Evaluations on New Drugs Drugs 12: 321-361 (1976) © ADIS Press 1976

Clonazepam: A Review of its Pharmacological Properties and Therapeutic Efficacy in Epilepsy R.M. Pinder, R.N. Brogden, T.M. Speight and G.S. Avery Australasian Drug Information Services, Auckland

Manuscript reviewed by: E. Birket·Smith, Department of Neurology, Aalborg Hospital South, Aalborg, Denmark. M.J. Eadie, Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, Australia. E.F. Hvidberg, Clinical Pharmacology Research Unit, Rigshospitalet, Copenhagen, Denmark. M. Lund, Department of Neurology, Glostrup Hospital, Glostrup, Denmark. J.G. McLeod, Department of Medicine, University of Sydney, Sydney, Australia. CD. Marsden, Department of Neurology, Institute of Psychiatry, Denmark Hill, London, England. E. H. Reynolds, Department of Neurology, King's College Hospital, Denmark Hill, London, England.

Table of Contents Summary . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . 1. Pharmacodynamic Studies . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Anticonvulsant Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1 Human Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Effects on the EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Site of Action .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Other Central Effects 1.4.1 Respiratory Centre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.2 Cough Centre . . . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.3 Sedative Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... . 1.4.4 Effects of 5-Hydroxytryptamine Metabolism . . . . . . . . . . . . . . . . . 1.5 Muscle Relaxant Properties .. . ... . ... . .. .. . . . . . . . . . .. . . . . 1.6 Miscellaneous Pharmacodynamic Effects . . . . . . . . . . . . . . . . . . . . . . 1. 7 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 7.1 Acute and Sub-Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 1.7.2 Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7.3 Dysmorphology and Reproduction Studies . . . . . . . . . . . . . . . . . . 2. Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1 Half-life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2 Relationship Between Plasma Levels and Therapeutic or Side~ffects .. . 2.2 Distribution .. .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

322 325 325 325 326 327 328 328 328 329 329 329 330 330 330 330 330 331 331 331 331 331 333 333

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3. Therapeutic Trials 3.1 Controlled Trials 3.1.1 Minor Motor Seizures 3.1.2 Generalised Tonic-aonic and Focal Motor Seizures .. 3.1.3 Psychomotor or Temporal Lobe Epilepsy . . . . . . . . 3.1.4 Myoclonic/Atonic Seizures . . . . . . . . . . . . . . . . . . 3.2 Open Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Minor Motor Seizures . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Generalised Tonic-aonic Seizures . . . . . . . • . . . . . . . . . . . . . . 3.2.3 Partial Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4 Myoclonic Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5 Akinetic and Atonic Seizures . . • . . . . . . . . . . . . . . . . . . . . . . . 3.2.6 Comparison with Other Antiepileptic Drugs . . . . . . . . . . . . . . . . . 33 Status Epilepticus . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... . 3.4 Other Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 Drug-Induced Dyskinesias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Choreiform Movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3 Fulgurant Pain ••••••••••.•••••••.••.•.•••••••••• 4. Factors Mfecting Patient Response . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 aonazepam Alone or with Other Drugs? .................... . 4.2 Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Effect on Grand Mal and Other Seizures . . . . . . . . . . . . . . . . . . . . 5. Side-Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Side-Effects and Dosage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Influence of Concomitant Therapy on Side-Effects ......... . . ...... . 6. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . ....................... . 7. Dependence Potential 8. Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Overdosage 10. Dosage . . .

Summary

333 334 334 336 336 336 337 337 341 342 343 345 346 346 347 347 348 348 348 348 349 351 352 353 354 355 356 356 356 357

Synopsis: Oonazepam 1 or 5-(2-chlorophenyl)-l, 3-dihydro-7-nitro-2H- l,4-benzodiazepin-2-one, is a close structural and pharmacological relative of nitrazepam. It has a broad spectrum of activity against the various types of epilepsy, and is effective in many patients whose condition has proved resistant to other antiepileptic drugs. Its chief uses are in status epilepticus, in which intravenous c10nazepam may replace diazepam as the drug of first choice, and in the minor motor seizures of childhood, particularly petit mal absences, the Lennox-Gastaut syndrome and infantile spasms. Clonazepam is also at least as effective as current treatment in psychomotor and myoclonic epilepsies, but seems unlikely to replace phenytoin and the barbiturates in the treatment of grand mal or focal motor seizures except in patients resistant to standard therapy. Initial success with clonazepam am be followed by loss of effect, but benefit can often be restored, at least initially, by temporary inte"uption and re-institution of treatment. Side-effects are common with clonazepam. Most patients experience drowsiness and fatigue, which are frequent causes of withdrawal, together with lesser incidences of ataxia, dystonia, hypotonia, and hyperactivity. These effects usually disappear with continued therapy, and are minimised by gradual introduction of the drug over 2-4 weeks. Hypersalivation and excessive bronchial secretion may be a problem in children and infants. 1 'aonopin', 'Rivotril' (Roche)

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Pharmilcodynamic studies: The anticonvulsant properties of clonazepam have been demonstrated in man and in animals. Limited experimental studies in epileptic patients have shown that the drug raises the threshold for seizures induced by bemegride or by intermittent light stimulation. An intravenous dose of Img clonazepam was as effective in this respect as 5 to 10mg diazepam or 100mg chlordiazepoxide given by the same route. In animals, clonazepam displays a broad spectrum of activity against systemically administered convulsants of diverse mode of action, including pentylenetetrazole, bemegride, cocaine, local anaesthetics, strychnine and thiosemicarbazide. It elevates the threshold for electric shock seizures in rodents and protects against light-induced seizures in cats and the photomyoclonic syndrome in baboons. Qonazepam prevents propagation of seizure activity induced by cortical application of penicillin derivatives or ouabain. In most of these respects, it is more effective than either diazepam or standard anticonvulsant drugs like phenytoin, trimethadione or phenobarbitone. Intravenous clonazepam produces rapid beta activity in the EEG of both normal subjects and epileptic patients. This is associated with prevention of the development, and suppression of the spread, of abnormal EEG discharges in most patients and in most types of epilepsy. Experiments in animals have generally comllmed the attenuating effects on generalised seizure activity and on the propagation of focal discharges to distant cerebral regions, but there is some dispute as to whether clonazepam has any effect on focal epileptic activity. Focal EEG abnormalities in both humans and animals may be decreased, unaffected or even increased by clonazepam. In therapeutic trials, EEG normalisation does not always accompany therapeutic benefit with clonazepam, particularly in patients with focal seizures. In addition to its effects on those brain areas involved in the mediation of epileptic phenomena, clonazepam has depressant effects on the respiratory and cough centres in animals. It was more potent than other benzodiazepines, notably diazepam and nitrazepam, in both respects. In animals, clonazepam has tranquillising and sedative properties typical of the benzodiazepines. In normal humans, sedation was evident at doses above Img orally. At the spinal cord level, clonazepam depresses various motor reflex pathways and potentiates presynaptic inhibition. Qonazepam causes a dose-dependent rise in brain and CSF levels of 5-hydroxytryptamine and its metabolites in both man and animals, which disappears with chronic treatment. Qonazepam has negligible effects on the peripheral autonomic nervous system, and there have been no reports of cardiovascular disturbances in man. The drug has a low acute and sub-acute toxicity, and produced no untoward effects on chronic administration or during dysmorphology and reproduction studies in animals. PhaTmilcokinetic studies have shown that clonazepam is well absorbed following oral administration to man. Peak plasma levels are reached within 1 to 10 hours, usually 2 to 4 hours, and decline slowly over several days. There are wide individual variations in the levels reached at the same dose. Peak plasma levels appear to be poorly correlated with either the antiepileptic action or the side-effects of the drug. The plasma half-life for clonazepam is about 1 to 2 days. Qonazepam is excreted mainly in the urine, but very little of the administered dose appears as the unchanged drug. There is extensive metabolism to 7-aminoand 7-acetamino-clonazepam, which are excreted unchanged, as conjugates, or after further biotransformation to their 3-hydroxy derivatives. Plasma levels of 7-aminoclonazepam tend to parallel those of the parent drug during chronic administration, when the steady-state 24-hour urinary excretion of clonazepam and its metabolites is about 5 to 20% of the administered dose. Therapeutic trials: Published trials have shown clonazepam to be effective in maintenance doses of about 4 to 8mg daily in the treatment of petit mal epilepsy and minor motor seizures of childhood, and in refractory grand mal epilepsy, focal motor seizures and

Clonazepam: A Review

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temporal lobe epilepsy. It is also very effective in myoclonic epilepsy, and by the intravenous route in status epilepticus. Despite its apparently broad spectrum of antiepileptic activity, the degree of therapeutic effectiveness of clonazepam often does not reach the success rate achieved with standard antiepileptic agents in many forms of seizure though it has usually been used in patients already resistant to other antlepileptic drugs. Patient selection for oral therapy can be made by initial administration of intravenous clonazepam; those patients who demonstrate normalisation of the EEG, particularly of spike and wave components, are generally most likely to respond to oral clonazepam. Status epilepticus is the major indication for intravenous clonazepam, which appears to be more effective than the present drug of choice, diazepam, in all types of patient. Single doses of 1 to 4mg are usually sufficient to reverse status and to abolish or ameliorate paroxysmal activity in the EEG, but multiple injections may be required in some patients. In most studies, clonazepam has been effective in about 80 to 90% of such patients, often in those who have failed to respond to intravenous diazepam or phenobarbitone. Oral clonazepam may become the drug of choice for treating minor motor seizures of childhood. In petit mal absences clonazepam appears to be at least as effective as ethosuximide, producing a greater than 50% reduction in seizures in about 75% of patients. Seizure activity in children with the Lennox-Gastaut syndrome is abolished in about one-third of patients and reduced significantly in frequency in a further one-third, these patients often having failed to respond to nitrazepam or conventional antiepileptic drugs. At least half of infants with infantile spasms experience a reduction in seizures of greater than 50%, with about one-third of the total group being seizure-free during clonazepam treatment, often after the failure of nitrazepam or cortricotrophin. Some evidence suggests, however, that the initial spectacular success, particularly in cases of Lennox-Gastaut syndrome, infantile spasms and the Ramsay-Hunt syndrome, may decline so that clonazepam is ineffective after several months. This decline, which can occur, though less frequently, during the treatment of other types of epilepsy, can be overcome in somll patients by temporary interruption and re-institution of treatment. Oonazepam appears to control myoclonic seizures, including those of the photomyoclonic type, that are quite unaffected by nitrazepam or other forms of antiepileptic therapy. In some patients the development of tolerance can be overcome by repeated dosage increments before fmal control is established or limiting side-effects appear. Oonazepam is effective in psychomotor or temporal lobe epilepsy, reducing seizures by over 50% in about half of patients with about 27% of these becoming seizure-free. Oonazepam is effective in grand mal, whether primarily or secondarily generalised, and in focal motor seizures, but its efficacy is not such that it will replace the presently available drugs of choice. However, it is useful in treating patients whose seizures are refractory to, or who are intolerant of, these drugs, though it has little influence on the focal EEG abnormalities. Initial reports of the use of clonazepam to treat drug-induced dyskinesias, choreiform movements in patients with various types of chorea, and fulgurant pain, warrant further investigation. Oonazepam given alon~ appears to be as efficacious as when it is added to other antiepileptic drugs. There is no unequivocal evidence to indicate whether or not clonazepam has a significant precipitating or potentiating effect on grand mal seizures, but it may do so in occasional patients. Tolerance to the therapeutic effects of the drug may occur in some instances, and usually does so within the first 6 months of therapy. However, the incidence of tolerance is generally thought to be less than that seen with other benzodiazepines and many patients have received the drug for several years without loss of therapeutic effect. Patients who relapse on long-term clonazepam may still derive benefit from small oral doses taken as needed, or full benefit may be restored in some patients by temporary interruption of treatment.

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Side-effects are frequent during clonazepam therapy, and many patients experience them in one form or another. The syndrome of drowsiness, somnolence, lethargy and fatigue is the principal side-effect, occurring in about half of patients initially but usually disappearing with continued treatment. It is often sufficiently severe to necessitate dosage reduction or withdrawal of drug, but, like the other side-effects, is minimised by gradual introduction of clonazepam. Oonazepam may also produce muscular inco-()rdination and ataxia, hypotonia and muscle weakness, and hyperactivity with aggressive behaviour. Increased salivary and bronchial secretion may be a particular problem in infants and young children. Most of these side-effects are transient and self-limiting, but individual tolerance varies widely and there appears to be no general correlation with dose or plasma levels. There is no evidence to support contentions that clonazepam side-effects are more frequent and severe in patients given the drug in combination with other antiepileptics rather than alone. Precautions: Simultaneous administration of clonazepam and other antiepileptic drugs, particularly phenytoin, may modify the plasma levels of either or both drugs. The dosage of each must be adjusted so as to obtain the desired optimum effect. Like all antiepileptic drugs, clonazepam may modify the patient's reactions to a varying extent depending upon dosage and individual susceptibility. Patients should abstain from heavy drinking of alcohol while under clonazepam treatment, since alcohol may modify the action of clonazepam or give rise to unpredictable side-effects. Strict supervision of young children and infants is necessary, as hypersalivation and excessive bronchial secretion may be problems. As with all antiepUeptic drugs, withdrawal of clonazepam must be gradual and not abrupt. Sudden withdrawal may precipitate status epilepticus. Domge of clonazepam is essentially individual, and depends upon age, tolerance to side-effects, and clinical response. In order to minimise side-effects, it is necessary to increase the daily dose progressively until the maintenance dose suited to each individual patient has been reached, usually after 2 to 4 weeks of treatment. Maintenance doses in infants, young children, children of school-age, and adults are respectively 0.5 to lmg, 1.5 to 3rog, 3 to 6rog and 4 to 8rog daily. These should be given in 3 or 4 divided oral doses, and may be safely exceeded if necessary. Initial doses should not exceed 0.05mg/kg in children and infants, or 1.5rog in adults, given daily in divided doses. The maximum recommended dose in adults is 20mg daily. Parenteral treatment of status epUepticus with clonazepam requires 0.5rog in infants and children or lmg in adults, given by slow intravenous injection. This dose may be repeated if required, by intramuscular injections or slow intravenous 'infusion.

1. Pharmacodynamic Studies

Clonazepam is a benzodiazepine derivative, related to the well known anxiolytic drugs of that series. It resembles diazepam and particularly nitrazepam most closely in structure, and like these drugs it possesses marked anticonvulsant properties (fig. I). It has been the subject of previous review (Browne, 1976; Taylor et ,aI., 1976).

