Clonazepam: Drug Whys


Generic Name: clonazepam (multiple generics available)
Common U.S. Brand Names: Klonopin (Genentech USA)
Popularity: 23rd most commonly prescribed drug in U.S. (2002-2012)
Class: benzodiazepine

Treatment Uses: For treatment of panic disorders and seizures.  Used off label (meaning without FDA approval) for treatment of restless leg syndrome, sleep walking disorder (REM sleep behavior disorder), control of social phobias, burning mouth syndrome, essential tremor, neuralgia, multifocal tic disorder, bipolar disorder and adjunct therapy for schizophrenia. 

Dosing and Administration: For panic disorder in adults, the recommended initial oral dose of clonazepam is 0.25 twice daily for three days, increasing by 0.25 to 0.5 milligrams per day to a maximum of 4 milligrams daily.  Increases should be done no more often than every three days.  For seizures in adults, the recommended starting dose is 0.5 milligrams three times daily, increasing at the total daily dose by 0.5 to 1 milligram increments at three day intervals to a total daily maximum dose of 20 milligrams (divided into three doses).  When used for anxiety in adults, typical dosing starts at 0.25 milligrams twice daily, increased by 0.25 milligrams daily every one to two days, up to a maximum of 4 milligrams per day.  Usual maintenance doses for seizure control range from 2 to 8 milligrams daily in 1 or 2 divided doses.  Restless leg syndrome dosing ranges from 0.5 to 2 milligrams taken daily at bedtime.  Typical dosing for neuralgias ranges from 2 to 4 milligrams once daily.  Burning mouth syndrome dosing is typically 0.25 milligrams at bedtime for one week, increased weekly by increments of not more than 0.25 milligrams to a maximum of 3 milligrams daily in three divided doses.  For essential tremor, oral dosing is typically started at 0.5 milligrams at bedtime, increased every three to four days to a maximum dose of 6 milligrams daily.  Sleepwalking dosing ranges from 0.25 to 2 milligrams taken 30 minutes before bedtime, increased to a maximum of 4 milligrams taken just before sleep.

Safety and effectiveness of clonazepam for treatment of panic disorders in children under 18 years of age has not been established.  For treatment of seizures in children up to 10 years old or up to 30 kilograms, oral clonazepam is recommended to start at 0.01 to 0.03 (maximum 0.05) milligrams per kilogram per day, divided into two or three daily doses.  Upwards titration can be done every three days in 0.25 to 0.5 milligram increments to a maximum total daily dose of 0.1 to 0.2 milligrams per kilogram per day, divided into three daily doses.  Adult dosing schedules are usually used for pediatric patients over 10 years old or weighing greater than 30 kilograms.

An FDA-approved patient medication guide must be dispensed with clonazepam.

Extreme caution should be used in discontinuing treatment to avoid withdrawal symptoms including seizures.  Clonazepam should be tapered off for any patients on long-term therapy (greater than four weeks duration).  Taper by 0.125 milligrams twice daily every three days until the medication is completely withdrawn. 

Clonazepam release does not appear to be affected by food.  Oral clonazepam tablets should be taken with water and swallowed whole.  Oral disintegrating tablets should be removed from the blister pack with dry hands and placed in the mouth where it can readily dissolve and be swallowed, with or without water.  Any unused portion should be discarded as it may not remain stable. 

There are insufficient studies of clonazepam in patients with renal insufficiency or liver disease.  Because clonazepam is extensively metabolized in the liver, it seems reasonable to exercise caution in patients with hepatic insufficiency using the lowest possible doses and slowly titrating upward.  The manufacturer recommends against using clonazepam in any patient with significant liver disease.  Metabolites of clonazepam are excreted by the kidneys; the manufacturer suggests caution when prescribing clonazepam for patients with renal insufficiency.  Insufficient numbers of geriatric patients were included in studies of clonazepam to determine if they respond differently than younger patients.  Because of the higher incidence of renal and liver insufficiency in older patients, prescribers are encouraged to use the lowest possible starting doses and carefully up titrate clonazepam in older patients.

Overdoses of clonazepam generally manifest sleepiness, confusion, diminished levels of consciousness, and respiratory depression.  Treatment is supportive.  Flumazenil should not be administered to patients with epilepsy treated with benzodiazepines such as clonazepam due to the risk of status seizures.  Flumazenil selectively blocks benzodiazepine binding at CNS receptors, reversing clonazepam induced sedation but should be used as an adjunct, not primary management of benzodiazepine overdose.  Prior to administering flumazenil, the airway should be secured, ventilation initiated and intravenous access assured.  Use of flumazenil, however, may not reverse respiratory depression and, in patients with long term benzodiazepine use or in poly-substance overdoses involving cyclic antidepressants, can induce seizures. 

