Clonazepam

Registered South African indications:

• Epilepsy
• Panic disorder

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other benzodiazepines
• Severe respiratory insufficiency
• Acute pulmonary insufficiency
• Acute narrow-angle glaucoma
• Severe hepatic insufficiency
• Myasthenia gravis
• Sleep apnoea
• Patients in a coma or with spinal or cerebellar ataxia
• In the event of acute intoxication with alcohol, other anti-epileptic medicines, hypnotics, analgesics, neuroleptic agents, antidepressants, or lithium
• Patients known to be abusing medicines, other substances, or alcohol

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other benzodiazepines
• Acute pulmonary insufficiency
• Severe respiratory insufficiency
• Sleep apnoea syndrome
• Severe hepatic insufficiency
• Myasthenia gravis
• Patients in a coma
• Patients known to be abusing pharmaceuticals, drugs, or alcohol

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Suicidal ideation and behaviour 
• Depression
• Pulmonary insufficiency
• Respiratory depression 
• Debilitated patients
• Abrupt withdrawal
• Spinal or cerebellar ataxia
• Acute substance intoxication
• Children
• Porphyria
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: drp, inj, tab 

South African registered indications and dosages

Oral

Epileptic disease
- All clinical forms of epileptic disease, especially typical or atypical petit mal, focal seizures with elementary or complex symptomatology, generalised primary or secondary tonic-clonic seizures, status epilepticus in all its clinical forms
Panic disorder
- With or without agoraphobia

• Oral (drp, tab): Max initial dose: 1.5mg/day, in 3 divided doses; Titrate by 0.5mg every 3 days as required, until either seizures are adequately controlled, or undesired effects preclude any further increase; Maintenance: 3-6mg/day is usually sufficient, it should be individualised for each patient depending on upon response; Max: 20mg/24hrs

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Dosage is essentially individual and it will be determined in each patient according to clinical response and tolerance. To avoid initial side effects, it is essential to increase the daily dose progressively until the maintenance dose suited to the individual patient has been reached

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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 2-4 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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Clonazepam can be administered concurrently with one or several other anti-epileptic agents, in which case the dosage of each medicine must be adjusted to achieve the optimum effect. Treatment with clonazepam must not be stopped abruptly, but must be reduced in a stepwise manner

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Parenteral treatment

Epileptic disease
- Status epilepticus in all its forms

• IV: 1mg, by slow injection; Repeat as required, possibly by IV infusion (1-4mg are usually to reverse the status); Injection rate: Must not exceed 0.25-0.5mg/min; Max total dose: 10mg

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The IV administration is mainly used for treatment of status epilepticus

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Slow intravenous injection:
The 1ml ampoule solution containing 1mg active ingredient may only be employed after addition of 1ml diluent in order to avoid local irritation to the veins. A vein of sufficient calibre must be chosen. The injection solution should be prepared immediately before use. Intravenous injection should be administered slowly with continuous monitoring of ECG, 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

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Intravenous infusion:
Clonazepam (only the ampoule with the active substance) can be diluted for infusion with the following media in a ratio of 1 ampoule (1mg) to at least 85ml (e.g. 3 ampoules in 250ml) 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 absorbed on polyvinyl chloride (PVC). It is therefore, recommended that either glass containers 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.  Do not prepare clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur

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Intramuscular administration:
The intramuscular route should only be used by way of exception or if IV administration is not feasible. (After intramuscular injection T_max is 3 hours)

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Panic disorder
- With or without agoraphobia

• IV: 0.25mg, twice daily (0.5mg/day); An increase to the target dose of 1mg/day, after 3 days may be required for most patients; Titrate by 0.125-0.25mg twice daily, every 3 days as required until panic disorder is controlled or until side-effects make further increases undesired; Some individual patients may benefit from doses of up to a maximum of 4mg/24hrs 

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To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable

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Treatment should be discontinued gradually, with a decrease of 0.125mg twice a day every 3 days, until the medicine is completely withdrawn. There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam for extended periods should periodically re-evaluate the long-term usefulness of the product for the individual patient

Paed. forms avail. in SA and covered in this monograph: drp, inj, tab

South African registered indications and dosages

Epileptic disease
- All clinical forms of epileptic disease, especially typical or atypical petit mal, focal seizures with elementary or complex symptomatology, generalised primary or secondary tonic-clonic seizures, status epilepticus in all its clinical forms

Up to 10 years (or up to 30kg bodyweight)

• Oral (drp, tab): Initial: 0.01-0.03mg/kg, in 2-3 divided doses; Titrate by 0.25-0.5mg every 3rd day as required until either a maintenance of 0.1mg/kg of bodyweight per day is reached, or until seizures are controlled or side-effects prevent a further increase; Max: 0.2mg/kg bodyweight/24hrs

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To obtain optimum adjustment of the dose in infants and children the use of the drop form (1 drop contains 0.1mg active substance) and the tablets 0,5 mg is recommended.  The single-scored 0.5mg tablet facilitates administration of low doses in the early phase of treatment

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Correct method of administration of clonazepam drops:
The drops should be mixed with water, tea or fruit juice and administered with a spoon
Never administer clonazepam drops directly into the mouth from the bottle. After each opening, make sure the dropper is secured within the neck of the bottle

