Clonazepam - Drug Monograph

Introduction

Clonazepam is a benzodiazepine medication primarily used for its anticonvulsant and anxiolytic properties. Marketed under brand names including Klonopin, it was first approved by the FDA in 1975 and remains an important therapeutic option in neurological and psychiatric practice. As a Schedule IV controlled substance, clonazepam requires careful prescribing practices due to its potential for dependence and abuse.

Mechanism of Action

Clonazepam enhances the effect of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. It binds to specific sites on the GABA-A receptor, increasing the frequency of chloride channel opening. This hyperpolarizes neurons, making them less likely to fire and resulting in CNS depression. The drug's anticonvulsant effects are mediated through suppression of seizure spread rather than elevation of seizure threshold.

Indications

FDA-approved indications:

• Treatment of Lennox-Gastaut syndrome (petit mal variant)
• Akinetic and myoclonic seizures
• Panic disorder with or without agoraphobia

Off-label uses (evidence-supported):

• Other forms of epilepsy
• Acute mania adjunctive treatment
• Restless legs syndrome
• Neuralgic pain conditions
• REM sleep behavior disorder

Dosage and Administration

• Adults: Initial dose 1.5 mg/day divided TID, increase by 0.5-1 mg every 3 days (max 20 mg/day)
• Pediatric: 0.01-0.03 mg/kg/day divided BID-TID (max 0.2 mg/kg/day)

• Initial: 0.25 mg BID, increase to target dose of 1 mg/day
• Maintenance: 0.5-4 mg/day divided BID-TID

• Hepatic impairment: Reduce dose by 50%
• Renal impairment: Use caution, consider dose reduction
• Geriatric: Start with 0.25-0.5 mg/day (increased fall risk)
• Administration: May be administered with or without food

Pharmacokinetics

• Absorption: Well absorbed orally (90% bioavailability), Tmax 1-4 hours
• Distribution: Vd 3 L/kg, 85% protein bound, crosses blood-brain barrier and placenta
• Metabolism: Extensive hepatic metabolism via CYP3A4 to inactive metabolites
• Elimination: Half-life 30-40 hours, excreted primarily in urine (as metabolites)
• Steady-state: Achieved in 5-7 days with regular dosing

Contraindications

• Hypersensitivity to benzodiazepines or any component of formulation
• Acute narrow-angle glaucoma
• Significant hepatic impairment
• Concurrent use with strong CYP3A4 inhibitors in patients with hepatic dysfunction
• History of drug abuse (relative contraindication)

Warnings and Precautions

• Risk of abuse, misuse, addiction, dependence, and withdrawal reactions
• Concurrent use with opioids may result in profound sedation, respiratory depression, coma, and death

• Suicidal ideation and behavior
• Impaired cognitive and motor performance
• Paradoxical reactions (agitation, aggression)
• Depression and mood changes
• Respiratory depression (especially in COPD patients)
• Withdrawal seizures with abrupt discontinuation
• Teratogenicity (Pregnancy Category D)

Drug Interactions

• Opioids: ↑ CNS depression, respiratory depression
• Alcohol: ↑ Sedation, impaired coordination
• Other CNS depressants: Additive effects

• CYP3A4 inhibitors (ketoconazole, clarithromycin): ↑ Clonazepam levels
• CYP3A4 inducers (carbamazepine, rifampin): ↓ Clonazepam levels
• Oral contraceptives: May alter clonazepam metabolism

• Valproic acid: Possible absence status epilepticus
• Phenytoin: Altered levels of both drugs

Adverse Effects

• Somnolence (37%)
• Dizziness (8-27%)
• Coordination abnormalities (5-30%)
• Depression (7%)

• Memory impairment
• Fatigue
• Pharyngitis
• Constipation
• Appetite changes

• Respiratory depression
• Suicidal ideation
• Severe dermatological reactions
• Blood dyscrasias
• Hepatic enzyme elevations
• Withdrawal seizures

Monitoring Parameters

• Comprehensive metabolic panel
• CBC
• Pregnancy test (if applicable)
• Substance use history assessment

• Seizure frequency and characteristics
• Panic attack frequency and severity
• Cognitive and motor function assessment
• Signs of misuse or dependence
• Mood and suicidal ideation screening
• Fall risk assessment (especially elderly)
• Respiratory function (in patients with pulmonary disease)

• Not routinely required
• Consider in treatment failure, suspected toxicity, or drug interactions
• Therapeutic range: 20-70 ng/mL

Patient Education

• Take exactly as prescribed; do not increase dose without medical supervision
• Avoid alcohol and other CNS depressants
• Do not abruptly discontinue (risk of withdrawal seizures)
• May cause drowsiness - avoid driving or operating machinery until effects known
• Use effective contraception; notify provider if pregnancy is planned or suspected
• Store securely to prevent misuse by others
• Report any thoughts of self-harm or worsening depression
• Rise slowly from sitting/lying position to prevent falls
• Keep all follow-up appointments

• Taper gradually under medical supervision
• Withdrawal symptoms may include anxiety, insomnia, tremors, and seizures
• Seek immediate medical attention for severe withdrawal symptoms

References

1. FDA Prescribing Information: Klonopin (clonazepam) 2. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. 3. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563. 4. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. 5. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276. 6. Ashton H. Benzodiazepine equivalence table. In: Benzodiazepines: How They Work and How to Withdraw. Newcastle University; 2002. 7. Lader M. Benzodiazepines revisited—will we ever learn?. Addiction. 2011;106(12):2086-2109.