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Medication Safety Issues
Sound-alike/look-alike issues:
Clonazepam may be confused with clofazimine, clonidine, clorazepate, clozapine, lorazepam
Klonopin® may be confused with clofazimine, clonidine, clorazepate, clozapine, lorazepam
Pronunciation
(kloe NA ze pam)
U.S. Brand Names
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Use
Alone or as an adjunct in the treatment of petit mal variant (Lennox-Gastaut), akinetic, and myoclonic seizures; petit mal (absence) seizures unresponsive to succimides; panic disorder with or without agoraphobia
Use: Dental
Burning mouth syndrome
Use: Unlabeled/Investigational
Restless legs syndrome; neuralgia; multifocal tic disorder; parkinsonian dysarthria; bipolar disorder; adjunct therapy for schizophrenia
Restrictions
C-IV
Pregnancy Risk Factor
D
Pregnancy Implications
Clonazepam was shown to be teratogenic in some animal studies. Clonazepam crosses the placenta. Benzodiazepine use during pregnancy is associated with increased risk of congenital malformations. Nonteratogenic effects (including neonatal flaccidity, respiratory and feeding problems, and withdrawal symptoms) during the postnatal period have also been reported with benzodiazepine use. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Clonazepam enters breast milk; clinical effects on the infant include CNS depression, respiratory depression reported (no recommendation from the AAP).
Contraindications
Hypersensitivity to clonazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); significant liver disease; narrow-angle glaucoma; pregnancy
Warnings/Precautions
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.
Disease-related concerns:
• Depression: Use caution in patients with depression, particularly if suicidal risk may be present.
• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Impaired gag reflux: Use with caution in patients with an impaired gag reflux.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution in patients with respiratory disease.
Concurrent drug therapy issues:
• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.
• Valproic acid: Concurrent use with valproic acid may result in absence status.
Special populations:
• Debilitated patients: Use with caution in debilitated patients.
• Elderly: Use with caution in the elderly; benzodiazepines have been associated with falls and traumatic injury.
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.
Other warnings/precautions:
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Worsening of seizures may occur when added to patients with multiple seizure types. Monitoring of CBC and liver function tests has been recommended during prolonged therapy.
• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Adverse Reactions
Reactions reported in patients with seizure and/or panic disorder. Frequency not defined.
Cardiovascular: Edema (ankle or facial), palpitation
Central nervous system: Amnesia, ataxia (seizure disorder ?30%; panic disorder 5%), behavior problems (seizure disorder ?25%), coma, confusion, depression, dizziness, drowsiness (seizure disorder ?50%), emotional lability, fatigue, fever, hallucinations, headache, hypotonia, hysteria, insomnia, intellectual ability reduced, memory disturbance, nervousness; paradoxical reactions (including aggressive behavior, agitation, anxiety, excitability, hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams); psychosis, slurred speech, somnolence (panic disorder 37%), suicidal attempt, vertigo
Dermatologic: Hair loss, hirsutism, skin rash
Endocrine & metabolic: Dysmenorrhea, libido increased/decreased
Gastrointestinal: Abdominal pain, anorexia, appetite increased/decreased, coated tongue, constipation, dehydration, diarrhea, gastritis, gum soreness, nausea, weight changes (loss/gain), xerostomia
Genitourinary: Colpitis, dysuria, ejaculation delayed, enuresis, impotence, micturition frequency, nocturia, urinary retention, urinary tract infection
Hematologic: Anemia, eosinophilia, leukopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased (transient), hepatomegaly, transaminases increased (transient)
Neuromuscular & skeletal: Choreiform movements, coordination abnormal, dysarthria, muscle pain, muscle weakness, myalgia, tremor
Ocular: Blurred vision, eye movements abnormal, diplopia, nystagmus
Respiratory: Chest congestion, cough, bronchitis, hypersecretions, pharyngitis, respiratory depression, respiratory tract infection, rhinitis, rhinorrhea, shortness of breath, sinusitis
Miscellaneous: Allergic reaction, aphonia, dysdiadochokinesis, encopresis, “glassy-eyed” appearance, hemiparesis, lymphadenopathy
Drug Interactions
Substrate of CYP3A4 (major)
CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, opioid analgesics, and other sedative agents; monitor for increased effect.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clonazepam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of clonazepam. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
Disulfiram: Disulfiram may inhibit the metabolism of clonazepam; monitor for increased benzodiazepine effect.
Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data.
Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect.
Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation.
Valproic acid: The combined use of clonazepam and valproic acid has been associated with absence seizures.
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Clonazepam serum concentration is unlikely to be increased by grapefruit juice because of clonazepam's high oral bioavailability.
Herb/Nutraceutical: St John's wort may decrease clonazepam levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Mechanism of Action
The exact mechanism is unknown, but believed to be related to its ability to enhance the activity of GABA; suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex
Pharmacodynamics/Kinetics
Onset of action: 20-60 minutes
Duration: Infants and young children: 6-8 hours; Adults: ?12 hours
Absorption: Well absorbed
Distribution: Adults: Vd: 1.5-4.4 L/kg
Protein binding: 85%
Metabolism: Extensively hepatic via glucuronide and sulfate conjugation
Half-life elimination: Children: 22-33 hours; Adults: 19-50 hours
Time to peak, serum: 1-3 hours; Steady-state: 5-7 days
Excretion: Urine (<2% as unchanged drug); metabolites excreted as glucuronide or sulfate conjugates
Dosage
Oral:
Children <10 years or 30 kg: Seizure disorders:
Initial daily dose: 0.01-0.03 mg/kg/day (maximum: 0.05 mg/kg/day) given in 2-3 divided doses; increase by no more than 0.5 mg every third day until seizures are controlled or adverse effects seen
Usual maintenance dose: 0.1-0.2 mg/kg/day divided 3 times/day, not to exceed 0.2 mg/kg/day
Adults:
Burning mouth syndrome (dental use): 0.25-3 mg/day in 2 divided doses, in morning and evening
Seizure disorders:
Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5-1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day)
Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20 mg/day
Panic disorder: 0.25 mg twice daily; increase in increments of 0.125-0.25 mg twice daily every 3 days; target dose: 1 mg/day (maximum: 4 mg/day)
Discontinuation of treatment: To discontinue, treatment should be withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.
Elderly: Initiate with low doses and observe closely
Hemodialysis: Supplemental dose is not necessary
Dental Usual Dosing
Burning mouth syndrome: Adults: Oral: 0.25-3 mg/day in 2 divided doses, in morning and evening
Administration: Oral
Orally-disintegrating tablet: Open pouch and peel back foil on the blister; do not push tablet through foil. Use dry hands to remove tablet and place in mouth. May be swallowed with or without water. Use immediately after removing from package.
Monitoring Parameters
CBC, liver function tests; observe patient for excess sedation, respiratory depression
Reference Range
Relationship between serum concentration and seizure control is not well established
Timing of serum samples: Peak serum levels occur 1-3 hours after oral ingestion; the half-life is 20-40 hours; therefore, steady-state occurs in 5-7 days
Therapeutic levels: 20-80 ng/mL; Toxic concentration: >80 ng/mL
Patient Education
Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, loss of appetite, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help). If medication is used to control seizures, wear identification that you are taking an antiepileptic medication. Report excessive drowsiness, dizziness, fatigue, or impaired coordination; CNS changes (confusion, depression, increased sedation, excitation, headache, agitation, insomnia, or nightmares) or changes in cognition; respiratory difficulty or shortness of breath; changes in urinary pattern, changes in sexual activity; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances, excessive perspiration, or excessive GI symptoms (cramping, constipation, vomiting, anorexia); worsening of seizure activity, or loss of seizure control. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
Hepatic clearance may be decreased allowing accumulation of active drug. Also, metabolites of clonazepam are renally excreted and may accumulate in the elderly as renal function declines with age. Observe for signs of CNS and pulmonary toxicity.
