Description: Clonazepam is an oral benzodiazepine used primarily in the management of seizures. It shares many of the pharmacologic activities of the benzodiazepines, with noticeable efficacy as an anticonvulsant. Clonazepam is clinically effective in the prophylaxis of petit mal (absence) seizures, petit mal variant seizures (Lennox-Gastaut syndrome), akinetic and myoclonic seizures, and nocturnal myoclonus. It is ineffective in the management of generalized tonic-clonic seizures. Several reports in the literature have documented that clonazepam was effective in relieving symptoms of restless leg syndrome (RLS)ý. Clonazepam was approved by the FDA in June 1975. Clonazepam is a DEA schedule IV controlled substance. (Continued below Video)

Mechanism of action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS, and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and coma. The action of these drugs is mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and thereby increasing the inhibition of the ascending reticular activating system. Benzodiazepines block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.

Pharmacokinetics: Clonazepam is absorbed rapidly following an oral dose. It is distributed widely throughout body tissues and is approximately 85% protein-bound. Clonazepam's onset of action is 20-60 minutes and persists for up to 6-8 hours in children and up to 12 hours in adults. The half-life of clonazepam is approximately 22-33 hours in children and 19-50 hours in adults. Clonazepam is extensively metabolized by the liver through nitro- reduction into several inactive metabolites, which are then excreted in the urine.

non-FDA-approved indication

CONTRAINDICATIONS/PRECAUTIONS: Clonazepam should not be used in patients with preexisting respiratory depression or in cases of acute ethanol intoxication, shock, or coma because the drug can worsen CNS depression. Clonazepam should not be used in patients with diseases that decrease respiratory function such as chronic obstructive pulmonary disease (COPD).

Large quantities of clonazepam should not be prescribed for patients with known suicidal ideation or tendencies.

Clonazepam can impair mental ability and alertness, so patients should be warned not to drive a motor vehicle or operate heavy equipment while taking this drug.

Clonazepam is rarely beneficial for patients with depressive neuroses or psychosis and can induce paradoxical effects in these patients; the drug should therefore be administered extremely cautiously, if at all, to such patients.

Clonazepam is rated pregnancy category C. The effects on the fetus are unknown, so clonazepam should be given with caution, if at all, to pregnant women.

Clonazepam and other benzodiazepines should be administered cautiously to patients with renal impairment or hepatic disease; liver and renal function should be monitored regularly during prolonged therapy.

Abrupt discontinuation of clonazepam after prolonged use can cause seizures in susceptible patients. Abrupt discontinuation of benzodiazepine therapy has been reported to cause withdrawal symptoms including irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur following abrupt cessation after excessive or prolonged doses, but it can occur following the discontinuance of therapeutic doses administered for as few as 1-2 weeks. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as clonazepam. Abdominal cramps, confusion, depression, perceptual disturbances, sweating, nausea, vomiting, parasthesias, photophobia, hyperacusis, tachycardia, and trembling also occur during benzodiazepine withdrawal, but the incidence of these reactions is lower. Convulsions, hallucinations, delirium, and paranoia also can occur. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.

The clearance and/or elimination of many drugs are reduced in the elderly. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. Benzodiazepines have been associated with falls in the elderly and the consumer advocate group, Public Citizen, has recommended these drugs not be used in the elderly.

DRUG INTERACTIONS: The interaction between clonazepam and phenytoin is unpredictable. Clonazepam has been reported to increase, decrease, and cause no change in phenytoin serum concentrations. Since benzodiazepines, in general, are not considered to possess significant effects on hepatic enzyme activity, it is possible that the two drugs compete for a similar metabolic pathway. A subtle alteration in phenytoin metabolism when metabolism is nearly saturated may explain the unpredictable nature of the resulting phenytoin concentrations. Phenytoin concentrations should be monitored closely whenever clonazepam is added or discontinued.

Patients receiving levodopa for Parkinson's disease can experience decreased control of the symptoms of this disease when benzodiazepines are added to their regimen. Benzodiazepines should be administered cautiously to such patients.

Cimetidine, erythromycin, or disulfiram can decrease the hepatic metabolism of clonazepam if administered concomitantly. Patients receiving clonazepam therapy should be monitored for signs an exaggerated benzodiazepine response when cimetidine, erythromycin, or disulfiram is initiated.

Concomitant administration of clonazepam with CNS-depressant drugs, including opiate agonists, phenothiazines, barbiturates, ethanol, HA-blockers, general anesthetics, and tricyclic antidepressants, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.

Increase digoxin serum concentrations have been noted when patients were administered diazepam and alprazolam. In addition, the clearance of digoxin was decreased by these benzodiazepines. Conversely, alprazolam has been reported to have no effect on digoxin pharmacokinetics. Pending further clarification of this interaction, patients receiving a benzodiazepine and digoxin concurrently should be monitored for increased serum digoxin levels.

Oral contraceptives can increase the effects of clonazepam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to clonazepam.

