Clonazepam

Clonazepam is an Antiseizure agent belonging to the Benzodiazepine class.

Clonazepam is a long-acting benzodiazepine with intermediate onset commonly used to treat panic disorders, severe anxiety, and seizures.

Clonazepam is wholly and rapidly absorbed from the gastrointestinal tract. It has Bioavailability of Approximately 90%. The time taken to reach peak plasma concentration is approximately 1-4 hours. The apparent volume of distribution of clonazepam is approximately 3 L/kg. It is 85% bound to Plasma protein. Clonazepam is Extensively metabolized in the liver via glucuronide and sulfate conjugation; converted to 7-amino clonazepam (major inactive metabolite), and 7-acetamido- and 3-hydroxy-derivatives (minor metabolites). It is primarily excreted via urine (50-70%, <2% as an unchanged drug) and in faeces (10-30%).

Clonazepam shows side effects like Drowsiness, light-headedness, headache, tiredness, dizziness, irritability, talkativeness, difficulty concentrating etc.

Clonazepam is available in the form of Oral Tablets.

Clonazepam is available in India, US, Canada, France, Germany, Ireland, Italy, Netherlands, and Spain.

Clonazepam belongs to the Benzodiazepine class and acts as Antiseizure Agent.

Clonazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors. This binding act enhances the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors. This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells. Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action.

The Onset of action of Clonazepam is approximately 20-40 minutes.

The Time to peak plasma concentration of Clonazepam is approximately 1-4 hours.

Clonazepam is available in the form of an Oral Tablet.

Clonazepam Tablet is taken orally, usually in 2 divided doses.

Clonazepam treats or prevents different types of seizures or fits (fainting or uncontrolled movements caused by electrical disturbance in the brain). Clonazepam is also used for the treatment of panic attacks and sleep disorders.

Clonazepam is an Antiseizure agent belonging to the Benzodiazepine class.

Clonazepam works by affecting neurotransmitters in the brain. Neurotransmitters are chemicals that nerves release to communicate with other nearby nerves.

Clonazepam is approved for use in the following clinical indications

• Anxiety
• Myoclonus
• Rapid eye movement sleep behavior disorder
• Seizure disorders, refractory
• Tardive dyskinesia
• Vertigo, acute episodes

• Anxiety

Oral: Initial: 0.5 mg/day in 2 divided doses; may be given as needed or scheduled. May increase dose based on response and tolerability up to 4 mg/day in 2 to 4 divided doses. In severe agitation due to psychosis, some experts consider increasing doses, if needed and tolerated, up to a reported maximum of 8 mg/day in divided doses.

• Myoclonus

Oral: Initial: 0.5 mg/day in 2 divided doses; may gradually increase daily dose based on response and tolerability to a usual dose of 1.5 to 3 mg/day in 3 divided doses.

• Rapid eye movement sleep behavior disorder

Oral: Initial: 0.25 to 0.5 mg within 30 minutes of bedtime; usual dose range: 0.25 to 2 mg before bedtime. In most patients, 0.5 to 1 mg before bedtime is sufficient and better tolerated than doses >1 mg.

• Seizure disorders, refractory

Monotherapy: Initial: 0.5 to 1.5 mg/day in 1 to 3 divided doses.

Adjunctive therapy: Initial: 0.5 to 1 mg/day in 1 to 3 divided doses.

Dosage adjustment: May increase dose based on response and tolerability in increments of 0.5 to 1 mg every 3 to 7 days to usual maintenance dose of 2 to 8 mg/day in 1 to 2 divided doses; maximum dose: 20 mg/day.

• Tardive dyskinesia

Oral: Initial: 0.5 mg/day; increase daily dose based on response and tolerability by 0.5 mg every 5 days up to 4 mg/day in 2 divided doses.

• Vertigo, acute episodes

Oral: 0.25 to 0.5 mg every 8 to 12 hours as needed for up to 48 to 72 hours.

Clonazepam is available in various strengths as 1 mg; 0.5 mg; 2 mg; 0.25 mg; 0.125 mg.

Consumption of alcohol should be avoided also caffeine intake should be limited.

Clonazepam is contraindicated in patients with

• History of sensitivity to benzodiazepines
• Clinical or biochemical evidence of significant liver disease
• Acute narrow angle glaucoma (it may be used in patients with open-angle glaucoma who are receiving appropriate therapy).