Additional Information
Ethosuximide or valproic acid may be preferred for treatment of absence (petit mal) seizures. Clonazepam-induced behavioral disturbances may be more frequent in mentally handicapped patients. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms. Flumazenil, a competitive benzodiazepine antagonist at the CNS receptor site, reverses benzodiazepine-induced CNS depression.
Anesthesia and Critical Care Concerns/Other Considerations
Flumazenil, a competitive benzodiazepine antagonist at the CNS receptor site, reverses benzodiazepine-induced CNS depression. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation), gum soreness, and coated tongue.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Comment
There are two subtypes of GABA receptors (GABA-A and GABA-B) and three different benzodiazepine receptors (Bz1, Bz2, and Bz3). Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors. The role of GABA-B receptors is unclear. Benzodiazepines have no specificity for benzodiazepine receptor subtypes.
Clonazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the sedative, hypnotic, and anticonvulsant effects. It does not develop to the anxiolytic or skeletal muscle relaxing effects. Psychological and physical dependence may occur with prolonged use of benzodiazepines. The onset of withdrawal symptoms is usually seen on the first day without drug and lasts 5-7 days in patients receiving short half-life benzodiazepines, whereas, the onset occurs after 5 days with a duration of 10-14 days after abrupt discontinuance of long half-life benzodiazepines. Risk factors for abuse include alcohol abuse, personality disorders in the patient or the patient's parent(s).
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Assess for signs of CNS depression. Assess for history of addiction; long-term use can result in dependence, abuse, or tolerance; periodically evaluate need for continued use. For inpatient use, institute safety measures and monitor effectiveness and adverse reactions. For outpatients, monitor therapeutic effectiveness and adverse reactions at beginning of therapy and periodically with long-term use. Taper dosage slowly when discontinuing. Assess knowledge/teach patient seizure precautions (if administered for seizures), appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 0.5 mg, 1 mg, 2 mg
Klonopin®: 0.5 mg, 1 mg, 2 mg
Tablet, orally disintegrating: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg
Klonopin® Wafers: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg
Pricing: U.S. (www.drugstore.com)
Tablet, orally-disintegrating (Clonazepam ODT)
0.125 mg (60): $69.99
0.25 mg (60): $72.99
0.5 mg (60): $70.99
2 mg (60): $100.00
Tablet, orally-disintegrating (Klonopin Wafer)
0.125 mg (60): $95.99
0.25 mg (30): $49.99
0.5 mg (30): $50.07
1 mg (30): $54.99
Tablets (Clonazepam)
0.5 mg (30): $13.99
1 mg (30): $10.49
2 mg (30): $12.99
Tablets (Klonopin)
0.5 mg (30): $41.99
1 mg (30): $45.99
2 mg (30): $59.99
Extemporaneously Prepared
A 0.1 mg/mL oral suspension has been made using five 2 mg tablets, purified water USP (10 mL), and methylcellulose 1% (qs ad 100 mL). The expected stability of this preparation is 2 weeks if stored under refrigeration; shake well before use.
Nahata MC and Hipple TF, Pediatric Drug Formulations, 2nd ed, Cincinnati, OH: Harvey Whitney Books Co, 1992.
References
Barnett AM, “Treatment of Epilepsy With Clonazepam,” S Afr Med J, 1973, 47(37):1683-6.
Bladin PF, “The Use of Clonazepam as an Anticonvulsant - Clinical Evaluation,” Med J Aust, 1973, 1(14):683-8.
Brogden RN and Goa KL, “Flumazenil. A Preliminary Review of Its Benzodiazepine Antagonist Properties, Intrinsic Activity, and Therapeutic Use,” Drugs, 1988, 35(4):448-67.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Sugai K, “Seizures With Clonazepam: Discontinuation and Suggestions for Safe Discontinuation Rates in Children,” Epilepsia, 1993, 34(6):1089-97.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2008
Content last modified March 2008
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