Epitra

Approved Indications:

• Seizure Disorders:
• Lennox-Gastaut syndrome
• Akinetic seizures
• Myoclonic seizures
• Absence seizures (petit mal) refractory to other medications
• Panic Disorder, with or without agoraphobia (in adults)

Clinically Accepted Off-Label Uses:

• Generalized Anxiety Disorder (GAD)
• Social Anxiety Disorder
• Sleep Disorders, including REM sleep behavior disorder and parasomnias
• Acute Mania in Bipolar Disorder (adjunctive use)
• Tardive Dyskinesia (symptomatic treatment)
• Essential Tremor
• Restless Legs Syndrome
• Catatonia (in combination with antipsychotics or ECT)
• Alcohol Withdrawal (acute phase) – short-term use only

Route: Oral administration (tablets and orally disintegrating tablets)

Adults:

• Seizure Disorders:
• Initial: 1.5 mg/day in 3 divided doses
• Titrate by 0.5–1 mg every 3 days
• Maintenance: 2–8 mg/day in 2–3 divided doses
• Maximum: 20 mg/day
• Panic Disorder:
• Initial: 0.25 mg twice daily
• Titrate to 1 mg/day after 3 days
• Maintenance: 0.5–2 mg/day (in divided doses)
• Max: 4 mg/day

Pediatrics (Seizures):

• ≤10 years or ≤30 kg:
• Initial: 0.01–0.03 mg/kg/day in 2–3 divided doses
• Maintenance: Up to 0.1 mg/kg/day (max 0.2 mg/kg/day)
• >10 years or >30 kg: Adult dosing applies

Elderly:

• Start at lowest dose (e.g., 0.125–0.25 mg/day)
• Titrate cautiously to minimize CNS depression and falls

Hepatic Impairment:

• Use with caution; reduce dose and monitor for sedation and coordination problems

Renal Impairment:

• No formal adjustment needed, but use caution in severe renal dysfunction

Clonazepam enhances the activity of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. It binds to the benzodiazepine site on the GABA-A receptor complex, increasing the frequency of chloride channel opening. This hyperpolarizes neuronal membranes, stabilizing them and reducing neuronal excitability, which results in anticonvulsant, anxiolytic, sedative, muscle relaxant, and hypnotic effects.

• Absorption: Rapid and complete after oral administration
• Bioavailability: ~90%
• Peak Plasma Time: 1–4 hours
• Distribution: Widely distributed; crosses blood-brain barrier and placenta; 85% protein-bound
• Metabolism: Hepatic via CYP3A4 to inactive metabolites
• Half-life: 18–50 hours (average ~30–40 hours)
• Elimination: Renal (mainly as metabolites); <2% excreted unchanged in urine

• Pregnancy: Category D – Positive evidence of human fetal risk (e.g., congenital malformations, neonatal withdrawal); use only when benefits outweigh risks.
• Lactation: Clonazepam is excreted in breast milk. Not recommended during breastfeeding due to risks of sedation, poor feeding, and respiratory depression in the infant.

• Primary Class: Benzodiazepine
• Subclasses: Antiepileptic, Anxiolytic

• Known hypersensitivity to clonazepam or other benzodiazepines
• Severe liver disease (e.g., hepatic encephalopathy, acute hepatic failure)
• Acute narrow-angle glaucoma
• Significant respiratory depression
• History of benzodiazepine dependence (unless under specialized supervision)

• Addiction, Abuse, and Misuse: Risk of dependence and misuse, particularly with long-term use
• Withdrawal Risk: Abrupt discontinuation can cause seizures, agitation, tremors, hallucinations, and anxiety
• Sedation and CNS Depression: Avoid use with alcohol or other CNS depressants
• Suicidal Thoughts/Behavior: Monitor during initiation and dose changes
• Paradoxical Reactions: Anxiety, aggression, agitation, or hallucinations (especially in children/elderly)
• Depression Worsening: Caution in patients with depressive disorders
• Respiratory Depression: Increased risk in patients with chronic respiratory disease or concurrent opioid use

Very Common:

• Drowsiness
• Dizziness
• Fatigue
• Coordination disturbances (ataxia)

Common:

• Depression
• Memory impairment
• Irritability
• Increased salivation
• Behavioral changes (especially in children)

Less Common/Rare:

• Paradoxical anxiety or agitation
• Hallucinations or psychosis
• Liver enzyme elevation
• Blood dyscrasias
• Respiratory depression (in overdose or vulnerable patients)
• Anterograde amnesia

Dose-dependent effects: Many side effects increase with higher dosages or rapid titration.

• CNS Depressants (alcohol, opioids, antipsychotics, antihistamines): Increased risk of sedation and respiratory depression
• Valproic Acid: May increase clonazepam levels
• Phenytoin, Carbamazepine: May reduce effectiveness by inducing hepatic metabolism
• CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin): May increase clonazepam plasma levels
• CYP3A4 Inducers (e.g., rifampin): May decrease clonazepam levels
• SSRIs/SNRIs: Caution due to risk of additive CNS depression

• FDA Boxed Warning (2020): All benzodiazepines, including clonazepam, carry warnings about the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.
• Updated Clinical Practice Guidelines: Recommend lowest effective dose for shortest duration; long-term use should include regular reassessment.
• Combination with Opioids: Strong advisory against co-prescription due to enhanced risk of overdose and death.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity & Light: Protect from excessive moisture and light
• Handling Precautions: Keep out of reach of children; schedule IV controlled substance
• Formulations: Store tablets in tightly closed containers; orally disintegrating tablets should remain sealed until use