1.1 Anticonvulsant Properties 1.1.1 Human Studies Experimental studies of the anticonvulsant properties of clonazepam in man are limited. Rossi et aI. (1973) showed that intravenous doses of O.02mg/kg were sufficient to raise the threshold for bemegride-induced seizures by about 4-fold in 13 epileptic patieI1ts. Poire and Beck (I 973) found that 1mg clonazepam intravenously abolished

Clonazepam: A Review

seizure activity and normalised the EEG pattern in epileptic patients exposed to intermittent light stimulation. It was at least as effective in these doses as 10mg diazepam or l00mg chlordiazepoxide. Gastaut et aI. (1969) compared the effects of intravenous clonazepam and diazepam in 7 photosensitive epileptics and 10 patients with primary or secondary generalised epilepsy. Both drugs were effective within 1 minute in abolishing EEG paroxysms, but the duration of action was 103 minutes for diazepam (10mg) and 59 minutes for clonazepam (1 mg). Subsequent administration to patients with photo-induced epilepsy or Lennox syndrome showed that clonazepam was about 5 times more potent than diazepam; durations of action in the two types of epilepsy were 65 minutes (clonazepam, hng) and 80 minutes (diazepam 5mg). and 190 minutes (clonazepam 2mg) and 150 minutes (diazepam 10rog) respectively. 1.1.2 Animal Studies Clonazepam displays a broad spectrum of anti· convulsant properties in animals (Banziger and Hane, 1967; Blum et aI., 1973; Lechat et aI., 1970; Swinyard and Castellion, 1965). It has activity against systemically administered convulsants of diverse mode of action, including pentylenetetrazole, bemegride, cocaine, local anaesthetics, strychnine, thiosemicarbazide and 2,4-dimethyl5-hydroxy-methylpyrimidine. It elevates the threshold for electroshock seizures in rodents and protects against light-induced seizures in cats and the photo-myoclonic syndrome in baboons. Oonazepam prevents propagation of the seizure activity induced by cortical application of penicillin derivatives or ouabain. In most of these respects clonazepam is more effective than either diazepam or standard anticonvulsant agents like phenytoin, trimethadione or phenobarbitone. In other studies, clonazepam (1 to 2mg/kg, iv) produced a highly significant reduction in seizure activity and the number of deaths in rats receiving large doses of cocaine (Blum et aI., 1973; Eidel-

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O.N

Clonazepam

N) CH 3

I

0

CI

Diazepam

~1 -N

O.N

Nitrazepam

Fig. 1. Chemical structures of clonazepam, diazepam and nitrazepam. Metabolic products of clonazepam in man include the 7-amino and 7-acetamino derivatives (by reduction and acetylation of the nitro group) and the 3-hydroxy derivatives of these 3 compounds (hydroxylation of the methylene group of the benzodiazepine) (see section 2.3).

Clonazepam: A Review

berg et aI., 1965). The threshold of seizure-induction by bemegride was increased by 3 to 4-fold after doses of 0.1 to 0.2mg/kg clonazepam (Blum et aI., 1973; Giunta et aI., 1970; Rossi et aI., 1973). During bemegride infusions at the rate of 2ml/minute, seizure activity appeared within 105 seconds in untreated cats but after 653 seconds in cats treated with 0.2mg/kg clonazepam (Van Duijn, 1973). Poire and Beck (1973) found 1mg clonazepam to be as effective as 100mg chlordiazepoxide in cats exposed to intermittent light. Clonazepam was markedly more potent than other benzodiazepine derivatives and phenytoin, trimethadione, pentobarbitone or phenobarbitone against convulsions induced by intravenous administration to mice of local anaesthetics such as procaine or lidocaine (Blum et aI., 1973; Gogolak et al., 1973). It was equally effective in rabbits receiving large doses of benzylpenicillin intravenously (Blum et aI., 1973). In the baboon Papio papio, intramuscular doses of 0.1 to 1mg/kg prevented the photomyoclonic syndrome, in comparison with the higher doses required of phenobarbitone (13.7 to 35mg/kg) and phenytoin (5 to 15mg/kg) [Blum et aI., 1973] . 1.2 Effects on the EEG Epilepsy is associated with abnormal and excessive discharges in the EEG. Clonazepam prevents the development of, and suppresses, abnormal EEG discharges in most patients and in most types of epilepsy. In the normal individual, clonazepam (0.25mg, iv) produced an immediate change in the EEG, initially in the frontal recordings but then overall and consisting of rapid activity at 20Hz (poire and Beck, 1973; Poire and Royer, 1969). Simultaneously the amplitude and quantity of a-rhythm diminished. Similar effects on the EEG were evident with other benzodiazepines, but the rapid activity was more abundant with 1mg clonazepam than with lOmg diazepam or 100mg chlordiaze-

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poxide. There was often superimposed on this a slower secondary activity associated with a reduction in behavioural awareness. Following the injection of 0.25mg clonazepam (iv) to epileptic patients, in parallel with the appearance of rapid activity in normals, there was attenuation and then disappearance of both the abnormal EEG discharges produced by intermittent photic stimulation and of the associated clinical manifestations (Poire and Beck, 1973; Poire and Royer, 1969). One minute after injection, the amplitude of seizure responses in the occipitalrolando region had dropped to 1 to 10% of their previous values. The effects were comparable to those seen with large doses of chlordiazepoxide, diazepam, or nitrazepam, but the markedly more prolonged duration of action of clonazepam often led to continued attenuation even 24 hours after injection. Clonazepam was particularly effective against the EEG sequelae of hyperphotosensitivity associated with injection of cardiazol or bemegride. Similar attenuation of EEG abnormalities by clonazepam is evident in epileptic patients during spontaneous discharges. Studies in children, adolescents and adults (Hakkinen, 1973; Poire and Beck, 1973; Poire and Royer, 1969; Rosenmayr and Groh, 1973) have shown the drug to be effective in a variety of epileptic states (see section 3). Hiikkinen (1973) studied adult epileptics with marked EEG abnormalities particularly spike and wave complexes, and in whom discharges occurred between seizure or could be activated repeatedly without clinical manifestations. Clonazepam, 1 to 2mg intravenously, generally had marked attenuating effects on both spike and wave components and on total duration of generalised paroxysms. In children and adolescents, Rosenmayr and Groh (1973) observed rapid beta activity at 16 to 30Hz in 74 of 80 patients following intravenous clonazepam in doses of 0.03 to O.3mg/kg. 52 of 80 (65%) patients showed complete normalisation or marked improvement of their abnormal EEG. One child showed exacerbation and 27 were

Clonazepam: A Review

unaffected, though 4 of the latter had normal EEG immediately before administration of clonazepam. The immediate EEG changes produced by intravenous clonazepam have been suggested as a specific criterion for subsequent oral antiepileptic therapy (Groh and Rosenmayr, 1974). The drug is also markedly effective in normalising EEG abnormalities due to myoclonic seizures induced in epileptic patients by hypoglycaernia (poire and Beck, 1973). Animal studies have generally confIrmed the attenuating effects on generalised seizure activity and on propagation of focal discharges to distant cerebral regions, but there is some dispute as to whether clonazepam has any effect on focal epi· leptic activity (Giunta et ai., 1970; Gogolak et ai., 1973; Rossi et ai., 1973; Petsche, 1972; Van Duijn, 1973). 1.3 Site of Action Focal EEG abnormalities in both human subjects and animals may be decreased (poire and Royer, 1969; Fariello and Mutani, 1970; Van Duijn, 1973), unaffected (Giunta et al., 1970; Oller-Daurella et al., 1969 to 1970), or even increased (Hooshmand, 1972) by clonazepam. There is nevertheless general agreement that in animals at least clonazepam prevents the propagation of electroencephalographic and behavioural seizure activity from experimental epileptogenic foci produced by local application to the cortex of benzylpenicillin, ouabain, cobalt or alumina (Blum et ai., 1973; Giunta et al., 1970; Gogolak et al., 1973; Guerrero-Figueroa et aI., 1969a,b; Petsche, 1972; Rossi et al., 1973). This inhibition usually occurs in the absence of any effect on focal electrical activity. In the most comprehensive studies of site of action, Guerrero-Figueroa et al. (1969a,b) observed the effects of clonazepam upon seizure activity induced in cats and monkeys by application of alUmina, cobalt, or penicillin to various parts of the brain. Clonazepam produced a decrease in the

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amplitude of local evoked potentials recorded from normal and secondary epileptogenic limbic tissues, similar to that observed in rats follOwing cortical application of cocaine (Eidelberg et aI., 1965), and suppression of the spread of primary epileptiform discharges. There was no effect on spontaneous epileptiform activity generated by the irritant focus, in limbic, cortical or centrencephalic structures. Local evoked potentials from the midbrain reticular formation were facilitated by clonazepam, which did not affect either the evoked potentials or spontaneous primary and secondary epileptiform activity recorded from cortical or midline structure epileptogenic tissues. It has been suggested that clonazepam may act in epilepsy by mimicking the action of glycine at its central neuroeffector sites. Young et ai. (1974) found that the rank order of potency of 21 benzodiazepines, including clonazepam, as glycine agonists correlated with their order of potency in preventing pentylenetetrazole seizures or maximal electroshock seizures. 1.4 Other Central Effects In addition to its effects on those brain areas involved in the mediation of epileptic phenomena, clonazepam has depressant effects on the respiratory and cough centres. It is more potent than other benzodiazepines, notably diazepam and nitrazepam, in both respects. Clonazepam has tranquillising and sedative properties typical of the benzodiazepines.

1.4.1 Respiratory Centre In studies in decerebrate cats, clonazepam reo duced tidal volume and the slope of its relationship to Paco2 (Florez, 1971). The inspiratory response to direct electrical stimulation of the inspiratory centre was depressed to the same extent as the CO 2 -respiratory responsivity. Clonazepam produced these effects at doses (O.1mg/kg, iv) consistently lower than those (O.5mg/kg) re-

Clonazepam: A Review

quired of other benzodiazepines such as diazepam and nitrazepam. Clonazepam appears to affect respiration by depressing primarily the mechanisms involved in the generation of tidal volume, an effect induced at the ponto-medullary rather than the spinal level since it also occurred in cats when the drug was injected into the vertebral artery. Gastaut et aI. (1969) found no evidence for effects on respiratory rhythm following intravenous injection of 1mg in 33 normal subjects. However, clonazepam can cause respiratory depression in some patients (see section 4).

1.4.2 Cough Centre Clonazepam is a potent and specific antitussive in cats (Chou and Wang, 1975). It was 20 times more effective by intravertebral than by intravenous injection, suggesting a central site of action at the brainstem cough centre, and was 35 times more potent than codeine and 12 times as effective as dextromethorphan. The antitussive effect was not well correlated with the muscle relaxant activity, since clonazepam was 6 times more potent than diazepam as an antitussive whereas the two drugs were equipotent in depressing polysynaptic spinal reflexes. 1.4.3 Sedative Effects In 12 healthy volunteers, Hollister (1975) found that single orat doses of 0.5 or 1mg clonazepamwere well tolerated, but higher doses were associated with increasing sedation. In the longterm treatment of epilepsy, however, higher doses can be tolerated with continued use of the drug (see section 5.1). In tests for effects on muscle co-ordination in mice, such as the rotarod or traction tests, clonazepam was more effective in producing inco-ordination than other benzodiazepines or antiepileptic agents (Blum et al., 1973). It was from 2 to 10 times more potent than diazepam, 5 to 100 times phenobarbitone, and 12 to 300 times phenytOin, with an oral EDso as low as O.3mg/kg in the rotarod test. This order of potency is not reflected in

329

man, and clonazepam produces less sedation than diazepam. Clonazepam has little effect on spontaneous locomotor activity (Blum et aI., 1973). Oral doses of 30mg/kg had negligible effects in mice, though higher doses of lOOmg/kg produced mixed stimulation and depression of locomotion. In rats, oral doses of l00mg/kg were without effect, in contrast to the Significant reduction in motor activity associated with chlordiazepoxide (100mg/kg) or chlorpromazine (3mg/kg). Low doses of clonazepam, O.lmg/kg iv, selectively suppressed the evoked potentials produced in cats in the hippocampal region by stimulation of the amygdala (Blum et al., 1973). The effect was dose-dependent, and clonazepam was more potent than either diazepam or hexobarbital. Higher doses of IOmg/kg (iv) in cats raised the threshold for cortical arousal by 100%.

1.4.4 Effects on 5-Hydroxytryptamine Metabolism The possible role of brain 5-hydroxytryptamine (5-HT) in experimental epilepsy is indicated by the elevated seizure threshold associated with raised brain 5-HT during the administration of conventional anticonvulsant drugs, and the increased seizure susceptibility associated with lowered brain 5-HT (see Jenner et al., 1975a). Brain 5-HT turnover (as measured by raised 5-HIAA levels) may be increased in human epileptics given anticonvulsant drugs but lowered in untreated subjects with action myoclonus, and the latter improve dramatically when treated with 5-hydroxytryptophan. Clonazepam (0.5 to 8mg/kg, ip) caused a dosedependent rise in brain 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations in mice, at doses lower than either diazepam or phenytoin (Jenner et al., 1975a,b). These effects were no longer evident, however, in animals following chronic treatment for 8 days with 4mg/kg/day clonazepam. In clinical studies in 3 patients with action myoclonus, the excellent initial response to clonazepam disappeared in 2

330

Clonazepam: A Review

patients after some 6 to 8 weeks of continuous therapy. 5-HT and 5-HIAA levels were elevated following successful clonazepam therapy, but no details were reported of the levels in the patients who relapsed (see section 4). 1.5 Muscle Relaxant Properties Clonazepam depresses various motor reflex pathways in spinal cats and in those with midcollicular sections (Blum et al., 1973; Tseng and Wang, 1971). The amplitude of mono- and polysynaptic reflex potentials was reduced in a dosedependent manner within 10 minutes of intravenous injection of clonazepam, which was effective over the dose range 0.05 to 10mg/kg. Clonazepam was equipotent with diazepam and 3 times as effective as phenobarbitone. Swinyard and Castellion (1966), however, found no evidence for an effect of clonazepam (0.025 to 2.5mg/kg, iv) on the transmission of isolated impulses in monosynaptic and polysynaptic pathways or on posttetanic potentiation in spinal cats, but it did markedly decrease the response to repetitive stimulation. Similar results were observed in cats for the depressant effect of clonazepam on the spontaneous tonicity associated with'Y -motoneuron activity (Blum et al., 1973). Clonazepam and diazepam were again equipotent and more effective than phenobarbitone. Clonazepam and diazepam increased the amplitude and duration of dorsal root potentials in spinal and midcollicular cats after intravenous doses of 0.05 to Img/kg. Clonazepam may therefore enhance presynaptic inhibition, in contrast to phenobarbitone which reduced the amplitude of potentials at doses above 1.0mg/kg (Blum et al., 1973). 1.6 Miscellaneous Pharmacodynamic Effects Clonazepam has negligible effects on the peripheral autonomic nervous system. Studies in ani-

mals have revealed only a few minor and transient changes (Blum et al., 1973), and there have been no reports of cardiac disturbances in man (Gastaut et al., 1969). In dogs, 0.3 to 1mgfkg clonazepam produced small (10 to 17%) and transient increases in systolic blood pressure, with no change in heart rate. Higher doses, 3 or 10mg/kg, produced agitation and ataxia in all animals. There was no apparent relationship between dose and effects on blood pressure. Rats receiving oral doses of 0.1 to 0.3mg/kg clonazepam showed no changes in blood pressure or heart rate. Clonazepam, given to rats in oral doses of 1 to 10mg/kg, reduced urinary sodium excretion by 50% at the highest dose level, with concomitant effects on urinary volume . and potassium excretion. In dogs, however, oral doses of Img/kg influenced neither urinary volume nor urinary potassium and sodium.