• Sleep-related activities

Hazardous sleep-related activities such as sleep-driving, cooking, and eating food, and making phone calls while asleep have been noted with benzodiazepines.

• Suicidal ideation

Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% of treated patients compared to 0.24% of patients receiving placebo); risk observed as early as one week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression.

• Depression

Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk exists, except for acute or emergency situations (e.g., acute agitation, status epilepticus).

• Glaucoma

May be used in patients with open-angle glaucoma who are receiving appropriate therapy; contraindicated in acute narrow angle glaucoma.

• Hepatic impairment

Use caution in patients with hepatic impairment; accumulation is likely to occur. Contraindicated in patients with significant hepatic impairment.

• Hypersalivation

Clonazepam may produce an increase in salivation; use with caution in patients who have difficulty handling secretions.

• Porphyria

Use with caution in patients with porphyria; it may have a morphogenic effect.

• Renal impairment

Clonazepam metabolites are really eliminated; however, the metabolites are inactive or weakly active; therefore, the clinical significance of metabolite accumulation has not been determined. Caution may be warranted if using in patients with kidney impairment, particularly if they may be more susceptible to clonazepam-related adverse effects (eg, elderly, use of concomitant medications with CNS effects).

• Respiratory disease

Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.

Consumption of alcohol should be avoided while you are taking Clonazepam as it can cause drowsiness and even difficulty in breathing. Activities that require high mental alertness (such as driving and operating heavy machines) should be avoided.

The effects of Clonazepam on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Clonazepam and any potential adverse effects on the breast-fed infant from Clonazepam or from the underlying maternal condition.

There are no adequate and well-controlled studies of Clonazepam in pregnant women. Available human data on the risk of teratogenicity is inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.

Consumption of alcohol should be avoided also caffeine intake should be limited.

Common

Decreased libido, Abdominal pain, constipation, decreased appetite, Dysmenorrhea, impotence, urinary frequency, urinary tract infection, vaginitis, Hypersensitivity reaction, Influenza, Confusion, decreased mental acuity, delayed ejaculation, depression, dysarthria, emotional lability, fatigue, memory impairment, nervousness Myalgia, Blurred vision, Bronchitis, cough, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, Ankle edema, chest pain, edema, flushing, leg thrombophlebitis, orthostatic hypotension, palpitations, pedal edema, Acne flare, alopecia, burning sensation of skin, cellulitis, contact dermatitis, dermal hemorrhage, dermatological reaction, excoriation of skin, pruritus, pustular rash, xeroderma, Gout, increased libido, increased thirst, loss of libido, weight gain, weight loss, Abdominal distress, ageusia, dyspepsia, flatulence, frequent bowel movements, gastric distress, gastrointestinal inflammation, heartburn, hemorrhoids, hunger, increased appetite, motion sickness, sialorrhea, toothache, Bladder dysfunction, cystitis, dysuria, ejaculatory disorder, irregular menses, mastalgia, pelvic pain, urinary incontinence, urinary retention, urinary tract hemorrhage, urine discoloration, Tongue edema, Candidiasis, fungal infection, herpes simplex infection, infectious mononucleosis, streptococcal infection, viral infection, Local inflammation, Aggressive behavior, alcohol intoxication, ankle pain, anxiety, apathy, depersonalization, disinhibition (organic), disturbance in attention, excitement, falling, heavy headedness, hyperactive behavior, hypertonia, hypoesthesia, illusion, increased dream activity, insomnia, malaise, migraine, nightmares, outbursts of anger, pain, paresis, paresthesia, shivering, sleep disorder, slowed reaction time, suicidal ideation, twitching, twitching of eye, vertigo, yawning, Arthralgia, back pain, bone fracture, foot pain, jaw pain, knee effusion, knee pain, lower back pain, lower extremity pain, lower limb cramp, muscle cramps, muscle strain, neck pain, shoulder pain, sprain, tendinopathy, tremor, Diplopia, eye irritation, hordeolum, periorbital edema, visual disturbance, visual field defect, xerophthalmia, Otalgia, otitis, Polyuria, Dyspnea, epistaxis, exacerbation of asthma, hoarseness, pleurisy, pneumonia, sneezing, Accidental injury, burn, fever, wound.

