KLONOPIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KLONOPIN (KLONOPIN).
Benzodiazepine that binds to GABA-A receptors at the benzodiazepine binding site, enhancing the effect of GABA and increasing chloride ion influx, leading to neuronal hyperpolarization and decreased neuronal excitability.
| Metabolism | Primarily metabolized by CYP3A4 to inactive metabolites (7-aminoclonazepam) and also undergoes nitroreduction; minor metabolism via CYP2C19. |
| Excretion | Renal excretion: ~50-70% as glucuronide metabolites, ~30% as unchanged drug (with enterohepatic recirculation); fecal: <2% |
| Half-life | 30-40 hours in adults; prolonged in elderly (up to 50-80 hours) and hepatic impairment; clinical context: steady-state achieved in 5-10 days |
| Protein binding | 85-87%; primarily albumin |
| Volume of Distribution | 1.5-4.4 L/kg; high Vd indicates extensive tissue distribution and accumulation in lipophilic compartments |
| Bioavailability | Oral: ~90%; sublingual: comparable or slightly higher due to bypass of first-pass metabolism |
| Onset of Action | Oral: 20-60 minutes (peak effect 1-2 hours); sublingual: faster absorption (onset ~15 minutes) |
| Duration of Action | 6-8 hours for single dose (seizure prophylaxis effect lasts 12-24 hours due to active metabolites); accumulation with multiple dosing prolongs effect |
| Molecular Weight | 315.71 |
0.5 mg orally three times daily; maximum 20 mg/day
| Dosage form | TABLET |
| Renal impairment | CrCl <10 mL/min: use caution, dose reduction of 25-50% recommended; CrCl 10-50 mL/min: no adjustment needed |
| Liver impairment | Child-Pugh Class A: use 50% of usual dose; Child-Pugh Class B: use 25% of usual dose; Child-Pugh Class C: not recommended |
| Pediatric use | 0.01-0.03 mg/kg/day orally divided every 8 hours; maximum 0.05 mg/kg/day |
| Geriatric use | Initiate at 0.25 mg twice daily; titrate slowly; maximum 2 mg/day |
| 1st trimester | Associated with increased risk of congenital malformations (oral clefts) when used in first trimester; avoid use if possible. |
| 2nd trimester | Continue only if clearly needed; risk of adverse effects on fetal development. |
| 3rd trimester | Risk of neonatal withdrawal syndrome and floppy infant syndrome; avoid use near term. |
Clinical note
Comprehensive clinical and safety monograph for KLONOPIN (KLONOPIN).
| Placental transfer | Clonazepam crosses the placenta; detectable in fetal plasma at concentrations comparable to maternal levels. |
| Breastfeeding | Clonazepam is excreted into breast milk in low concentrations; monitor infant for sedation, poor feeding, and developmental milestones; caution in preterm or low-birth-weight infants. |
■ FDA Black Box Warning
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
| Serious Effects |
Severe hepatic impairmentNarrow-angle glaucomaKnown hypersensitivity to benzodiazepinesConcurrent use with delavirdine
| Precautions | Risk of respiratory depression, especially with opioids or other CNS depressants, Risk of dependence, tolerance, and withdrawal reactions, Risk of abuse and misuse, Seizures may worsen upon abrupt discontinuation, CNS depression and impaired psychomotor function, Suicidal ideation and behavior (rare), Paradoxical reactions (hyperactivity, aggression), Neonatal withdrawal syndrome if used during pregnancy, Hepatic impairment may require dose adjustment |
| Food/Dietary | Avoid grapefruit and grapefruit juice as it may increase drug levels. Do not consume alcohol. Take with food if gastrointestinal upset occurs. |
Loading safety data…
| Lactation Rating |
| L3 (Moderately Safe) - Avoid if possible |
| Teratogenic Risk | First trimester: Increased risk of oral clefts (OR 1.79–2.0) with benzodiazepine use. Second and third trimesters: Risk of floppy infant syndrome (hypotonia, lethargy, respiratory depression) and neonatal withdrawal (irritability, tremors, feeding difficulties). Late third trimester or labor: Risk of neonatal respiratory depression and 'floppy infant' syndrome. Chronic use: Possible neurobehavioral effects. |
| Fetal Monitoring | Fetal ultrasound for structural anomalies (cleft palate) if first trimester exposure. Close neonatal monitoring for respiratory depression, hypotonia, withdrawal symptoms. Maternal monitoring for sedation, dizziness, ataxia, and suicidal ideation. |
| Fertility Effects | May interfere with ovulation at high doses due to increased prolactin (mild effect). No clear evidence of impairment in male or female fertility in humans. |
| Clinical Pearls | Avoid abrupt discontinuation due to withdrawal seizures. Use lowest effective dose for shortest duration, especially in elderly. Monitor for respiratory depression when co-prescribed with opioids. Onset of action is 20-60 min for oral, 2-5 min for IV. |
| Patient Advice | Do not drive or operate heavy machinery until you know how this medication affects you. · Avoid alcohol and other CNS depressants. · Do not stop taking this medication suddenly; taper under medical supervision. · May cause dependence; use only as prescribed. · Report any new or worsening mood changes, suicidal thoughts, or unusual behaviors. |