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Between 10-16 years

• Oral (drp, tab): Initial: 1-1.5mg/day, in 2-3 divided doses; Titrate by 0.25-0.5mg every 3rd day, as required until the individual maintenance dose (usually 3-6mg/day) is reached

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Dosage is essentially individual and depends above all on the age of the patient. It will be determined in each patient according to clinical response and tolerance. To avoid initial side effects, it is essential to increase the daily dose progressively until the maintenance dose suited to the individual patient has been reached

---

Clonazepam can be administered concurrently with one or several other anti-epileptic agents, in which case the dosage of each medicine must be adjusted to achieve the optimum effect. Treatment with clonazepam must not be stopped abruptly, but must be reduced in a stepwise manner

---

Parenteral treatment

Epileptic disease
- Status epilepticus in all its forms

Infants and children

• IV: 0.5mg, by slow injection or by IV infusion

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The IV administration is mainly used for treatment of status epilepticus

---

Slow intravenous injection:
The 1ml ampoule solution containing 1mg active ingredient may only be employed after addition of 1ml diluent in order to avoid local irritation to the veins. A vein of sufficient calibre must be chosen. The injection solution should be prepared immediately before use. Intravenous injection should be administered slowly with continuous monitoring of ECG, 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

---

Intravenous infusion:
Clonazepam (only the ampoule with the active substance) can be diluted for infusion with the following media in a ratio of 1 ampoule (1mg) to at least 85ml (e.g. 3 ampoules in 250ml) 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 absorbed on polyvinyl chloride (PVC). It is therefore, recommended that either glass containers 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.  Do not prepare clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur

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Intramuscular administration:
The intramuscular route should only be used by way of exception or if IV administration is not feasible. (After intramuscular injection T_max is 3 hours)

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There is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age

Pregnancy

• Caution
• Preclinical studies in animals have shown reproductive toxicity and 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. Clonazepam should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus
• During pregnancy, clonazepam may be administered only if there is a compelling indication. Clonazepam has harmful pharmacological effects on pregnancy and the foetus/newborn child. 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. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed a physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy

Breastfeeding

• Caution; not recommended
• Clonazepam 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 clonazepam, breastfeeding should be discontinued

Renal Impairment

• Caution; no dose adjustment recommended

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Elderly

• Caution; dose adjustment recommended
  Initial: 0.5mg/day in 4 divided doses; The maintenance dose should be attained after 2 to 4 weeks; Max: 20mg/24hrs

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Anterograde amnesia 
• Depression
• Physical and psychological dependence 
• Paradoxical excitation
• Dizziness
• Somnolence
• Fatigue
• Co-ordination disturbances
• Poor concentration
• Restlessness
• Confusion 
• Disorientation
• Headache
• Dysarthria
• Ataxia
• Generalised convulsions
• Nystagmus
• Increase in the frequency of seizures  
• Irritability
• Insomnia

Cardiovascular Disorders

• Cardiac failure 
• Cardiac arrest
• Thrombophlebitis (inj)

Respiratory Disorders

• Respiratory depression 
• Salivary or bronchial hypersecretion with drooling
• Upper respiratory infection
• Influenza
• Sinusitis

Gastrointestinal Disorders

• Nausea
• Gastrointestinal symptoms

Hepatobiliary Disorders

• Abnormal hepatic function tests 

Genitourinary Disorders

• Urinary incontinence
• Loss of libido
• Impotence

Endocrine and Metabolic Disorders

• Incomplete precocious puberty

Musculoskeletal Disorders

• Muscle weakness
• Occasional muscular hypotonia

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Puritus
• Transient hair loss
• Pigmentation changes

Immune, Blood and Lymphatic System Disorders

• Isolated cases of blood dyscrasias
• Allergic reaction 
• Anaphylaxis
• Angioedema

Sensory Disorders

• Double vision 
• Nystagmus  

• Central nervous system depressants
• Antiepileptic agents
• Theophylline
• Primidone
• Amprenavir
• Cimetidine
• Disulfiram
• Fluvoxamine
• Ritonavir
• Rifampicin
• Levodopa
• Alpha blockers 
• Moxonidine
• Angiotensin-converting enzyme inhibitors
• Adrenergic neurone blockers
• Angiotensin-II receptor antagonists
• Beta blockers
• Calcium channel blockers
• Clonidine
• Diazoxide
• Diuretics
• Hydralazine
• Methyldopa
• Minoxidil
• Nitrates 
• Nitroprusside
• General anaesthetics
• Tricyclic and tricyclic-related antidepressants
• Antihistamines
• Antipsychotics
• Baclofen
• Lofexidine
• Mirtazapine
• Nabilone
• Tizanidine

None routine. Specific cases may require

• Psychiatric evaluation
• Respiratory function (inj)
• Vital signs (inj)

Clonazepam potentiates the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. This results in increased inhibition of the ascending reticular activating system, thereby blocking cortical and limbic arousal that occurs following stimulation of the reticular pathways. It suppresses the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with temporal or other locations as well as irregular spikes and wave discharges.

Tablet 0.5mg

• Clonam (Dezzo)
• Rivotril (Roche) originator

Tablet 2mg

• Clonam (Dezzo)
• Rivotril (Roche) originator

Injection (per ml) 1mg

• Rivotril (Roche) originator

Drops (per ml) 2.5mg

• Rivotril (Roche) originator