1.7 Toxicology

1. 7.1 Acute and Sub-Acute Toxicity The acute toxicity of clonazepam is very low. The LDso was greater than 4,OOOmgfkg in rats and mice, either 24 hours or 10 days follOwing oral or intraperitoneal administration (Blum et al., 1973). In mice and rats given sub-toxic doses of 300 to 1,000mg/kg clonazepam orally, the principal signs were somnolence and sedation. 1.7.2 Chronic Toxicity In rats given 30, 150 or 30Omg/kg clonazepam on 6 days per week for 6 months, there was no evidence for any haematological or biochemical abnormalities or changes in urinalyses (Blum et aI., 1973). Some animals in the middle and high-dose groups showed increased weight and enlargement of the liver and adrenals, and there were occasional incidences of fatty deposits in the liver. Essentially similar results were observed in dogs receiving oral doses of 3, 10, or 3Omg/kg clon-

Clonazepam: A Review

azepam on 6 days per week for 12 months (Blum et al., 1973).

1. 7. 3 Dysmorphology and Reproduction Studies There was no evidence for any effects of clonazepam upon mother or fetus, when given to rats, mice, or ,abbits in oral or intravaginal doses of I to 100, 1 to 20, or 1 to 2.5mg/kg daily (Blum et al., 1973), except for a non-dose-dependent increase in congenital abnormalities in one species of rabbit. 2. Pharmacokinetic Studies Clonazepam is well absorbed following oral administration to man. Peak plasma levels are reached within 1 to 10 hours, usually 2 to 4 hours, and decline slowly over several days. There are wide individual variations in the levels reached at the same dose. Peak plasma concentrations appear to be poorly correlated with either the antiepileptic action or the side-effects of the drug. Clonazepam is excreted mainly in the urine, but very little of the administered dose appears as unchanged drug. There is extensive metabolism to 7amino- and 7-acetamino-clonazepam, which are excreted unchanged, as conjugates, or after further biotransformation to their 3-hydroxy derivatives. 2.1 Absorption The results of single- and multiple-dose studies in normal subjects, and in epileptic and non-epileptic patients, show that clonazepam is well absorbed (table I). Plasma levels reach a maximum within 10 hours of dosage, usually within 2 to 4 hours, and over 80% of the oral dose is absorbed compared to intravenous administration (Eschenhof, 1973). Maximum plasma concentrations of clonazepam vary widely between individuals. In 27 newly-diagnosed epileptic patients receiving daily doses of 6mg clonazepam for up to 12

331

months, SjO et al. (1975) found plasma levels of the drug to vary between 30 and 80ng/mI, with an average of sOng/mI. These levels were paralleled by those of the principal metabolite, 7-aminoclonazepam. Dreifuss et al. (1975) observed proportionately similar levels of 13 to 72ng/mI in 10 children with absence seizures who received 1.5 to 4mg clonazepam daily during a 17-week study. The lower levels found by Huang et al. (1974), averaging 25 to 30ng/mI follOwing doses of 6mg daily, may have been due to the coadministration of other antiepileptic drugs including ,phenytoin, primidone and barbiturates. In 5 healthy volunteers receiving doses of O.5mg clonazepam twice daily for 15 days, plasma levels averaged 8.8ng/mI (Berlin and Dahlstrom, 1975). 2.1.1 Half-Life The half-life for elimination of clonazepam from plasma in normal subjects has been estimated to be about 1 to 2 days (table I). In the only study in epileptic patients receiving clonazepam therapy, Dreifuss et al. (1975) determined the half-life to be 22 to 33 hours with a mean of 28.7 hours. In a study in 5 healthy volunteers receiving oral doses of 0.5mg clonazepam twice daily for 15 days, the plasma half-lives after cessation of treatment were of the same magnitude as those found after single doses in the same subjects (Berlin and Dahlstrom, 1975). This suggests that drug-metabolising liver enzymes are not induced by clonazepam, but the observations require confumation in more prolonged studies in epileptic patients. 2.1.2 Relationship Between Plasma Levels and Therapeutic or Side-Effects Neither the therapeutic effects nor the sideeffects of clonazepam can be related to its plasma levels or to the rate of increase in plasma concentration (see section 5.1). In studies in epileptic patients (Dreifuss et al., 1975; Huang et al., 1974; Sjo et al., 1975), therapeutic benefit was evident at plasma levels ranging from 13 to 90ng/mI, and

332

Clonazepam: A Review

Table I. Some pharmacokinetic properties of clonazepam in man Author

Num- Type of ber subject of subjects

Dose of clonazepam in mg (mean); route of administration

TIme to reach peak levels in hours (mean)

Plasma eliminat ion half-life in hours (mean)

<1 1-4 <1 1-3 <1 1-9 1-10 1-8 «2) 2-4

24-60 (37.5)

7.1-23.6 (16.8) 11.8-15.3 (13.4) 8.7-10.8 (10) 5.4-12.6 (9.7) 9.7-10.6 (10.3) 26.6-51.9 (41.5) 6.5-13.0 10-26

4.6-12.0 (8.8) 13-72 (33.3)

2-3

Peak plasma levels in nglml (mean)

Single-dose administration Berlin and Dahlstrom (1975) Eschenhof (1973)

Kaplan et al. (1974) Naestoft et al. (1973)

8

Normal

4

Normal

8

Nonepileptic inpatients Normal Normal

10 2

2; iv 2;po 1.5; iv 1.5; po 1.5; iv 1.5; po 9.0; po 2; po 2-4; po

28.3-56.4 (40.6) 26.5-49.2 (42.2) 30.5-40.3 (34.9) 26.8-32.2 (29.9) 18.7-39 (26.4) 22-38

Multiple-dose administration Berlin and Dahlstrom (1975) Dreifuss et al. (1975)

5 10

Huang et al. (1974)1 Naestoft et al. (1973) Sjo et al. (1975)

46 3 27

Normal Children, absence seizures Epileptics Epileptics Epileptics

1; po 1.5-4 (2.2); po

1-14 (6); po 5-90 (25-30) 5-6; po 27-46 30-80 (50) 6; po

31-42 (34.6) 22-33 (28.7)

1-3 1-5 (3-4)

1 Patients also received other antiepileptic drugs including phenytoin, primidone, and barbiturates

side-effects at values from 40 to 265ng/ml. However, Huang et al. (1974) concluded that levels of 25 to 30ng/ml were effective for the control of grand mal and temporal lobe epilepsy, but lower levels were sufficient for myoclonic and photic epilepsy. Knop et a1. (1975) found that plasma levels of 30 to 60ng/ml provided effective control in the majority of patients with various types of epilepsy. High plasma levels of clonazepam may be associated with the development of status epilepticus (Hvidberg, personal communication). Sjo, et a1. (1975) noted that 3 of 5 dysphoric patients had significantly high clonazepam levels, while 4 patients who suffered withdrawal symptoms had

high levels of the 7-amino metabolite. All 8 volunteers in the study of Berlin and Dahlstrom (1975) experienced slurred speech, poor co-ordination and sleepiness, for 3 hours, associated with plasma clonazepam levels of 7.1 to 23.6ng/ml. In general, it is still not possible to defme a lower limit for the plasma levels of clonazepam and its metabolite at which therapeutic benefit is experienced, or an upper limit at which sideeffects may appear. This may be due principally to the wide individual variation in both kinds of response to clonazepam. In patients treated with conventional doses, measurement of plasma levels may be unnecessary except in special circumstances (Sjo et aI., 1975).

Clonazepam: A Review

2.2 Distribution There are no published studies of the distribution of clonazepam, but the degree of binding in vitro to human serum albumin is variously given as 47% (MUller and Wollert, 1973) or 82% (Hofmann La Roche, unpublished data, 1973).

2.3 Metabolism and Excretion Urinary excretion of unchanged clonazepam is usually less than 1% of the administered dose in the first 24 hours, in both normal subjects after single doses (Eschenhof, 1973; Kaplan, 1974) and in epileptic patients during chronic treatment (Sjo et aI., 1975). Clonazepam is extensively metabolised, principally by reduction to 7-aminoclonazepam and acetylation to 7-acetaminoclonazepam, with trace amounts of the 3-hydroxy derivatives of all three compounds and their glucuronide and sulphate conjugates (Eschenhof, 1973; Knop et aI., 1975; Naestoft and Larsen, 1974) (see figure 1). Plasma levels of 7-aminoclonazepam tend to parallel those of the parent drug during chronic administration (Sjo et al., 1975). Single-dose oral administration of 1.5 to 9mg clonazepam to normal subjects and non-epileptic patients resulted in 7-day excretion of 49.4 and 68.8% of the dose in the urine and 9.1 to 30.6% in the faeces (Eschenhof, 1973). In epileptic patients receiving daily doses of 6mg, Sjo et ai. (1975) found the steady-state total 24-hour urinary excretion of clonazepam and its metabolites to be about 5 to 20% of the dose given.

3. Therapeutic Trials In most studies patients have continued to receive other antiepileptic drugs while being

333

treated with clonazepam. In many cases, the patients have not responded to conventional medication, and clonazepam has generally been studied in these drug-refractory epilepsies. It appears to be effective in the treatment of petit mal epilepsy, minor motor seizures of childhood, refractory grand mal epilepsy and temporal lobe epilepsy. It is also very effective in the treatment of myoclonic and focal motor seizures and in status epilepticus. Despite this apparently broad spectrum of antiepileptic activity, the degree of therapeutic effectiveness of clonazepam often does not reach the success rate achieved with standard antiepileptic agents in many forms of seizure, though its use in patients already resistant to other drugs may militate against its efficacy. On the other hand it is frequently effective in some drug-refractory seizures. This lack of a clear range of indications is not helped by the poor correlation between therapeutic effects and plasma levels of clonazepam (see section 2.1.2). However, patient selection for oral therapy can be made, with a reasonable degree of reliability, by initial administration of intravenous clonazepam. Two studies (Bianchi Saus et aI., 1973; Groh and Rosenmayr, 1974) in mixed epileptic populations have demonstrated a strong correlation between the degree of therapeutic response to oral therapy and the level of EEG amelioration or normalisation after a single injection (table II). The populations studied so far are too small to allow any meaningful appraisal of the relationships between the type of epilepsy and EEG and therapeutic responses, but in general patients with generalised spikes and waves in the EEG were those most likely to show EEG normalisation (and hence therapeutic benefit) irrespective of the associated form of seizure (Groh and Rosenmayr, 1974; Rett, 1973). In most patients EEG normalisation accompanies therapeutic benefit, but in others, particularly those with focal features, a reduction in seizure activity may not necessarily be accompanied by EEG normalisation.

334

Clonazepam: A Review

Table II. The response of epileptic patients to long-term oral clonazepam therapy as a function of their initial response to single-dose intravenous clonazepam Author

Bianchi Saus et al. (1973)

Groh and Rosenmayr (1974)

EEG response (iv clonazepam)

No. of pts.

Therapeutic results after > 6 months oral clonazepam free from attacks

improved

unchanged

1 (11%) 15 (100%)

1 (11%)

Normalised Improved Unchanged

9 15 6

7 (78%)

Normalised Improved Unchanged

46 32 20

34 (74%) 13 (40.6%) 2 (10%)

3.1 Controlled Trials The results of controlled trials in patients with various types of epilepsy (table III) show that clonazepam is Significantly superior to placebo in reducing seizures, either when added to previously inadequate antiepileptic medication or in newlydiagnosed patients who have received no other antiepileptic drug. The optimal dose appears to be about 4 to 6mg daily, though some patients may not achieve this level because of limiting side· effects and others may obtain full benefit at lower doses. Maximum efficacy occurs within the first 2 to 3 weeks of treatment.

3.1.1 Minor Motor Seizures Clonazepam is particularly effective in the minor motor seizures of childhood, especially petit mal absences. In a double-blind crossover trial in 18 epileptic children, including 8 with petit mal absences, 6 with l..ennox-Gastaut syndrome and 4 with West's syndrome (hypsarrhythroia), clonazepam or placebo was given in doses of 3 to 6mg daily for an average of 5 months (Turner et aI., 1970). Patients continued to take other antiepileptic medication, which had failed to provide adequate control of seizures in most cases. The levels of clinical and

6 (100%) 9 (19.5%) 8(25%) 1 (5%)

3 (6.5%) 11 (34.4%) 17 (85%)

EEG improvement showed a significant advantage for clonazepam over placebo (P < 0.01). There was no significant difference between the effects of clonazepam on each individual type of epilepsy. Side-effects, principally fatigue and lethargy, were observed in 12 patients whilst on clonazepam. Dreifuss et ai. (1975) have reported on 10 children with absence seizures who are part of a group of 100 participating in a double-blind trial designed to compare the efficacy of clonazepam with that of ethosuximide both given with a placebo. The children received doses of 0.028 to O.I11mg/kg clonazepam daily for 8 weeks. Eight of them showed a greater than 50% reduction in seizure frequency, with elimination of seizures in 3 patients. One patient showed a 10% decrease and one a 6% increase. Drowsiness developed in 5 patients during the 8 weeks on clonazepam, and other side-effects included ataxia, hyperactivity and increased body weight. No results are reported for the group receiving ethosuximide plus placebo. In a further double-blind study in petit mal absences, Chandra (1973) randomly assigned 39 patients to receive clonazepam (0.1 to 0.2rng/kg) or diazepam (about 20rng) as the sole daily anticonvulsant drug. Seventeen of the 19 patients who received clonazepam had a 55% or greater reduc-

Clonazepam: A Review

335

Table III. Summary of design and results of controlled therapeutic trials of clonazepam in patients with various types of epil epsy 1 Author

No. (and type) of patients

Design of trial 2

Dai Iy dose of clonazepam

Birket·Smith et al. (1973)

21 (psychomotor)

SBCO

6mg 3

a weeks

Clonazepam

> placebo

Chandra (1973)

39 (petit mal absence) 4

DBBP

0.1-0.2mg/kg (19 patients) -20mg diazepam (20 patients)

6 months

Clonazepam

> diazepam

Edwards and Eadie (1973)

(generalised) 10 (focall

DBCO

6mg

Mikkelsen et al. (1975)

14 (focal) 3 (secondary genera· lised grand mall

SBCO

6mg3

a weeks

Clonazepam

> placebo

Mikkelsen et al. (1976)3

10 (petit mal absence) 10 (myoclonic atonic epilepsy) 4 (jJetit mal absence)4 4 (myoclonic atonic epilepsy)4

SBCO

3-6mg

a weeks

Clonazepam

> placebo

SBCO

3-6mg

8 weeks

Clonazepam

> placebo

SBCO

3-6mg

8 weeks

Clonazepam

> placebo

SBCO

3-6mg

a weeks

Clonazepam

> placebo

DBCO

3-6mg

5 months

Clonazepam

> placebo

Turner et al. (1970)

a

a

(petit mal absence) 6 (LennoxGastaut) 4 (hypsarrhythmia)

Duration of trial

16 weeks

Result (reduction of seizures)

Clonazepam > placebo

All patients continued to take other antiepileptic medication (which had provided insufficient controll, except where otherwise stated. 2 SBCO, single-blind with crossover; DBBP, double-blind, between-patient comparison ; DBCO, double-blind with crossover. 3 6 patients in each trial failed to achieve the stated dose because of dose-limiting side-effects. 4 Newly diagnosed patients, who received no other antiepileptic drug during the trial .

tion in seizure frequency over 6 months, and 14 of 19 had complete control of seizures. Only one of the 20 patients on diazepam had a 55% or greater reduction in seizures, and none had complete control. None of the diazepam group showed disap-

pearance of the 3 cycle-per-second spike-and-wave in the EEG, while 17 of the clonazepam group did so. Differences in seizure control and EEG improvement were highly Significant for the two drugs.