Rare

Rash, hives, swelling of the eyes, face, lips, tongue, or throat, difficulty breathing or swallowing, hoarseness, difficulty breathing.

• Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin.

• Buprenorphine

CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

• Cannabinoid-Containing Products

CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.

• Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.

• Clozapine

Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines before initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined.

• Daridorexant

May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.

• Dexmedetomidine

CNS Depressants may enhance the CNS depressant effect of Dexmedetomidine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants and consider dose reductions of either agent to avoid excessive CNS depression.

• Doxylamine

It may enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diplegics (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.

• Hydroxyzine

May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine and another CNS depressant.

• Lemborexant

May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of Lemborexant and concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary.

• Methotrimeprazine

May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patients closely for evidence of CNS depression.

• Opioid Agonists

CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

• Oxycodone

CNS Depressants may enhance the CNS depressant effect of Oxycodone. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

• Paraldehyde

CNS Depressants may enhance the CNS depressant effect of Paraldehyde.

• Vigabatrin

It may enhance the CNS depressant effect of Clonazepam. Vigabatrin may increase the serum concentration of Clonazepam.

• Yohimbine

May diminish the therapeutic effect of Antianxiety Agents.

• Zolpidem

CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

The common side effects of Clonazepam include the following

• Common side effects

Drowsiness, dizziness, unsteadiness, problems with coordination, difficulty thinking or remembering, increased saliva, muscle or joint pain, frequent urination, blurred vision changes in sex drive or ability.

• Rare side effects

Rash, hives, swelling of the eyes, face, lips, tongue, or throat, difficulty breathing or swallowing, hoarseness, difficulty breathing.

• Pregnancy

Pregnancy Category D

There are no adequate and well-controlled studies of Clonazepam in pregnant women. Available human data on the risk of teratogenicity is inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence and subsequently withdrawal, during the postnatal period.

• Nursing Mothers

The effects of Clonazepam on the breastfed infant and milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Clonazepam and any potential adverse effects on the breast-fed infant from Clonazepam or the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.

• Geriatric Use

Clinical studies of Clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. The kidneys excrete metabolites of Clonazepam; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be helpful to assess hepatic and/or renal function at the time of dose selection. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Clonazepam and observed closely.

Symptoms: Somnolence, confusion, dysarthria, nystagmus, ataxia, areflexia, apnoea, hypotension, cardiorespiratory depression, or coma.

Management: Supportive and symptomatic treatment. Maintain clear airway and adequate ventilation. Consider administration of activated charcoal within 1-2 hours of ingestion and protect airway for drowsy patients. Gastric lavage may be considered in case of mixed ingestion. Flumazenil may be used for severe CNS depression; use with extreme caution particularly in those receiving chronic therapy and in presence of TCAs. Hypotension may be treated with levarterenol or metaraminol.

• Pharmacodynamic

Clonazepam is common among benzodiazepines and includes anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations, as well as irregular spikes and waves. Moreover, the agent can also decrease the frequency, amplitude, duration, and spread of discharge in minor motor seizures. Generalized EEG abnormalities are more readily suppressed by clonazepam than focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalized and focal epilepsies.

• Pharmacokinetics

Absorption

Clonazepam is Rapidly and completely absorbed from the gastrointestinal tract. It has Bioavailability of Approximately 90%. Time taken to reach peak plasma concentration is approximately 1-4 hours.

Distribution

The apparent volume of distribution of clonazepam is approximately 3 L/kg. It is 85% bound to Plasma protein.

Metabolism and Excretion

Clonazepam is Extensively metabolized in the liver via glucuronide and sulfate conjugation; converted to 7-aminoclonazepam (major inactive metabolite), and 7-acetamido- and 3-hydroxy-derivatives (minor metabolites). It is primarily excreted via urine (50-70%, <2% as unchanged drug) and in faeces (10-30%).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017533s061lbl.pdf
• https://go.drugbank.com/drugs/DB01068
• https://www.uptodate.com/contents/clonazepam-drug-information?search=clonazepam&source=panel_search_result&selectedTitle=1~131&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://medlineplus.gov/druginfo/meds/a682279.html
• https://www.drugs.com/dosage/clonazepam.html