Clonazepam

Enhanced effects on sedation, respiration and haemodynamics may occur when clonazepam is co-administered with any centrally acting depressants e.g. alcohol, and other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle relaxants and may result in mutual potentiation of drug effects.

In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.

St. John’s Wort may reduce the effectiveness of benzodiazepine.

Concomitant administration of hepatic enzyme activators such as barbiturates can accelerate the metabolism of clonazepam without affecting its protein binding.

In combination with clonazepam, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects.

The concomitant use of clonazepam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of clonazepam possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression.

Imidazoles increase the effectiveness of benzodiazepine.

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as clonazepam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited.

When clonazepam is used in conjunction with other antiepileptic drugs, side effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment. The combination of clonazepam and sodium valproate has, rarely, been associated with the development of absence status epilepticus. Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered.

Concomitant administration of liver enzyme activators such as hydantoins may accelerate the metabolism of clonazepam without affecting its protein binding.

Carbamazepine may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.

Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action.

Clozapine increases the risk of clonazepam toxicity.

Fluconazole increases the effectiveness of benzodiazepine.

Indinavir increases the effectiveness of benzodiazepine.

Nelfinavir increases the effectiveness of benzodiazepine.

Omeprazole increases the effectiveness of benzodiazepine.

Phenobarbital may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.

Phenytoin may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.

An increase in the serum concentration of primidone has been occasionally observed during concomitant treatment with clonazepam.

Known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.

Ritonavir increases the efficacy of benzodiazepine.

Saquinavir increases the effectiveness of benzodiazepine.

Valproic acid may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.

Telithromycin may decrease the clearance of clonazepam.

Tipranavir may reduce the metabolism and clearance of clonazepam.

Voriconazole can increase the concentration of clonazepam in the blood serum, by reducing its metabolism.

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 heart beat 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.

Although, clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breast-feed. If there is a compelling indication for clonazepam, breast-feeding should be discontinued.

Fertility

Preclinical studies in animals have shown reproductive toxicity and 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. Clonazepam should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus.

As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on clonazepam, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients' reactions, depending on individual susceptibility. 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.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive.
• Do not drive until you know how the medicine affects you.
• It is an offence to drive while under the influence of this medicine.
• However, you would not be committing an offence (called “statutory defence”) if:
  • The medicine has been prescribed to treat a medical or dental problem and
  • You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
  • It was not affecting your ability to drive safely.

The following have been observed:

Immune System Disorders:

Allergic reactions and very rare 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 clonazepam, 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, vivid dreams and psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue clonazepam therapy.

In rare cases loss of libido may occur.

Nervous System Disorders:

Somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia and co-ordination disturbance. 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. Causing of generalised fits was observed very rarely.

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.

Common: nystagmus

Cardiac Disorders:

Cardiac failure including cardiac arrest has been reported.

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. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.

In infants and young children, particularly those with a degree of mental impairment, clonazepam 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, gastrointestinal and epigastric symptoms.

Skin and Subcutaneous Tissue Disorders:

The following effects may occur in rare cases: urticaria, pruritus, rash, transient hairloss, pigmentation changes and angioedema.

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). During IV administration, a vein of sufficient calibre must be chosen and the injection administered very slowly, with continuous monitoring of respiration and blood pressure. In adults, the rate of injection must not exceed 0.25–0.5mg (0.5–1ml of the prepared solution) per minute. 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.

Investigations:

In rare cases decreased platelet count may occur. As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.

Dependence and withdrawal.

Although clonazepam has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.