Clonazepam: A Review

Mikkelsen et al. (1976) studied 10 patients with simple absences, who had failed to respond to conventional therapy. The effects of clonazepam were compared with those of placebo, both being added to the previous medication under singleblind crossover conditions. Sequential analysis showed that clonazepam was Significantly superior to placebo. During clonazepam treatment, 8 patients became free from seizures and one had a more than 75% reduction in their frequency, with the maximal efficacy after about 2 weeks. Only 2 patients were free from seizures during placebo administration, and one patient responded to neither treatment. Side-effects of somnolence, fatigue, drowsiness and co-ordination disturbances occurred in most patients, but either subsided spontaneously or were controlled by a slow increase or slight reduction of dose. Mental sideeffects such as agitation, confusion and aggressiveness were more troublesome, and caused discontinuation of clonazepam in 2 patients. In a subsequent study in 4 newly diagnosed patients with simple absences who received no other antiepileptic medication, Mikkelsen et al. (1976) found clonazepam to be superior to placebo in 3 patients, while the fourth withdrew because of side-effects. Side-effects were similar to those in the larger trial. 3.1.2 Generalised Tonic-Qonic and Focal Motor Seizures In a group of patients with focal seizures with or without secondary generalisation, Mikkelsen et al. (1975) found that 10 of 17 patients became seizure-free during treatment with clonazepam under single-blind crossover conditions, with a reduction of greater than 75% in a further 5 patients. Only 3 patients were free from seizures dUring placebo administration. However, 15 patients experienced side-effects on clonazepam, principally somnolence, drowsiness and co-ordination disturbances. One patient with previous grand mal seizures withdrew while on clonazepam due to increased frequency of grand mal.

336

Edwards and Eadie (1973) observed significant improvement during clonazepam treatment in 5 of 8 (62%) patients with generalised epilepsy and in 8 of 10 (80%) of those with focal epilepsy. One patient with generalised epilepsy became worse, but none improved on placebo. 3.1.3 Psychomotor or Temporal Lobe Epilepsy Birket-Smith et al. (1973) gave placebo followed by clonazepam to 21 patients with psychomotor epilepsy during a single-blind crossover trial lasting 8 weeks. The patients had not been satisfactorily controlled by other antiepileptic medication; phenytoin alone or in combination with carbamazepine, phenobarbitone or primidone (15 patients), primidone plus carbamazepine (4 patients) and carbamazepine plus phenobarbitone (1 patient). Sequential analysis demonstrated that clonazepam added to previous treatment was significantly better than placebo added to previous treatment (P < 0.05), with 12 clonazepam and 1 placebo preferences and 8 tied cases. Of the 12 clonazepam preferences, 4 had no seizures, 6 a reduction of more than 75%, and 2 a reduction of more than 50% in the number of seizures. Three other patients, who had no reduction in the number of seizures, experienced a marked diminution in their intensity and duration. The maximum efficiency of clonazepam occurred within the first 3 weeks. Most patients on clonazepam experienced side-effects such as somnolence, drowsiness, fatigue and co-ordination disturbances, but these 'Were controlled by a slower rate of increase or a slight reduction in dosage. 3.1.4 Myoclonic/Atonic Seizures In a single-blind crossover study lasting 8 weeks, Mikkelsen et al. (1976) gave clonazepam or placebo to 10 patients with myoclonic atonic epilepsy (bilateral massive epileptic myoclonus with atonic seizures), who continued to take their previously inadequate medication. Sequential analysis showed a significant advantage for clonazepam. During clonazepam treatment, 2 patients

337

Clonazepam: A Review

were free from seizures, 5 experienced a greater than 75% reduction in their frequency, while 3 patients had small or no benefit. Placebo administration was ineffective in 7 patients, and provided greater than 75% control in only 1 patient. No side-effects occurred in 5 patients, although the dose (0.4 to 6mg, mean 2.3mg) for effective control was considerably lower than in a similar trial in patients with petit mal absences (see section 3.1.1). Two patients had transient sideeffects and 3 had lasting sedation. One patient withdrew because of somnolence and behaviour disturbances. In a subsequent study in four patients who had not received any previous antiepileptic medication, Mikkelsen et ai. (1976) observed that clonazepam was superior to placebo in 2 and had an equal effect in a third. The fourth patient, with myoclonic atonic epilepsy and many concomitant absences, became free from all attacks while on clonazepam.

3.2 Open Trials Most of the studies with clonazepam have involved patients who are already refractory to other antiepileptic medication. The drug has been given to patients for varying periods of time, and trials are therefore not strictly comparable. It is well known that antiepileptic drugs in general, and benzodiazepines in particular (Browne and Penry, 1973), may lose their efficacy on continued treatment. However, this has not been a major problem with clonazepam at the present time, except for the l.ennox-Gastaut and Ramsay-Hunt syndromes, and infantile spasms (see section 4.2). Nevertheless, the proportions of patients with varying degrees of benefit to be described in sections 3.2.1 to 3.2.6 are to be taken as a guide to the efficacy of clonazepam rather than as absolute figures of activity. The results have been summarised in this way, despite the obvious disadvantage of different follow-up periods in different trials, because the information is too voluminous

to cite each trial individually for each type of epilepsy.

3.2.1 Minor Motor Seizures Petit Mal Absences Ethosuximide or sodium valproate are the drugs of choice for treating petit mal absences. Complete control of seizures can be obtained in about 50% of patients, with a Significant reduction in seizure frequency in a further 25% (Woodbury and Fingl, 1975; Simon and Penry, 1975). Clonazepam appears to be at least as effective as these drugs, and is also active against some otherwise drugresistant petit mal absences. Several controlled trials have confrrmed its superiority to placebo (Mikkelsen et aI., 1976; Turner et aI., 1970) and to diazepam (Chandra, 1973) in both n~wly-diag­ nosed and drug-refractory patients (see section 3.1.1). The seven largest uncontrolled trials (11 or more patients) reported a reduction in seizure frequency of 50% or more in from 50 to roO% of cases, with complete elimination of seizures in 7 to 91 % of patients (Bergamini et aI., 1970; Chandra, 1972; D'Onghia et aI., 1973; Gastaut, 1970; Lund and Trolle, 1973; Oller-Daurella, 1969,1973; Rey Pias, 1972). In general, clonazepam seems to produce a greater than 50% reduction in seizure frequency in about three-quarters of patients with petit mal absences (fig. 2). Many studies have found that petit mal absences respond particularly well to clonazepam, with most patients becoming free from seizures. Bladin (1973), for example, gave clonazepam alone, in initial doses of 8 to 10mg daily, to 7 patients with petit mal absences, including 1 patient with up to 50 seizures daily. Five became free from seizures while 2 required additional trimethadione or ethosuximide. Chandra (1972) observed improvement within 48 hours in 14 patients given 3 to 6mg clonazepam daily. Twelve continued to experience complete remission, but absence seizures returned in 2 patients within the

338

Clonazepam: A Review

fIrst week. Withdrawal of clonazepam at 3 to 6 months in 4 patients in remission resulted in a return to their former status. In an unblinded crossover study, Oller-Daurella (1969) compared the effects of clonazepam and succinirnide on seizure frequency in 9 children with petit mal absences. Clonazepam produced better control in 7 patients, though a small doubleblind study in 8 others failed to show a significant difference between clonazepam and placebo as adjunctive antiepileptic drugs. Clonazepam produced a greater than 50% reduction in seizures in 42 of 51 (82%) patients

with designated pyknoleptic petit mal, that is with very frequent absence seizures, with 30 patients (60%) being seizure-free (Groh and Rosenmayr, 1974; Kruse and Blankenhorn, 1973; Lund and Trolle, 1973; Munthe-Kaas and Strandjord, 1973). Atypical Absences This relatively rare form of seizure, with loss of consciousness of short duration, is less abrupt than typical petit mal absence in onset and termination. The EEG shows slow spike-and-wave activity but never typical 3 cycle-per-second spike-and-wave. In a total of 59 such patients, 19 became seizure-free,

Lennox-Gastaut syndrome (319 patients)

•

Free from seizures

D>

t:3 <

IlJ]

50% reduction 50% reduction

Unchanged, worse or result not reported

Petit mal absence (278 patients)

Infantile spasms (174 patients)

55%

Fig. 2. Proportion of epileptic patients with varying degrees of response to maintenance therapy with clonazepam. Patients had generally failed to respond adequately to, but continued to take, other antiepileptic medication. Data for this figure and for figures 3 and 4 were taken, where appropriate, from the following uncontrolled trials: (Aarli, 1973; Balassa and Deisenhammer, 1972; Barnett, 1973; Beaussart et aI., 1973; Bergamini et aI., 1970; Birket-Smith and Mikkelsen, 1972; Bladin, 1973; Carson and Gilden, 1975; Castroviejo, 1971; Chandra, 1972; D'Onghia et aI., 1973; Dumermuth and Kovacs, 1973, 1974; Eeg-Olofsson, 1973; Fazio et aI., 1975; Gastaut, 1970; Groh and Rosenmayr, 1971, 1973, 1974; Guldenpfennig, 1973; Hanson and Menkes, 1972; Hooshmand, 1972; Huang et aI., 1974; Kick and Dreyer, 1973; Kruse and Blankenhorn, 1973; Lance and Anthony, 1976; Lehtovaara, 1973; Lund and Trolle, 1973; Martin and Hirt, 1973; Masland, 1975; Mikkelsen and Birket-Smith, 1973; Munthe-Kaas and Strandjord, 1973; Negrin st aI., 1971; Nieto, 1973; Oller-Daurrella, 1973; Palacios et al., 1971; Rebollo, 1971; Rett, 1971, 1973; Rey Pias, 1972; Schlack, 1974; Scollo-Lavizzari et aI., 1974; Vassella et aI., 1973; Weinmann and Willms, 1973). See text for further explanation.

Clonazepam: A Review

14 were improved by more than 50% and 13 were unchanged (Carson and Gilden, 1975; Hanson and Menkes, 1972; Lund and Trolle, 1973; OllerDaurella, 1973). Four patients became free of seizures with clonazepam alone (Carson and Gilden, 1975). Hanson and Menkes (1972) gave clonazepam to 12 such patients after first discontinuing other medication for minor seizures. After 3 months complete control of seizures was evident in 7 patients, and all 12 had at least a 50% reduction in seizure frequency. Lennox-Gastaut Syndrome The most severe forms of epilepsy in children are infantile spasms with hypsarrhythmia (West's syndrome; see below) and the Lennox-Gastaut syndrome (myoclonic-astatic epilepsy). The latter is an epileptic encephalopathy with diffuse slow spike waves in the EEG, and was resistant to medication until the introduction of ACTH and nitrazepam. Clonazepam appears to be effective in many with this ·disease, including those who are resistant to other drugs. In the double-blind trial of Turner et al. (1970), clonazepam was Significantly superior to placebo over 5 months when added to conventional therapy in 6 patients with Lennox-Gastaut syndrome (see section 3.1). Patients were already receiving barbiturates, hydantoins, succinimides, carbamazepine, nitrazepam and ACTH, in various combinations. Uncontrolled trials have suggested that clonazepam abolishes seizure activity in about onethird of patients with Lennox-Gastaut syndrome, and reduces their frequency by gr~ater than 50% in a further one-third (fig. 2). In most cases, these patients had failed to respond to other benzodiazepines, ACTH or conventional antiepileptic drugs. In some patients, however, the drug has been without beneficial effect, even in doses as high as 30mg daily (Bladin, 1973). In a trial in 37 patients with Lennox-Gastaut syndrome, clonazepam 6mg daily for an average of

339

24 months was effective in abolishing seizures in 16 patients (35%) and reducing their frequency by greater than 50% in 15 others (37%). In the majority of the failures, significant improvement could be obtained by additional administration of ACTH or hydrocortisone (Dumermuth and Kovacs, 1973). Abolition or significant improvement in the petit mal variant pattern of the EEG were seen in 32 to 37% and 15 and 20% respectively of a larger population of 81 patients (Dumermuth and Kovacs, 1974). Vassella et al. (1973) gave clonazepam 0.1 to O.3mg/kg/day to 13 children with Lennox-Gastaut syndrome who had failed to respond to nitrazepam. Lasting improvement over 6 morrths of therapy was seen in 3 patients, with temporary remission lasting 3 weeks to 7 months in another 3 patients. The EEG was improved in 4 of the 6 cases. In 1 patient ACTH failed to improve the insufficient response to clonazepam. The failures included 2 patients in whom c10nazepam had to be stopped because of side-effects (ataxia and drowsiness). The Lennox-Gastaut syndrome is known to follow a course of natural remissions and recurrences, and this may explain the discrepancies between studies which have or have not noted a diminution of the effect of c10nazepam with time. Certainly the apparent development of 'tolerance' also occurs with other benzodiazepines such as nitrazepam. Bergamini et al. (1970; 1972) observed excellent control of seizures in 9 of 12 patients, but within 6 months all patients had reverted to their former status despite increased dosage. Groh and Rosenmayr (1971, 1973), in 37 patients of whom 22 experienced a reduction of greater than 50% in seizures, found that seizures recurred in 7 patients, usually after several months of therapy. In 65 patients, Kruse and Blankenhorn (1973) found that the percentage of patients with positive response fell from 63% in the frrst month to less than 30% after 12 months; the latter is within the range of chance for spontaneous remission in this epilepsy. Per contra, other long-term