ADVERSE REACTIONS: Most of the adverse effects associated with clonazepam therapy are CNS-related and dose-dependent including: headache, drowsiness, ataxia, dizziness, confusion, depression, slurred speech, syncope, lightheadedness, fatigue, tremors, and vertigo. Occasionally, paradoxical CNS stimulation can occur, particularly in psychiatric patients and hyperactive children. Symptoms of paradoxical CNS stimulation include hostility, nightmares, talkativeness, excitement, mania, tremulousness, sleep disturbances, increased muscle spasticity, acute rage reactions, anxiety, restlessness, euphoria, and hyperflexia. Benzodiazepine therapy should be discontinued if any of the signs of paradoxical CNS excitement occur.

Other adverse effects reported less frequently during therapy with clonazepam include: bradycardia, hypotension, rash, urticaria, blurred vision, diplopia, flushing, constipation, nausea/vomiting, libido decrease, hepatic dysfunction, and abdominal pain.

Even after short-term use of clonazepam, there is evidence of physiological dependence and consequent adverse withdrawal symptoms. Abrupt discontinuation of benzodiazepine therapy has been reported to cause withdrawal symptoms including irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur following abrupt cessation of excessive or prolonged doses, but it can occur following the discontinuance of therapeutic doses that have been administered for as few as 1-2 weeks. Abdominal cramps, confusion, depression, perceptual disturbances, sweating, nausea/vomiting, paresthesias, photophobia, hyperacusis, tachycardia, and trembling also occur during benzodiazepine withdrawal, but these reactions are less frequent. Convulsions, hallucinations, delirium, and paranoia also can occur. Benzodiazepines should be withdrawn cautiously and gradually, using a very gradual dosage- tapering schedule.

PATIENT INFORMATION:

What do clonazepam tablets do?

Clonazepam (Klonopin^TM ) is a benzodiazepine. Benzodiazepines belong to a group of medicines that slow down the central nervous system. Clonazepam is effective in treating certain types of seizures (convulsions). Federal law prohibits the transfer of clonazepam to any person other than the patient for whom it was prescribed. Do not share this medicine with anyone else. Generic clonazepam tablets are not yet available.

What should my doctor or pharmacist know before I take clonazepam?

They need to know if you have any of these conditions:

• an alcohol or drug abuse problem
• glaucoma
• kidney disease
• liver disease
• lung disease or breathing difficulties
• psycotic illness
• shock
• suicidal thoughts
• an unusual or allergic reaction to clonazepam, other benzodiazepines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take clonazepam tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If clonazepam upsets your stomach, take it with food or milk. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.

Special precautions for use in children:

The effect of long-term clonazepam use on mental and physical development in children has not been determined.

Elderly patients over 65 years old may have a stronger reaction to this medicine.

What if I miss a dose?

If you miss a dose and remember within an hour, take it as soon as you can. If it is more than an hour since you missed a dose, skip that dose and go back to your regular schedule. Do not take double or extra doses.

What other medicines can interact with clonazepam?

• alcohol
• barbiturate medicines for inducing sleep or treating seizures (convulsions)
• cimetidine
• digoxin
• disulfiram
• erythromycin
• female hormones, including contraceptive or birth control pills
• levodopa
• medicines for hay fever and other allergies
• medicines for mental depression
• medicines for mental problems and psychotic disturbances
• medicines for pain
• phenytoin

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking clonazepam?

Serious side effects with clonazepam include:

• confusion
• depression
• double vision or abnormal eye movements
• hallucinations (seeing and hearing things that are not really there)
• lightheadedness or fainting spells
• mood changes, excitability or aggressive behavior
• movement difficulty, staggering or jerky movements
• muscle cramps
• restlessness
• tremors
• weakness or tiredness

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with clonazepam include:

• constipation or diarrhea
• difficulty sleeping, nightmares
• dizziness, drowsiness, clumsiness, or unsteadiness; a "hangover" effect
• headache nausea, vomiting

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take clonazepam?

Visit your doctor for regular checks on your progress. Your body may become dependent on clonazepam. If you have been taking clonazepam regularly for some time, do not suddenly stop taking it. You must gradually reduce the dose or you may get severe side effects. Ask your doctor for advice before increasing or decreasing the dose. Even after you stop taking clonazepam it can still affect your body for several days.

If you suffer from several types of seizures, clonazepam may increase the chance of grand mal seizures (epilepsy). Let your doctor know, he or she may want to prescribe an additional medicine.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how clonazepam affects you. To reduce the risk of dizzy and fainting spells, do not stand or sit up quickly, especially if you are an older patient. Alcohol may increase dizziness and drowsiness. Avoid alcoholic drinks.

Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects.

If you are going to have surgery, tell your doctor or dentist that you are taking clonazepam.

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.

The P-I-E-N-O Parkinsn's List Drug Database Index

John Cottingham is the webmaster of this site.