Pharmacology/Pharmacokinetics/Stability: Oral clonazepam is readily absorbed, with an initial onset of action in 20 to 40 minutes from oral administration and reaching peak blood levels within 1 to 4 hours.  The duration of action in adults is less than 12 hours and in children, from 6 to 8 hours.  The half-life (time needed for half the active drug to be eliminated from the body) is relatively long, ranging from 30 to 40 hours.  Clonazepam is metabolized extensively in the liver, 2% is excreted by the kidneys.  There is evidence of fetal risk when clonazepam is taken during pregnancy.  Maternal benefit should outweigh fetal risk if continued.  It is unknown whether clonazepam is excreted in breast milk however, the manufacturer recommends that women taking clonazepam not breastfeed.

Clonazepam is a central nervous system (CNS) drug with an unknown mechanism of action in the body.  It is theorized to exert its anti-seizure and anti-panic effects by binding to specific benzodiazepine receptor sites, enhancing GABA (gamma-aminobutyric acid, the major CNS inhibitory neurotransmitter) effects.

Oral clonazepam tablets come in 0.5, 1 and 2 milligram strengths and oral disintegrating clonazepam tablets come in 0.125, 0.25, 0.5, 1 and 2 milligram strengths.  Color, shape, and size of tablets vary by manufacturer.  Tablets should be stored at room temperature between 68-77°F with occasional variations to 59-86°F permitted.  A 0.1 milligram per milliliter (mg/mL) oral clonazepam suspension can be made by a compounding pharmacy. 

Cautions and Warnings: Clonazepam can exacerbate narrow angle glaucoma and should not be given to these patients.  It may be used in patients with open angle glaucoma who are receiving appropriate treatment.  Clonazepam should be used cautiously in patients with liver disease for reasons previously described.  An increase in salivation is often associated with clonazepam use.  Caution should be used in prescribing clonazepam for patients with difficulty managing secretions.  In patients with severe pulmonary disease, clonazepam’s increased secretions coupled with its propensity to depress respirations mandates extremely cautious use. 

Patients should be cautioned to avoid activities requiring mental alertness or coordination when starting clonazepam until the effects of the drug are fully appreciated.  Like other benzodiazepines, clonazepam has potential for dependence and abuse.  Patients should also be warned about the potential interactions of alcohol and other CNS depressant drugs with clonazepam.

Antiepileptic drugs (AEDs) including clonazepam increase the risk of suicidal thoughts and behavior (a primary reason for the FDA instruction sheet dispensed with clonazepam).  Patients on clonazepam should be monitored for new onset depressive signs and symptoms, worsening of existing depression, suicidal thoughts or any significant changes in mood or behavior.  The risk of suicidal behavior has been seen as early as one week from starting treatment and continued throughout the time the AED was being taken.

Benzodiazepine withdrawal syndrome is a potentially dangerous condition that can result from abrupt discontinuation of clonazepam.  When prescribed for seizures, abrupt discontinuation of clonazepam can lead to status seizures.  Dose reduction or discontinuation should be accomplished as a taper (previously described) of 0.125 milligrams twice daily every three days until the medication is completely withdrawn.   Benzodiazepine withdrawal syndrome often begins with distorted perceptions such as sensations of movement or perceptions of body parts being separated from the body.  Sensations of floating, falling, and faulty depth perception have also been reported.  Confusion, muscle cramps, and blurred vision are common.  Hypertension, tachycardia, delirium, and seizures can result from abrupt withdrawal.  Symptoms resolve with reinstitution of clonazepam. 

Risk and severity of withdrawal symptoms appears greater in patient with long term use at higher doses, but can appear in any benzodiazepine treated patient.  Onset usually occurs 18 hours to 3 days following abrupt discontinuation or large dose decreases.

Important Side Effects and Interactions: Drowsiness is the most commonly reported clonazepam side effect, occurring in 37% to 50% of all patients.  Ataxia (balance problems) and coordination problems are reported by 5% to 30% of patients.  Dizziness occurs in 8% of patients and fatigue in 7%.  Problem behavior has been observed in 25% of patients.  A serious side effect, depression (at times with suicidal thoughts) is seen in 7% of patients.

There are 32 drugs and drug classes specifically reported to interact with clonazepam.  Most are either poorly documented or extremely uncommon.  Two are worth noting.  Opioid analgesics and other CNS depressant drugs have additive effects when combined with clonazepam and require close monitoring for respiratory and CNS depression when used in combination.  St. John’s Wart has been reported to significantly reduce effectiveness of all benzodiazepines, requiring up to 50% greater benzodiazepine dosing. 

Average Costs – U.S.

  • 0.5 mg and 1 mg tablet (generic)
    • Patient cost: $1.18 and $1.33 each*
    • Large Hospital cost: $0.03 and $0.05 each
      *(Wal Mart® and Target don’t include this med in their $4/month programs)

References:

  1. MICROMEDEXÒ Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed November, 2013).
  2. Albany Medical Center Pharmacy, Albany, New York.

 

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