Clonazepam: A Review

studies in a total of 115 patients have failed to show any change in the relative proportions of patients benefited, though some patients discontinued clonazepam for other reasons (Dumermuth and Kovacs, 1974; Rett, 1971, 1973). Infantile Spasms Infantile spasms with hypsarrhythmia or diffuse changes in the inter-seizure EEG may lead rapidly to permanent mental retardation if untreated. They are refractory to the usual antiepileptic agents, and corticotrophin or the adrenocorticosteroids are the only drugs which can reverse the intellectual impairment. Diazepam and nitrazepam may be useful adjuncts for the control of myoclonic symptoms, and clonazepam also appears to be an effective benzodiazepine in this type of epilepsy. The success rates for clonazepam reported by different authors vary widely possibly because of differences in the degree of duration of infantile spasms prior to treatment. Indeed some authors have suggested that the drug is ineffective. Barnett (1973) found that clonazepam did not affect salaam seizures in 3 patients, while Groh and Rosenmayr (1974) observed that they responded less readily to clonazepam than to nitrazepam in 15 patients. Clonazepam was of little benefit in a group of 6 babies studied by Hanson and Menkes (1972), and of no benefit in 26 children with primary or secondary hypsarrhythmia (Castroviejo, 1971). In 4 large uncontrolled trials (12 patients or more), complete control of seizures was reported in 12 to 36% of patients, and 50% or greater reduction in seizure frequency in 21 to 75% (Dumermuth and Kovacs, 1973; Martin and Hirt, 1973; Rett, 1971; Rebollo, 1971). In general, at least half of infants with hypsarrhythrnia may experience a reduction in seizures of greater than 50%, with almost one-third of the total group being seizure-free during clonazepam treatment (fig. 2). In a long-term study in 64 infants with hypsarrhythrnia, Dumermuth and Kovacs (1974)

340

found that clonazepam treatment produced complete disappearance of seizures in 26 to 36% of patients and a 50% or greater reduction in a further 27 to 33%, dependent upon that period of observation. Despite some withdrawals, the overall proportion of patients benefited by the drug remained the same over treatment periods lasting beyond 12 months. Hypsarrhythrnic activity disappeared in 10 to 29% of patients and was effectively controlled in a further 19 to 27%, but patients frequently retained hypsarrhythrnic EEG patterns while apparently being clinically free from seizures. Complete control of spasms was obtained with corticotrophin or hydrocortisone in 9 of 31 patients who were not controlled by clonazepam. Vassella et al. (1973) studied 24 children with infantile spasms and hypsarrhythmic EEG activity, who were all retarded in psychomotor development. Clonazepam was given in daily doses of 0.1 to O.3mg/kg. Lasting improvement over 16 months was seen in 5 patients, with cessation of spasms during the first 3 weeks of therapy, but was not always associated with abolition of hypsarrhythmic EEG patterns. Temporary remission of spasms was obtained for up to 7 months in 3 patients receiving O.lmg/kg clonazepam, but relapse did not respond to doses of up to O.3mg/kg. In 7 patients with infantile spasms, ACTH was given for 1 month in addition to clonazepam because of recurrence of seizures after good initial response to clonazepam alone. Five remained seizure-free for 1 to 17 months, and addition of ACTH markedly improved the EEG in 6 of the 7 children. In a further 4 patients receiving ACTH and clonazepam, seizures disappeared initially but recurred in 1 to 8 months despite continued clonazepam therapy. Four infants showed no response to clonazepam 0.25mg/kg. Despite the disappearance of hypsarrhythmia in 1 patient, he continued to show flexion spasms and head-drop. Six children failed to respond to nitrazepam plus phenobarbitone; following clonazepam treatment 1 became free of seizures, 1 improved markedly, 2 showed

341

Clonazepam: A Review

temporary remission, and 2 were unchanged. Clonazepam appeared to be as effective as nitrazepam.

•

D> 8<

3.2.2 Generalised Tonic-Qonic Seizures Phenytoin or carbamazepine may abolish generalised tonic-clonic seizures in about 60 to 65% of patients, and reduce their frequency and severity in another 20% (Lund, personal communication; Woodbury and Fingl, 1975). Clonazepam is effective in grand mal, whether primarily or secondarily generalised, but its efficacy is not such (fig. 3) that it will replace the presently available drugs of choice. However, c10nazepam may be useful in treating some cases of refractory grand mal. Most of the studies have involved patients who have failed to respond to other antiepileptic therapy, and who may therefore be regarded as refractory cases. In 8 large uncontrolled trials (with 10 or more patients), clonazepam has completely controlled grand mal seizures in from 10 to 70% of patients when it was added to their previous drugs, with more than 50% control in from 10 to 96% of patients (Barnett, 1973; Bergamini et aI., 1970; Groh and Rosenmayr, 1974; Huang et aI., 1974; Lehtovaara, 1973; Mikkelsen and Birket-Srnith, 1973; Munthe-Kaas and Strandjord, 1973; Rett, 1971, 1973). In general, clonazepam has produced complete control in about one-third of patients, with greater than 50% control in a further quarter (fig.3). In a study in 233 children with severe refractory epilepsy, treated with c10nazepam for up to 6 years, complete control of seizures was achieved, dependent upon observation time, in 42 to 50% of the patients with grand mal, with a marked reduction in seizure frequency in a further 35 to 44%, (Dumermuth and Kovacs, 1974). The most favourable results were obtained in patients with generalised spike wave paroxysms in the EEG, an impression confirmed in the studies of Rett (1971, 1973) in 220 children. On the other hand, some workers have found clonazepam to be relatively ineffective in grand

Free from seizures

50% reduction 50% reduction

Unchanged, worse or IT] result not reported

Grand mal (524 patients)

Psychomotor epilepsy (327 patients)

Focal motor seizures (112 patients)

32%

Fig. 3. Proportion of epileptic patients with varying degrees of response to maintenance therapy with clonazepam. Patients had generally failed to respond adequately to. but continued to take. other antiepileptic medication. Data are taken from the sources quoted in the legend to figure 2. The grand mal figures include 91 patients with concomitant focal motor. · psychomotor. myoclonic or absence seizures. but only the responses of the grand mal seizures were analysed. See text for further explanation.

Clonazepam: A Review

mal. Oller-Daurella (1973) reported a response rate (greater than 50% reduction in seizures) of less than 16% of 61 patients, Huang et al. (1974) of less than 30% in 17 patients, and Kruse and Blankenhorn (1973) of only about 40% in 54 patients. Negrin et ai. (1971) could find no evidence of benefit in 10 patients, when c10nazepam was given alone or together with hydantoins and barbiturates. In a study in which c10nazepam was used as the only drug for grand mal seizures, OllerDaurella (1969) found that 10 of 14 patients had no change or an increase in seizure frequency, and no patients achieved complete control.

3.2.3 Partial Seizures Focal Motor Seizures The main neurophysiological action of clonazepam is to prevent the spread of seizure activity from epileptogenic foci rather than to suppress the foci themselves (see section 1.3). Nevertheless, the drug is effective in preventing focal motor seizures, in controlled trials (Edwards and Eadie, 1973; Mikkelsen et aI., 1975) but often in the absence of any normalising influence on the EEG. Again, however, its efficacy is such that it seems unlikely to replace hydantoins or barbiturates except in patients whose seizures are refractory to these drugs. In 4 large uncontrolled trials (with more than 9 patients), c10nazepam completely suppressed seizure activity in from 12 to 60% of patients, with more than 50% reduction in seizures in from 55 to 80%. (Groh and Rosenmayr, 1973; Lund and Trolle, 1973; Oller-Daurella, 1973; ScolloLavizzari et ai. 1974). In general, about two-thirds of patients have experienced a greater than 50% reduction with complete control in over one-third (fig. 3). Clonazepam alone produced complete control of grand mal seizures in 14 of 27 patients, with greater than 50% reduction in seizure frequency in 6 others (D'Onghia et at, 1973). The groups of patients with focal motor seizures who have been treated with c10nazepam

342

are often too small to allow any conclusions to be drawn In two studies, however, the frequency of seizures was reduced by over 50% in 16 of 22 (73%) of 16 of 24 (67%) patients, with at least half of the total group being free of seizures (OllerDaurella, 1973; Scollo-Lavizzari et aI., 1974). Clonazepam seems to be more effective against focal epilepsies than against generalised seizures of the grand mal type, (fig. 3) and Gastaut (1970) has pointed out that its beneficial effect on partial seizures is never accompanied by facilitation of secondary generalisation (see section 4.3) Hypersynchronous EEG activity disappeared in only 16 to 32% of patients with focal motor seizures, with a significant reduction in a further 10 to 34% (Dumermuth and Kovacs, 1974), but these EEG changes were not related to therapeutic response. This is best illustrated in the 6 cases of epilepsia partialis continua, in whom freedom from attacks was generally achieved with clonazepam despite persistence of the epileptogenic focus in the EEG (Bianchi Saus and Panizza, 1973; Huang et at, 1974; Scollo-Lavizzari et aI., 1974). In the only studies of clonazepam alone for focal motor seizures (Hooshmand, 1972), seizures were not abolished in any of 4 patients, but 3 patients had a 50% or greater reduction in seizure frequency; Scollo Lavizzari et al. (1972) found that all 8 patients with focal seizures were completely controlled by clonazepam alone. Psychomotor or Temporal Lobe Epilepsy Psychomotor or temporal lobe epilepsy is often more refractory to medication than are other focal types of seizure. Phenobarbitone is effective, but phenytoin and primidone are the drugs of choice with the addition or substitution of carbamazepine. Clonazepam is effective in this type of epilepsy, and was Significantly superior to placebo when added to previously inadequate antiepileptic medication (see section 3.1.3). Uncontrolled studies have generally suggested that in daily doses of about 6mg, clonazepam is effective in reducing the number of seizures by

Clonazepam : A Review

greater than 50% in about half of patients with psychomotor epilepsy, with about 27% becoming seizure-free (fig. 3). Rarely patients may deteriorate on the drug, and about one-third fail to respond. There appears to be some diminution of efficacy in some patients receiving long-term therapy with clonazepam (Lund and Trolle, 1973; Masland, 1975; Mikkelsen and Birket-Smith, 1973; see section 4.2). In the 8 largest uncontrolled trials (with more than 15 patients), there has been a greater than 50% reduction in from 33 to 70% of patients, with complete control in from 10 to 50% (Bergamini et aI., 1970; Huang et aI., 1973; Kick and Dreyer, 1973; Lehtovaara, 1973; Lund and Trolle, 1973; Mikkelsen and Birket-Smith, 1973; Oller-Duarella, 1973; Scollo-Lavizzari et al., 1974). Kick and Dreyer (1973) studied 34 patients with various types of idiopathic or symptomatic psychomotor epilepsy which had been resistant to conventional anti-epileptic therapy. The average duration of disease was 17 years. Twelve patients showed improvement on clonazepam (2 to 12mg daily), that is a reduction of seizures by 50% in the first month. Seven of these 12 patients subsequently maintained marked improvement for 5 months or more, with 3 having no further seizures. Side-effects were minimal and mild. 3.2.4 Myoclonic Epilepsy

Myoclonic epilepsy is only moderately affected by hydantoins, barbiturates or succinimides. The most effective drugs are the benzodiazepines, particularly nitrazepam, and possibly sodium valproate. Assessment of the efficacy of clonazepam in myoclonic epilepsy is made difficult by the failure of many investigators to identify the type of patient under study, that is whether the seizures are really those of bilateral massive epileptic myoclonus Guvenile myoclonic epilepsy) or due to one of the other types of epilepsy with myoclonic seizures. In placebo-controlled trials (see sections 3.1.2 and 3.1.4), clonazepam controlled, or partially

343

controlled, myoclonic seizures associated with generalised epilepsy (Edwards and Eadie, 1973) and bilateral massive epileptic myoclonus associated with atonic seizures (Mikkelsen et aI., 1976). These patients had been quite unaffected by nitrazepam or other forms of antiepileptic therapy. In some patients clonazepam has seemed to control myoclonic seizures temporarily, but the epilepsy has then relapsed (see, for example, Edwards and Eadie, 1973; Jenner et ai., 1975a). This process can occur several times after repeated dosage increments before fmal control is established or before side-effects prevent further dosage increases (see section 4.2). Bilateral Massive Epileptic Myoclonus There are few studies of clonazepam in this relatively uncommon form of myoclonia, though the drug may be effective (fig. 4) and was superior to placebo as adjunctive medication in a controlled trial in 10 such patients (Mikkelsen et ai., 1976). In the largest uncontrolled trial (Rett, 1971, 1973), 25 of 44 children receiving clonazepam (0.2 to 18mg daily) for 1 to 2 years experienced a greater than 50% reduction in myoclonic seizures, with complete control in 13 patients. Other trials have included fewer patients, but have showed that clonazepam produced greater than 50% improvement in 12 of 17 patients, with complete control in over half of the total group (Gastaut, 1970; Lund and Trolle, 1973; Munthe-Kaas and Strandjord, 1973; OllerDaurella, 1973). Myoclonic Seizures Most studies have simply stated that patients had 'myoclonic epilepsy', and have failed to positively identify the type of seizure. Lance and Anthony (1976) studied 10 patients with myoclonic epilepsy, including some who clearly had the bilateral type, and found that c10nazepam abolished seizures in 2 patients and provided significant control in the remainder. Similar success was reported by Huang et al.

Clonazepam: A Review

(1974) in 5 patients with myoclonic epilepsy, with 3 patients being seizure-free and the other 2 showing significant improvement. In 9 patients, Hanson and Menkes (1972) observed that myoclonic seizures were completely controlled in 3 of the group and reduced in frequency by 50% or more in every patient. Several small trials in groups of less than 9 patients have generally showed that clonazepam alleviates myocl~nic seizures in most patients, with about one-third to one-half becoming seizure-free (Edwards and Eadie, 1973; Hooshmand, 1972; Kruse and Blankenhorn, 1973). Clonazepam is very effective in abolishing photomyoclonic seizures, particularly of the self-

Bilateral massive epileptic myoclonus (75 patients)

28%

•

Free from seizures

II]]

>50% reduction

o

< 50% reduction or unchanged

Fig. 4. Degree of response to clonazepam of patients with bilateral massive epileptic myoclonus (data from sources quoted in legend to figure 2 and the text). Patients had generally failed to respond adequately to, but continued to take, other antiepileptic drugs. 'Myoclonic epilepsy' was not always defined in many studies, and only those which positively identified patients as having bilateral massive epileptic myoclonus were included.

