0.8 4.4 7.2

Nausea 5.8 10.1 9.7 6.8 Coordination abnormal 0.3 3.1 4.4 6.0

Lightheaded feeling 1.0 1.6 6.2 4.7 Sinusitis 3.7 3.1 8.0 4.3

Concentration impaired 0.3 2.3 5.3 3.8

2.6.1.1 Laboratory Abnormalities No text.

2.6.2 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 section 2.4.2 Drug Abuse and Dependence.

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.


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With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.

Eye Disorder: 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 [86].

Respiratory Thoracic and Mediastinal System Disorders: Respiratory depression may occur, particularly on i.v. administration of clonazepam. This effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given [86]. 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 hairloss, 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 Disorder: In rare cases urinary incontinence may occur.

Reproductive System and Breast Disorder: 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). 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.

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 [26, 92].

Investigations: In rare cases decreased platelet count may occur.

2.6.2.1 Laboratory Abnormalities No text.


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2.7 Overdose [27, 28, 29, 31, 32, 33, 34] 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, apnoea, hypotension, cardiorespiratory depression and coma [87]. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients [37, 38]. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol [88].

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 [30, 36, 40, 41, 42]. 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 [35, 43, 44].

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 [36, 39, 41, 45, 46]. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants) [39]. 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.

3. PHARMACOLOGICAL PROPERTIES AND EFFECTS 3.1 Pharmacodynamic Properties

3.1.1 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


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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.

3.1.2 Clinical / Efficacy Studies No text.

3.2 Pharmacokinetic Properties

3.2.1 Absorption Clonazepam is rapidly and almost completely absorbed after oral administration of Rivotril tablets [47]. Peak plasma concentrations of clonazepam are reached in 1-4 hours [18, 47, 48]. The absorption half-life is around 25 mins [49]. The absolute bioavailability is 90% [47, 48]. 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 [50].

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 [18]. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged 55 ng/ml [10]. The plasma concentration-dose relationship of clonazepam is linear [10, 51, 52]. The target anticonvulsant plasma concentrations of clonazepam range from 20 to 70 ng/ml [10, 53, 54, 55]. The threshold plasma concentration of clonazepam in patients with panic disorders is about 17 ng/ml [56].

After i.m. administration, maximum plasma concentrations of clonazepam are reached in about 3 hours and the absolute bioavailability is 93% [47]. Irregularities in the absorption profiles of clonazepam after i.m. administration are occasionally observed [47].

3.2.2 Distribution Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures [11].

The distribution half-life is approximately 0.5-1 hour [48, 57]. The volume of distribution is 3 l/kg [47, 48, 55]. The plasma protein binding is 82-86% [53, 55, 58].

3.2.3 Metabolism Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam [59]. Hydroxylation at the C-3 position also


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occurs [59]. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites [53, 55, 60, 61].

The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds [59].

3.2.4 Elimination The mean elimination half-life is 30-40 hours [18, 47, 48, 49, 59, 62]. The clearance is 55 ml/min [47, 48].

50-70% of the dose is excreted in the urine and 10-30% in faeces as metabolites [59]. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose [10, 11, 51, 59, 62].

The elimination kinetics in children are similar to those observed in adults [54].

3.2.5 Pharmacokinetics in Special Populations Renal Failure:

Renal disease does not affect the pharmacokinetics of clonazepam [63]. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal disease [63].

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 [64].

3.3 Preclinical Safety

3.3.1 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 [65].

3.3.2 Mutagenicity Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam [66].


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3.3.3 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 [67, 68].

3.3.4 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 [69]. 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) [69].

3.3.5 Other No text.

4. PHARMACEUTICAL PARTICULARS 4.1 Storage This medicine should not be used after the expiry date (EXP) shown on the pack.

Some dosage forms of Rivotril are sensitive to light; therefore caution should be taken regarding storage [92, 93, 94, 95]:

- Ampoules: keep ampoules in the outer carton in order to protect from light

- Tablets in blister: keep blister in the outer carton in order to protect from light

- Tablets in bottle: store in the original package in order to protect from light

- 2.5 mg/mL drops: no special storage conditions

4.2 Special Instructions for Use, Handling and Disposal Intravenous infusion:

Rivotril (only the ampoule with the active substance) can be diluted for infusion with the following media in a ratio of 1 ampoule (1 mg) to at least 85 ml (e.g. 3 ampoules in 250 ml) to avoid precipitation: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% and glucose 10%. These mixtures are stable for 24 hours at room temperature.

The active ingredient can be adsorbed on PVC. It is therefore recommended that alternative material be used or, if PVC bags are employed, that the mixture be infused immediately and usually within 4 hours. The infusion time should not exceed 8 hours (See Section 2.2.1 Special Dosage Instructions) [89, 90].

Do not prepare Rivotril infusions using sodium bicarbonate solution, as otherwise precipitation of the solution may occur.


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Packs:

Drops, 2.5 mg/ml (1 drop = 0.1 mg active ingredient) 10 ml, 50ml

Tablets 0.5 mg 50, 100, 150

Tablets 2 mg 30, 100

Ampoule pack 1 containing:

5 ampoules 1 mg active ingredient in 1 ml solution

5 ampoules (1 ml) sterile water for injections as diluent, to be mixed before i.v. or i.m. injection


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5. REFERENCES 1. Rosenbaum J. F., Moroz G. et al.,

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2. Moroz G. and Rosenbaum J. F., Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages J Clin Psychiatry 1999; 60(9): 604-612 (CDS Vs 2.0)

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CORE DATA SHEET 6.0 RIVOTRIL (INTERNATIONAL …Epilepsy Rivotril can be administered concurrently with one or several other antiepileptic agents, in which case the dosage of each drug