344

induced type. Patients lose not only the response to photiC stimulation but also the desire for selfinduction of seizures (Bladin, 1973; Huang et aI., 1974; Rail, 1973). Oral doses of 6 to S rng daily are usually sufficient, though Pruvot and Pruvot (1973) found that 2 to 4mg daily was effective in blocking seizures in 12 patients with photomyoclonic epilepsy. Doses of 15 to 30mg of diazepam were required in the same patients. Huang et al. (1974) also observes that lower doses (and plasma levels) were required for control of photic epilepsy. Clonazepam may also be effective in progressive hereditary myoclonic epilepsy (UnverrichtLundborg syndrome), a disease which usually responds poorly to conventional therapy. laitinen and Toivaaka (1973) Gastaut (1970), and Beaussart et aI. (1973) have reported on a total of 5 patients in whom clonazepam 6 to Srng daily produced a marked improvement in the frequency and severity of seizures over periods of 3 to 30 months. The drug was equally effective in a single case of focal myoclonic epilepsy (Kojewnikov syndrome). Fazio et aI. (1975) reported complete control in 1 patient with post-encephalitic myoclonic seizures, and a greater than 50% reduction or no change in seizure frequency in 2 patients with the Unverricht-Lundborg syndrome. Clonazepam appears to be only temporarily effective in the Ramsay-Hunt syndrome of massive myoclonic jerks associated with grand mal seizures. In 7 of 10 patients clonazepam 4 to Smg daily produced complete abolition of seizures and normalisation of the EEG (Bergamini et aI., 1970; Mutani et aI., 1971), and Gastaut (1970) reported similar success in both of 2 patients. However, this initial benefit diminished during the course of therapy, with complete return of symptoms after 2 months in 1 patient, S months in another and 4 to 6 months in the remainder (Mutani et aI., 1971). In 2 cases the administration of clonazepam was stopped for 2 weeks after reappearance of full symptoms, which were abolished when the drug was re-instituted at the same dosage. Two

Clonazepam: A Review

patients failed to respond initially to clonazepam, and 1 became markedly worse. In some studies, patients with myoclonic epilepsy and grand mal seizures have been reported, but not identified as having the Ramsay-Hunt syndrome (Barnett, 1973; Carson and Gilden, 1975; Lehtobaara, 1973). Results with clonazepam have generally been favourable; for example, Lehtovaara (1973) observed complete control in 5 of 12 patients, with a further 3 having a greater than 50% reduction in seizures. Clonazepam has also been used in the treatment of intention myoclonus, with excellent results. Goldberg and Dorman (1976) found that 5 patients, 3 with post-anoxic encephalopathy and 2 with degenerative CNS disorders and all refractory to previous therapy, who received 7 to 12mg clonazepam were markedly improved. One patient continued treatment for over 4 years without signs of tolerance or toxicity. Clonazepam was very effective in treating myoclonic seizures in .association with typical and atypical absences, Catroviejo (1971) reported on 82 patients with atypical absence seizures; 23 patients had complete control of their myoclonic seizures, with greater than 50% control in 8 other patients. In 5 patients with typical absences, Bergamini et al. (1970) obtained complete control in 4 with slight improvement in another. Carson and Gilden (1975) reported excellent and good control of myoclonic seizures in 2 patients with typical absences. 3.2.5 Akinetic and Atonic Seizures These groups of seizure typ~. are considered together because they were so in several large uncontrolled trials. Clonazepam is effective in the treatment of such patients, particularly in those who experience momentary loss of posture or muscle tone, associated with myoclonia in some cases but with no evidence of hypsarrhythmia (fig. 5). In general, a reduction in the number of seizures of greater than 50% has been achieved in

345

over half of patients with atonic and/or akinetic seizures (Barnett, 1973; Carson and Gilden, 1975; Eeg-Olofsson, 1973; Castroviejo, 1971; Hanson and Menkes, 1972; Hooshmand, 1972; OllerDaurella, 1973; Rett, 1971, 1973). Several studies have selected patients who were resistant to other forms of therapy such as diazepam and nitrazepam (Carson and Gilden, 1975; Eeg'()lofsson, 1973; Hanson and Menkes, 1972); a reduction of greater than 50% in the number of seizures was observed in at least 78% of these patients when receiving average maintenance doses of 0.25 to 0.42mg/kg/day clonazepam. In Rett's two series (1971, 1973), 18 of 37 patients had a 50% or greater reduction in seizure frequency and 7 were completely controlled. However, whereas spike-and-wave variants in the EEG are a usual indication for clonazepam (see section 3), only 2 of the patients who benefited had this EEG

Akineticlatonic seizures (131 patients)

56.5%

Free from seizures or> 50% reduction

m O

•

< 50% reduction Unchanged. worse or result not reported

Fig. 5. Degree of response to clonazepam of patients with atonic and/or akinetic seizures. These categories were grouped in most studies, and include some patients with associated myoclonus (data from sources quoted in legend to figure 2 and from textl.

346

Clonazepam: A Review

pattern. Hooshmand (1972) found in 3 cases that the spike-and-wave EEG discharges were suppressed for 5 to 8 hours after an oral dose of clonazepam, but recurrred during the night. In a comparison of the frequency of akinetic seizures before and after a 3-month course of clonazepam,. Hanson and Menkes (1972) found complete suppression of attacks in 5 patients and a 50% or greater reduction of seizure frequency in an additional 8 patients.

3.2.6 Comparison with Other Antiepi/eptic Drugs The only controlled comparison of clona· zepam with another antiepileptic drug was that of Chandra (1973), who showed it to be superior to diazepam during a 6-month trial in patients with petit mal absences (see section 3.1.1). In various uncontrolled trials (see sections 3.2.1 to 3.2.5), retrospective comparison of the efficacy of clonazepam with that of standard drugs has shown it to be at least as effective in most types of patient. Lance and Anthony (1976) treated 32 patients (with various types of epilepsy) sequentially with clonazepam 3 to 12mg daily and sodium valproate 400 to 1,200mg daily. 11 patients responded better to clonazepam, 10 responded better to sodium valproate, 10 responded to neither, and one required both drugs. Clonazepam was superior in 4 patients with temporal lobe epilepsy, 5 patients with petit mal absences (1 associated with grand mal and 1 with atonic seizures), and 2 patients with atonic seizures. Sodium valproate was more effective in 2 patients with myoclonus, 6 patients with petit mal absences (2 associated with grand mal and 2 with atonic seizures), and 2 patients with grand mal alone. In most patients, the previous antiepileptic medication was reduced in dosage or number of drugs. Drowsiness was the most common sideeffect with clonazepam, occurring in about onethird of patients, while about one-third of the sodium valproate group experienced increased mental alertness following initial drowsiness.

3.3 Status Epilepticus Status epilepticus is the major indication for intravenous clonazepam, which appears to be more effective than the present drug of choice, diazepam. Single doses of 1 to 4mg are usually sufficient to reverse status and to abolish or ameliorate paroxysmal activity in the EEG, but mUltiple injections may be required. In most studies directed specifically towards status epilepticus, clonazepam has been effective in about 80 to 90% of all types of patients (table IV). This has often been so in patients who have failed to respond to parenteral doses of diazepam as high as 30mg and of phenobarbitone up to 1200mg (Bergamini et al., 1970, 1972; Gastaut, 1970; Gastaut et aI., 1971; Tridon and Weber, 1973). Response to intravenous clonazepam is usually rapid, within a minute and the effects of a single dose may last for over 24 hours in many patients (Ketz, 1973; Ketz et al. 1973). Side-effects have generally been less than those observed with diazepam, with respiratory depreSSion and somnolence in some patients (Beck and Tousch, 1973; Ketz, 1973). The rapid clinical effect corresponds to prompt extinction of generalised or focal discharges in the scalp EEG and to marked retardation of their spread (Ketz et aI., 1973). Stereo EEG studies during clonazepam injection have demonstrated the abolition of both spontaneous and evoked seizure discharges in various brain structures or limitation of their spread from deeper structures to the isocortex. Patients with generalised status epilepticus with or without convulsions (grand mal, petit mal) or focal status with or without secondary generalisation respond most readily to clonazepam. Less favourable responses may be seen in those with myoclonic status (Ketz, 1973; Papini, 1971). In most types of status epilepticus clonazepam induces lasting block of seizures, often lasting beyond 24 hours (Bergamini et aI., 1970, 1972; Ketz, 1973; Ketz et al., 1973). However, Jacksonian and tonic seizures may be only temporarily

347

Clonazepam: A Review

Table IV. Summary of therapeutic trials in which intravenous clonazepam has been used to treat status epilepticus Author

No. of patients

Initial dose, (mean) inmg

Beck and Tousch (1973)

194

0.5-10 (1.56)

81

Includes 19% who required multiDle dosage

16

1.0

88

Diazepam 10mg ineffective

8

2.0

100

Multiple doses required in hem iton ic and tonic status

Bergamini et al. (1970, 1972) Bladin (1973)

Response rate (%)

Comments

Gastaut (1970); Gastaut et al. (1971)

37

1-8.

97

Gimenez-Roldan et al. (1972)

17

1-6

82.3

Ketz (1973); Ketz et al. (1973)

65

1-4

83.3

Not so effective in myoclonic epilepsy as in generalised or focal status

Kruse and Blankenhorn (1973)

40

0 .5-2 (1.3)

75

>24 hour duration of effect after single dose in 60% patients

Martin and Hirt (1973)

13

0.4-3

77

Tridon and Weber (1973)

32

2.0

84

blocked, for periods of 1 to 2 hours (Bergamini et aI., 1970, 1972). Intravenous diazepam when used to treat status epilepticus can be associated with the precipitation of a tonic status (Prior et aI., 1972; Tassinari et aI., 1972). There is no evidence of this occurring with clonazepam as yet, but it is interesting that in status associated with the Ramsay-Hunt syndrome, clonazepam, though more potent and longer· lasting than diazepam in its therapeutic effects, may also produce a transitory increase of myoclonic jerks and EEG paroxysms (Bergaminiet aI., 1970; Mutani et a1.. 1971).

Some patients unaffected by 1,200mg phenobarbitone or 30mg diazepam

Diazepam 30mg ineffective in some cases

3.4 Other Indications

3.4.1 Drug-Induced Dyskinesias Therapeutic application of clomipramine infusions (150 to 200mg total dose) is limited by the occurrence of dyskinesias, which are controlled only poorly by diazepam or at doses which induce drowsiness and lethargy. Prospective studies in 42 patients given 1 to 3mg oral clonazepam daily in divided doses have shown that the drug conSistently improves the clomipramineinduced dyskinesias without producing drowsiness or increasing anxiety (O'Flanagan, 1975).

348

Clonazepam: A Review

3.4.2 Choreiform Movements Clonazepam may be useful in treating some types of chorea. Peiris et al. (1976) gave clonazepam in oral doses of 3.5 to 5.5mg, the maximally tolerated level, to 3 patients with Huntington's chorea, 3 with non-familial chorea, and 1 patient with senile chorea. A marked diminution or disappearance of choreiform movements and increased functional capacity was observed in all patients. Choreiform movements returned when clonazepam was withdrawn, with improvement again upon its reintroduction. Two patients with chorea of doubtful aetiology failed to respond to clonazepam, with severe ataxia limiting the daily dose to 1.5mg.

3.4.3 Fulgurant Pain Clonazepam may be effective in the treatment of fulgurant pain, particularly in patients resistant to carbamazepine. Early case reports (Tournilhac and Dordain, 1974) have been confirmed by more substantial studies. In a controlled trial, Caccia (1975) gave placebo for 5 days to 10 patients with facial neuralgia and/or cluster headache, followed by 7 to 15 days of treatment with clonazepam 4 to 8mg daily. Placebo was without effect in all cases, but clonazepam suppressed pain completely in 5 of 7 patients with trigeminal neuralgia and substantially relieved ~t in one other and in a patient with symptomatic neuralgia. Carbamazepine, which had been previously ineffective in 5 of the patients with trigeminal neuralgia where clonazepam was successful, was subsequently beneficial in the 2 clonazepam failures. Clonazepam alone had only a partial effect on pain intensity in 2 patients with cluster headache, and it did not reduce the frequency of attacks. Court and Kase (1976) gave clonazepam 6 to 8mg daily for 10 days to 25 patients affected by 30 episodes of tic doloureux. There was complete control of neuralgia in 40% and substantial benefit in a further 23.3%. 16 patients had previously been resistant to carbamazepine, and 8 of them

were .completely and 1 partially relieved by clonazepam. Marked drowsiness and unsteadiness of gait were present in about 80 to 88% of patients.

4. Factors Affecting Patient Response Unlike other antiepileptic drugs, clonazepam has a broad spectrum of activity though it may be somewhat more effective against petit mal absences and psychomotor seizures than some other types. In general, there seems little corre· lation between the type of EEG aberration and response, indeed clinical seizure activity frequently disappears without improvement in the EEG, except that patients with spike and wave variantparoxysms in the EEG apparently respond more readily (Rett, 1971, 1973). There also seems to be no correlation between response and age , sex, duration of illness, or type of previous therapy. Factors which may influence response include the use of clonazepam alone or in addition to previous medication, the development of tolerance, and the possible precipitation or potentiation of major seizures. 4.1 Clonazepam Alone or with Other Drugs? Clonazepam given alone to newly diagnosed patients or those who have experienced inadequate control whilst on other drugs may be as efficacious as when it is added to other anti-epileptic medication. There are no controlled studies, however, and the criteria for patient selection may well vary widely between groups. The two major studies are by Dumermuth and Kovacs (1974) and Schellert (1973), who categorised their results (figs. 6 to 8). These tend to show some advantage for clonazepam alone , particularly in the long-term and in the proportion of seizure-free patients, but it would be unwise to draw any flIm conclusions until controlled trials are carried out.

349

Clonazepam: A Review

Other studies have included that of Lund and Trolle (1973), who observed abolition of seizures of various types in 9 of 15 (60%) patients receiving only clonazepam, with greater than 50% improvement in 2 others; patients had previously failed on other drugs. Comparable figures for combined treatment with a variety of anti-epileptic drugs plus clonazepam were 15 of 45 (33%) and 14 of 45 (31%) patients respectively. Groh and Rosenmayr (1973) found that, in a mixed population of epileptics, 26 of 71 (37%) patients receiving clonazepam with other drugs were seizure-free compared to 19 of 29 (65%) on clonazepam alone. Greater than 50% reduction in seizures was seen in a further 25 (36%) and 4 (13%) patients respectively. Carson and Gilden (1975) found that clonazepam alone abolished seizures in 4 of 5 patients with atypical petit mal, with complete control or better than 50% control in 2 of 2 patients with infantile spasms.

Tousch (1973) studied 186 patients over 27 months, observing 45 cases of diminished efficacy in the first 15 months of clonazepam treatment. 35 of these necessitated withdrawal of clonazepam

•

Seizure-free

D

>50% reduction in seizures < 50% reduction or liule change:

~ Not Msessed Combination

Cl0nlllepam only

121

106

4.2 Tolerance Diminution of efficacy with continuing treatment is common to most anti-epileptic drugs, particularly the benzodiazepines (for a review, see Browne and Penry, 1973; Tousch, 1973). Clonazepam is no exception, but the general view is that it is better in this respect than diazepam or nitrazepam. Furthermore, clonazepam has been frequently given to patients who have already failed to receive continuing benefit from other benzodiazepines or other antiepileptic drugs. Most authors agree that diminished efficacy occurs mainly in the first 6 months of treatment, and that interruption of treatment for several weeks in patients who have become tolerant to clonazepam can often result, at least initially, in full benefit upon re-introduction of the drug. The immediate effect of small oral doses may also be exploited when taken as the need arises, even in patients who have relapsed on long-term therapy (Kruse and Blankenhorn, 1973).

81

n-

126

10

56

1\

Fig. 6. Proportion of epileptic patients with various degrees of seizure control during treatment with clonazepam alone or combined with other anti-epileptic drugs (after Dumermuth and Kovacs. 1974).

Clonazepam: A Review

and 26 occurred in the ftrst 3 months. Actuarial analysis of the ftgures gave a frequency of 28% for the development of tolerance to clonazepam over 15 months. Peterson (1967) has reported a recurrence frequency of over 50% (25 of 47 patients) with nitrazepam over 2 to 6 months of treatment, and Browne and Penry (1973) of 40% for diazepam. Browne (1976) gives an incidence of 33% (11 to 100%) for trials with clonazepam. Further studies in 959 patients treated successfully with clonazepam showed that diminished efftcacy occurred in 51 patients within the first 2 months, and in a further 25 by 4 months, 12 by 6 months, and 6 by 10 months (see Tousch, 1973). The data of Dumermuth and Kovacs .(1974) are illustrated in ftg. 6, where efftcacy fell over 12 months, more so for combination treatment than for clonazepam alone. Kruse and Blankenhorn (1973) observed a drop in the proportion of patients with signiftcant improvement from 62% (60 of 97) in the ftrst month, to 34% (31 of 93) after 6 months, 25% (18 of 92) after 12 months, 18% (12 of 85) after 24 months, and 14% (7 of 51) after 36 months. Chandra (1975) gave clonazepam 0.1 to 0.2mg/kg to patients with petit mal absences. Complete control of seizures was obtained in 53 of 78 patients treated for 1 year (68%), in 40 of 66 patients (61 %) treated for 2 or 3 years, and in 8 of 14' patients (57%) who received the drug for 4 years or more. A greater than 55% reduction in seizures was also seen in a further 13 (17%), 13 (21 %) and 3 (21 %) patients respectively. In 63 adult epileptic patients with various types of seizure, who received clonazepam over a period of 3 years, there was no decrease of therapeutic effects with time (Scollo-Lavizzari et aI., 1974). In a similarly mixed population of 33 patients who received clonazepam for more than 2 years (mean duration of treatment 3 years and 4 months), Bang et al. (1976) found that 63% of patients still experienced a greater than 50% reduction in seizures. This proportion was not signiftcantly different from the result of 70% of 54 patients

350

obtained by the same investigators 2 years previously. Masland (1975) found the benefit obtained with clonazepam in 14 patients with psychomotor epilepsy was transitory; initial success with 6 patients having complete freedom from seizures and 4 others a greater than 50% reduction were followed after 3 to 20 months by only I with

100 ~

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80

sa 56

____________________________-17

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~3

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;'~11~ Ii I~ I~ ~ Ii i~ .: r

1 ~ ~

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t

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-

__________________________

~8

Fig. 7. Comparison of the results obtained in 2,000 epileptics treated with clonazepam alone or combined with other anti-epileptic drugs (after Schellert, 1973). Fig. 8 Proportion of patients with 100%, or greater than 50%, improvement in seizure activity for various types of epilepsy treated with clonazepam alone or in combination with other anti·epileptic drugs (after Schellert, 1973).

Clonazepam: A Review

351

petit mal absences. It may be controlled by inclusion of phenytoin or barbiturates in the drug regimen (Eadie and Tyrer, 1974). There is no unequivocal evidence to indicate whether clonazepam treatment has a significant effect on the occurrence of grand mal seizures. In the studies of Dumermuth and Kovacs (1974) and Schellert (1973), which included 106 and 454 patients respectively who took clonazepam alone, there were no suggestions of increased grand mal seizure activity. Furthermore, despite a reduction in the number of seizure-free patients with grand mal epilepsy from 67% to 42% over 12 months of clonazepam treatment, Dumermuth and Kovacs (1974) observed a fairly constant proportion of 80 to 90% who achieved significant benefit. Huang et al. (1974) found no exacerbation of seizures by clonazepam in 17 patients with grand mal, only 3 of whom became seizure-free. There was no increase in the frequency of grand mal seizures in 5 of 6 patients successfully treated with clonazepam for mixed petit mal and grand mal seizures. Hanson and Menkes (1972) observed that clonazepam did not precipitate grand mal attacks in 59 patients with minor motor seizures or in 10 patients with partial focal and generalised major motor seizures. In 20 patients with petit mal absences, Gastaut (1970) noted the absence of any recrudescence of grand mal seizures when absences were abolished. Browne (1976), in a review, reports 17 cases of grand mal seizures becoming worse on clonazepam. Lund and Trolle (1973) and MuntheKaas and Strandjord (1973) found a total of 6 cases, 4 of whom already were experiencing such episodes prior to clonazepam treatment, in a population of 104 epileptics. In 31 patients with grand mal seizures, Mikkelsen and Birket-Smith 4.3 Effect on Grand Mal and Other Seizures (1973) found only 3 cases of exacerbation by clonazepam over 3 to 27 months of treatment. Precipitation of generalised tonic-clonic seizures Carson and Gilden (1975) observed worsening in 5 is a well-recognised phenomenon in epileptic of 17 patients with grand mal epilepsy. Bladin therapy, particularly succinimide treatment of (1973), though fmding no precipitation of grand

complete relief and 7 with a greater than 50% reduction. The results of Kruse and Blankenhorn (1973) were obtained mainly in children with the LennoxGastaut syndrome, a condition known to be subject to frequent spontaneous remission and recurrence. Bergamini et al. (1970, 1972) have also reported poor long-term results with clonazepam in the Lennox-Gastaut and Ramsay-Hunt syndromes (see section 3.2.1). Spectacular initial success was followed within 6 months by deterioration in all of the 22 patients. Patients with psychomotor epilepsy fared better, with significant improvement in 12 of 34 after 1 month falling to 7 of 34 after 5 months (Kick and Dreyer, 1973). 45 of 59 (76%) patients with intractable minor motor seizures derived Significant benefit from clonazepam at 3 months, with 34 of 59 (65%) continuing to do so at 18 months (Hanson and Menkes, 1972). However, Rett (1971), who categOrised his results for each type of epilepsy in 220 children, could fmd little evidence for the development of a greater level of tolerance to clonazepam in any particular type. The mechanism by which tolerance to the effects of clonazepam occurs is unknown. It remains to be determined whether this is a true physiological tolerance or depends upon hepatic enzyme induction. Other benzodiazepines can induce their own metabolism, and phenobarbitone can enhance diazepam metabolism (see Eadie and Tyrer, 1974). It is interesting that the time-course of tolerance in mice to the clonazeparn-induced rise in brain 5-hydroxytryptamine bears similarities to the loss of efficacy in patients with myoclonic seizures (Jenner et al., 1975b) [see section 1.4.4].

352

Clonazepam: A Review

mal in 5 patients treated for petit mal absences, noted that 2 of 6 patients with mixed petit malgrand mal were worse after clonazepam, particularly when given alone. In 20 patients with intractable minor motor seizures, clonazepam, even in very small doses (1 mg), produced excessive EEG low-voltage fast activity in the anterior head region (Hooshrnand, 1972); in those with petit mal absences, focal spike activity appeared as spikeand-wave forms disappeared. Gastaut (1970) and Bergamini et ai. (1970) have commented on the potentiation of seizure frequency in patients with petit mal absences, atypical absences or tonic seizures of secondary generalised epilepsy. Only 7 cases were found from a population of 116 patients, and never in those with grand mal, myoclonic or partial seizures. Such enhancement can lead to status epilepticus. Paradoxically, Gastaut (1970) and Bergamini et al. (1970) indicate that this consequence of oral treatment can be aborted in a few seconds by an intravenous injection of the same drug.

Hypotonia and muscle weakness may be responsible for reports of dysphagia, dysarthria and constipation. In children, behavioural disturbances such as aggression, hyperactivity, irritability and concentration difficulties are probably the most serious side-effects, but are controllable with methylphenidate or dextroamphetamine (Carson and Gilden, 1975; Hanson and Menkes, 1972). Increased salivary and bronchial secretion with mucous obstruction of the nasopharynx and bronchii may be tro).lblesome, particularly in infants and young children (Dumermuth and Kovacs, 1974; Martin and Hirt, 1973; ScolloLavizzari et aI., 1974; Vassella et al., 1973).

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Side-effects are frequent during clonazepam therapy, and many patients experience them in one form or another (fig. 9). The syndrome of drowsiness, somnolence, fatigue and lethargy is the principal side-effect, occurring in about half of patients initially but usually disappearing with continued treatment. However, it is often sufficiently severe to necessitate dosage reduction or evt!n withdrawal of drug, and several studies have reported its occurrence in almost all patients. Clonazepam is similar to diazepam and nitrazepam in this respect (Gastaut, 1970). There have been no serious side-effects in long-term studies, when patients have received clonazepam for up to 5 years (Bang et aI., 1975; Chandra, 1975; ScolloLavizz.ui. et aI., 1974). Clonazepam produces muscular inco-ordination in many patients, often progressing to ataxia.

10

Drowsiness, lethargy

Ataxia. Incoordination

Hypotonia. Hyper·Hypermuscle activity salivation weakness aggressive-

ness,

concentration difficulities

Fig. 9 Incidence of principal side-effects of clonazepam during trials involving over 1,400 patients. Data were used only where side-effects were specifically stated to be present or absent, and are taken from the following sources: Balassa and Deisenhammer. 1972; Barnett. 1973; Birket-Smith et al .• 1973; Bladin. 1973; Bonduelle and Sallou. 1973; Carson and Gilden. 1975; O'Onghia et al .• 1973; Oreifuss et al .• 1975; Oumermuth and Kovacs. 1973. 1974; Eeg-Olofsson 1973; Groh and Rosenmayr. 1971. 1973; Guldenpfennig, 1973; Hanson and Menkes. 1972; Huang et al.. 1974; Kruse and Blankenhorn. 1973; Lehtovaara. 1973; Lund and Trolle. 1973; Martin and Hirt. 1973; Mikkelsen et al.. 1975; Rett. 1971; Schlack. 1974; Sjo et al.. 1975; Vassella et al.. 1973).

Clonazepam: A Review

Tachycardia may follow intravenous clonazepam in patients with status epilepticus (Weinmann and Willms, 1973). There have been occasional reports of dizziness and vertigo, depressive mood, nausea and vomiting, anorexia, dyspepsia, visual and sleep disturbances, loss of libido and impotence, abnormal thirst, skin pigmentation and rashes, and facial oedema and malaise. Thrombocytopenia is a rare occurrence (Yeall and Hogarth, 1975). Clonazepam may cause weight gain in some patients, particularly children, which is possibly associated with hyperphagia (Dreifuss et aI., 1975; Hanson and Menkes, 1972). Long-term therapy has not been associated with any biochemical changes, or alterations in liver or kidney function (Chandra, 1975; Gastaut, 1970; Nieto, 1973; Rett, 1971). The side-effects of clonazepam are transient and self-limiting in most patients who experience them. In a comprehensive study, Rett (1971) found that 64 of the 76 patients experiencing sideeffects were free from them after 1 month of therapy, including 25 with somnolence-fatigue, 8 with muscular inco-ordination, 13 with muscle weakenss and 18 with dizziness. Withdrawal of clonazepam because of continuing severe sideeffects is uncommon, but most often occurs because of drowsiness, ataxia or hyperexcitability; Browne (1976) gives an incidence of 9 to 26% for withdrawals due to side-effects of clonazepam.

5.1 Side-Effects and Dosage Are the side-effects of clonazepam related to dosage? In 12 healthy volunteers, Hollister (1975) found that single oral doses of 0.5 or Img were well tolerated, but higher doses were associated with increasing sedation. However, it is clear that in the long-term treatment of epilepsy, higher doses can be tolerated with continued use of the

353

drug. Gradual increase of the dosage nllnmllses side-effects and reduces the drop-out rate in the first few weeks of treatment. Gastaut (1970) found that side-effects were usually present at doses above 6mg daily, though they occurred in some patients taking only 3mg and were absent in others receiving 9 or 12mg. Hooshrnand (1972) observed that the maximum tolerable dose associated with drowsiness and anorexia (1.5 to 2.0mg/kg) was ten times that required for optimal control of minor motor seizures (0.1 to 0.2mgjkg). In patients with psychomotor epilepsy, Kick and Dreyer (1973) noted that lethargy, apathy and dysphoria were present in patients taking 3 to 12mg clonazepam daily but muscular inco-ordination only at 10mg daily. D'Onghia et aI. (1973) studied 76 patients with various forms of epilepsy, and found that most types of side-effect occurred at a median daily dose of 5mg, though agitation and hyperactivity appeared in 10 patients receiving 2mg daily and aggressiveness in 8 patients on 4.5mg daily. Individual tolerance to the side-effects of clonazepam varies widely, and there appears to be no general correlation with dose or plasma levels (see section 2.1.2). Lehtovaara (1973) observed side-effects in 50% of patients receiving 2mg daily compared with only 25% of those on 8mg daily. Nevertheless, there does appear to be a relationship between the rate of dosage increase and the incidence of side-effects. Lund and Trolle (1973) found side-effects in 17 of 36 patients who initially received less than 3mg clonazepam, whereas they occurred in 22 of 24 patients who had 3mg or more, a statistically significant difference (P < 0.0005). An analysis of groups of patients treated according to different dosage schedules (table V) showed a statistically significant difference for the occurrence of side-effects and discontinuance of therapy between groups in which the maintenance dose was achieved after 1 and 2 or 1 and 3 weeks (P < 0.0005 and 0.05 respectively). There was no Significant difference

354

Clonazepam: A Review

Table V. Frequency of side-effects and discontinuance of therapy during clonazepam treatment in four groups of epileptic patients treated according to different dosage schedules Maintenance dose (6-8mg daily) reached after 1 week'

2 weeks ',2

Number of patients

26

36

21

27

Number with side-effects4

25 (96%)

28 (78%)

18 (86%)

23 (85%)

Discontinuance of clonazepam

11 (42%)

1 (3%)

03

3 (11%)

3 weeks'

1 Elian et al. (1973) 2 Birket-Smith (1973) 3 Maintenance dose of 6mg daily was not reached in 6 patients who completed the trial, due to side-effects (4rng in 2 patients; 3.5, 3, 2 and 1.5mg in the remainder). 4 Statistical analysis: 1 and 2 week schedules, p< 0.0005; 1 and 3 week schedules, p < 0.05; 2 and 3 week schedules, not significant.

between the groups achieving maintenance dosage within 2 or 3 weeks (Elian et aI., 1973). There is no relationship between the occurrence of side-effects and plasma levels of clonazepam. Berlin and Dahlstrom (1975) observed slurred speech, muscular inco-ordination and sleepiness in all 8 healthy volunteers, who had plasma levels of 7.1 to 23.6ng/mI following single oral doses of 2mg clonazepam. Huang et ai. (1974) noted sideeffects, prinCipally drowsiness, in 41 of 52 patients having plasma levels of 20 to 50ng/mI, with no serious side-effects in one patient with levels of 265ng/mI. Drowsiness, ataxia and hyperactivity were present in 6 of 10 children with petit mal absences treated with clonazepam by Dreifuss et ai. (1975), but the plasma drug levels (13 to 72ng/mI; mean, 31ng/mI) were not different from

those (19 to 52ng/mI; mean, 36ng/mI) in 4 patients who experienced no side-effects. Sjo et ai. (1975) gave clonazepam to 27 newly diagnosed epileptics, who all experienced sideeffects, principally drowsiness and muscular inco-ordination, associated with plasma levels of 30 to 80ng/mI. Neither the occurrence nor severity of these effects could be related to the plasma levels or the rate of increase in plasma concentrations of clonazepam. However, 3 of 5 patients who developed serious dysphoria had significantly high plasma levels compared to other patients at the same stage of treatment. 5.2 Influence of Concomitant Therapy on SideEffects There have been suggestions in the literature that side-effects are more prevalent in patients given clonazepam in combination with phenytoin, phenobarbitone and primidone than in those receiving clonazepam alone (Balassa and Deisenhammer, 1972; Bergamini et aI., 1970; Huang et aI., 1974; Kick and Dreyer, 1971). Hooshmand (1972) found that discontinuation of other anticonvulsant drugs in patients already receiving stable clonazepam therapy resulted in a reduction in drowsiness but with increased hyperactivity. These variable changes may reflect the diverse effects of clonazepam upon plasJRa levels of other anticonvulsants and vice-versa (see section 6). The two principal studies of the influence of concomitant therapy on clonazepam side-effects have failed to find a significant difference between groups of patients receiving different treatments. Dumermuth and Kovacs (1974) gave clonazepam alone or in combination with other antiepileptic drugs to 233 children with a variety of epileptic disorders. There was no Significant difference between the numbers of patients with side-effects on clonazepam alone (59.3%) compared to those receiving it with other drugs (50.4%), or between the numbers with each individual symptom

Clonazepam: A Review

(table VI). Lund and Trolle (1973) found no significant differences between the occurrence of side-effects in groups of patients receiving clonazepam alone or in combination with specified antiepileptic drugs (table VII).

355

Table VI. Incidence of side-effects during treatment of 233 children with clonazepam alone or in combination with other antiepileptic drugs (after Dumermuth and Kovacs, 1974). Symptom

Side-effects with clonazepam alone (118 patients)

In combination (115 patients)

Drowsiness/fatigue Hypotonia Ataxia Hypersalivation Dizziness Other No side-effects

44 25 15 9 9 6 48

34 (29.6%) 17 (14.8%) 22 (19. 1%) 11 (9.6%) 2 (1 .7%) 5(4.4%) 57 (49.6%)

6. Drug Interactions Clonazepam has been given together with most other antiepileptic drugs without untoward effect. However, it has been shown to cause both a rise in plasma phenytoin levels, in the manner of diazepam (Vajda et aI., 1971), and a fall. Eeg-Olofsson (1973) observed a rise in plasma phenytoin concentrations to toxic levels above 20J,tg/ml in 7 of 37 (19%) children receiving clonazepam 0.03 to 0.33mg/kg/day and phenytoin. Huang et al. (1974) found that average doses of 6mg clonazepam daily increased plasma phenytoin levels in 9 patients, all of whom had previously had phenytoin levels below the therapeutic range, decreased them in I patient, and had no effect in 3 patients. In 7 patients clonazepam had no influence on plasma prirnidone levels, with a slight increase in 2 patients and a decrease in one. Edwards and Eadie (1973) have shown that concurrent treatment with clonazepam caused a statistically significant fall in the mean plasma phenytoin levels in 17 patients already receiving phenytOin. Phenytoin doses were unchanged but the mean plasma level fell from 18.3J,tg/ml to 13.5J,tg/ml (P < 0.025), following administration of clonazepam 4 to 6mg daily. This fall was associated with an increase in plasma levels of the glucuronide conjugate of the major phenytoin metabolite, 5-(4-hydroxyphenyl)-5 -phenylhydantoin, suggesting that the effect of clonazepam might be due at least in part to increased phenytoin metabolism. Clonazepam levels in plasma may also be affected by phenytOin. Sjo et a1. (1975) gave the combination to five patients and detected a

(37.3%) (22.9%) (12.7%) (7.6%) (7.6%) (5. 1%) (40.7%)

Table VII. Incidence of side-effects in 60 patients receiving clonazepam alone or with other antiepileptic drugs (after Lund and Trolle,1973) Concomitant drug

No. of pts.

Sideeffects

No sideeffects

Clonazepam alone Phenytoin Phenobarbitone Phenytoin plus phenobarbitone or primidone

15 9 8 28

12(80%) 4(44%) 7 (87%) 16 (57%)

3(20%) 5 (56%) 1 (13%) 12 (43%)

considerable fall in plasma clonazepam concentrations and in the levels of the prinCipal metabolite 7-aminoclonazepam. This may count against enzyme induction as the possible mechanism. Addition of 250 to 400mg daily phenytoin caused plasma clonazepam levels to fall from 183 to 81ng/ml over 21 days in a patient on 12mg clonazepam daily, from 78 to 54ng/ml(8mg clonazepam; 7 days), from 65 to 27ng/ml (6mg; 20 days), from 51 to 34ng/ml (6mg; 42 days), and from 50 to 19n9/ml (6mg; 20 days). Lower plasma concentrations of clonazepam were also found in a group of patients treated with other antiepileptic drugs.

356

Clonazepam: A Review

Concomitant dextroamphetamine or methylphenidate have been used to control the lethargy and hyperactivity associated with clonazepam treatment. In 2 patients this combination produced CNS depression and respiratory irregularities for 2 to 3 hours, though in 10 other patients it was used without problems (Carson and Gilden, 1975). Diazepam is known to potentiate the action of CNS depressant drugs such as barbiturates and ethanol (Eadie and Tyrer, 1974), but there are no reports of such interactions with clonazepam. 7. Dependence Potential

The benzodiazepines generally have little or no dependence potential. Withdrawal symptoms can be precipitated, however, by the sudden cessation of clonazepam treatment; in particular, there may be a high risk of status epilepticus (Edwards, 1974; Lund and Trolle, 1973). Sjo et al. (1975) found that in a group of 13 patients who stopped clonazepam treatment while receiving 4.75 to 12mg daily, principally because of continuing seizures or severe dysphoric sideeffects, 4 patients developed dysphoria, irritability, restlessness, sleeplessness and tremor of the hands. The symptoms disappeared almost immediately when small doses (3 x O.25mg) of clonazepam were reinstituted. At the time of withdrawal, the same 4 patients had plasma levels of 7-arninoclonazepam, the principal metabolite of clonazepam, 3 to 4 times higher than those in the 9 subjects who did not experience withdrawal symptoms. There were no differences between the groups in plasma clonazepam levels. 8. Precautions

like all antiepileptic drugs, clonazepam may modify the patient's reactions (driving ability, behaviour in traffic etc) to a varying extent

depending upon dosage and individual susceptibility. Simultaneous administration of clonazepam and other antiepileptic drugs may modify the plasma levels of either or both drugs. The dosage of each must be adjusted so as to obtain the desired optimum effect. As with all antiepileptic drugs, withdrawal of clonazepam must be gradual and not abrupt, particularly in view of the risk of precipitating status epilepticus. Clonazepam can cause hyper salivation and excessive bronchial secretion, particularly in infants and young children. Strict supervision of such patients is necessary to ensure that the airways remain free. Patients should abstain from heavy drinking of alcohol while under clonazepam treatment, since alcohol may modify the action of clonazepam or give rise to unpredictable side-effects.

9. Overdosage There have been a number of reports of accidental and deliberate overdosage with clonazepam. Extreme drowsiness and ataxia seem to be the predominant signs, but the margin of safety may be wide even in the very young patient. None of the patients developed serious cardiac or respiratory depression, and all recovered without sequelae. Barnett (1973) reported on a child of 2 years who ingested about 16 to 20mg (1.8 to 2.2mg/kg) clonazepam, without suffering ill effects other than sleepiness for 24 hours. Bladin (1973) carried out gastric lavage on a 2~-year-old child who ingested 60mg clonazepam, but undertook no other forms of resuscitatory therapy apart from constant oxygenation and observation. Drowsiness and ataxia were severe but waned within 12 hours, though marked ataxia was still present for 48 to 72 hours. There was no evidence of circulatory or respiratory problems.

Clonazepam: A Review

Palacios et al. (1971) also used gastric lavage in a 21-year-old patient who ingested l00mg clonazepam with suicidal intent. After being in a coma for 2 days, the patient recovered uneventfully with no special care or therapeutic measures. Other cases of uneventful overdosage have included an adult who took 24mg (Edwards and Eadie, 1973) and a 1*-year-old child who took 6rng (Rey Pias, 1972).

10. Dosage Dosage of c10nazepam is essentially individual, and depends upon age, tolerance to side-effects, and clinical response. In order to minimise initial side-effects, it is necessary to increase the daily dose progressively until the maintenance dose suited to each individual patient has been reached, usually after 2 to 4 weeks of treatment. Maintenance doses in infants, young children, school-age children and adults are respectively 0.5 to 1.0rng, 1.5 to 3.0rng, 3 to 6rng, and 4 to 8mg daily. These should be given in 3 or 4 divided oral doses, and may be safely exceeded if necessary. Initial doses should not exceed 0.05rng/kg in children and infants or 1.5mg in adults, given daily in divided doses. The maximum recommended dosage in adults is 20rng daily. Parenteral treatment of status epilepticus with c10nazepam requires O.5rng in infants and children or 1mg in adults, given by slow intravenous injection. This dose may be repeated if required, by intramuscular injection or slow intravenous infusion.

References Aarli, J.A. : Effect of c10nazepam (Ro 5-4023) on epileptic seizures. Acta Neurologica Scandinavica 49 (Suppl. 53): 11 (1973). Balassa, M. and Deisenhammer, E.: Erste Untersuchungsergebrisse mit einem neuen Antikonvulsioum der

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Clonazepam: A Review

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Clonazepam: A Review

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kinetic profiles of clonazepam in dog and humans and of flunitrazepam in dog. Journal of Pharmaceutical Sciences 63: 527 (1974). Ketz, E.: Status epilepticus - Behandlung mit Rivotril. Schweizerische Medizinische Wochenschrift 103: 1134 (1973). Ketz, E.; Bernouilli, C. and Siegfried, J.: Clinical and EEG study of clonazepam (Ro 54023) with particular reference to status epilepticus. Acta Neurologica Scandinavica 49 (Suppl. 53): 47 (1973). Kick, H. and Dreyer, R.: Klinische Erfahrungen mit Clonazepam (Ro 54023). In Kruse, Epilepsie, pp. 30-34 (Thieme Verlag, Stuttgart 1971). Kick, Ii and Dreyer, R.: Klinische Erfahrungen mit Clonazepam unter besonderer Berucksightigung psychomotorische Anfalle. Acta Neurologica Scandinavica 49 (Suppl. 53): 54 (1973). Knop, IiF.; Kleijn, E. van der and Edmunds, LC.: The determination of clonazepam in plasma by GLC. Pharmaceutisch Weekblad 110: 297 (1975). Kruse, R. and Blankenhorn, V.: Zusammenfassender Erfahrungsberight iiber die klinische Anwendung und Wirksamkeit von Ro 54023 (Qonazepam) auf verschiedene Formen epileptischer Anfalle. Acta Neurologica Scandinavica 49 (Suppl. 53): 60 (1973). Laitinen, L. and Toivakka, E.: Clonazepam (Ro 54023) in the treatment of myoclonus epilepsy. Acta Neurologica Scandinavica 49(Suppl. 53): 72 (1973). Lance, J.W. and Anthony, M.: Sodium valproate and clonazepam in the treatment of intractable epilepsy. Unpublished data (1976) (A preliminary report of this work appeared in Proceedings of the Australian Association of Neurologists 12: 55 (1975». Lechat, P.; Boismare, F.; Streichenberger, G. and D' Armagnac, J.: Evaluation experirnentale des proprietes antiepileptiq ues d'une nouvelle benzodiazepine: Ie Ro 054023. Therapie 25: 893 (1970). Lehtovaara, R.: A clinical trial with clonazepam. Acta Neurologica Scandinavica 49 (Suppl. 53): 77 (1973). Lund, M. and Trolle, E.: Clonazepam in the treatment of epilepsy. Acta Neurologica Scandinavica 49 (Suppl. 53): 82 (1973). Martin, D. and Hirt, IiR.: Klinische Erfahrungen mit Clonazepam (Rivotril) in der Epilepsiebehandlung bei Kindem. Neuropaediatrie 4: 245 (1973). Masland, R.L: A controlled trial of clonazepam in temporal lobe epilepsy. Acta Neurologica Scandinavica 51 (Suppl. 60): 49 (1975). Mikkelsen, B. and Birket-Smith, E.: A clinical study of the benzodiazepine Ro 54023 (clonazepam) in the treatment of epilepsy. Acta Neurologica Scandinavica 49 (Suppl. 53): 91 (1973).

Clonazepam: A Review

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Clonazepam: A Review

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Authors' address: R.M. Pinder, R.N. Brogden, T.M. Speight and G.S. Avery, Australasian Drug Information Services, P.O. Box 34~30, Birkenhead, Auckland 10 (New Zealand).