Klonopin Uses, Dosage, Side Effects and Interactions

Description and composition of Klonopin

Klonopin is a benzodiazepine that contains Clonazepam as its active ingredient. It also contains inactive ingredients called excipients in sufficient quantities.

Therapeutic Class of Klonopin: Antiepileptic, Benzodiazepines; Antipanic agent.

Clonazepam comes in different dosage forms including tablets and injections. It also comes in different strengths.

Pharmacology of Klonopin

Klonopin, like other benzodiazepines, has anticonvulsive, sedative, muscle relaxing and anxiolytic properties.

The exact mechanism by which clonazepam exerts its anticonvulsant and antipanic actions is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS.

Based on animal data and EEG investigations in man, clonazepam is shown to rapidly suppresse many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with temporal or other locations as well as irregular spikes and waves.

Pharmacokinetics

Following oral administration, Klonopin is rapidly and completely absorbed, reaching peak plasma concentrations between 1 and 4 hours after an oral dose; absolute bioavailability of clonazepam is about 90%; approx. 85% bound to plasma proteins.

Like other benzodiazepines, clonazepam crosses the placenta and has been detected in breastmilk.

Extensively metabolised in the liver via oxidative hydroxylation and reduction of the 7-nitro group with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all 3 compounds, and their glucuronide and sulfate conjugates; the main metabolite 7-amino-clonazepam has no antiepileptic activity whereas the nitro compounds are pharmacologically active. CYP3A4 is implicated in clonazepam reduction and oxidation.

Elimination half-life is between 20 and 60 hours (mean 30 hours); 50-70% of the oral dose is excreted in the urine and 10-30% in the faeces, almost exclusively in the form of free or conjugated metabolites.

Less than 0.5% appears as unchanged; less than 2% of the administered dose excreted as unchanged clonazepam in the urine.

Pharmacokinetics in special clinical situations Renal impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on kinetic criteria no dose adjustment is required in patients with renal failure.

Hepatic impairment: Clonazepam pharmacokinetics has not been studies in patients with hepatic impairment. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair its elimination and should therefore be used with caution in this population.

Elderly patients: Clonazepam pharmacokinetics in the elderly has not been studied. It should be used with caution in elderly and debilitated patients as they may be more susceptible to the CNS-depressant effects of the drug 

Uses of Klonopin

Oral

Management of most types of epilepsy in infants and children, especially absences (petit mal), myoclonic seizures and tonic-clonic fits, whether due to primary generalised epilepsy, or to secondary generalisation of partial epilepsy. In adults, all varieties of generalised epilepsy (including myoclonic, akinetic, tonic and tonic-clonic seizures), and in partial epilepsy (including psychomotor seizures).

Parenteral:

Intravenous (IV) use, for status epilepticus.

Note: Efficacy by the intramuscular (IM) route has not been established

 Dosage of Klonopin

Start low and go slow; treatment should be started with low doses and gradually increased based on individual patient’s response and tolerance. Lower initial doses recommended for the elderly as they are more sensitive to the effects of centrally depressant drugs and may experience confusion.

Total daily doses may initially be given in 3 or 4 equally divided doses; if doses are not equally divided, give the largest dose at bedtime.

Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue or reduce the dosage

Adult dose

Oral

Epilepsy Initial dosage: Total daily doses to be given in 3 or 4 divided doses;

Alternatively, give the initial dose at night for 4 days; then gradually increase over 2-4 weeks based on patient’s response and tolerance.

Initially, 1 mg/day (not exceeding 0.5 mg/day in elderly).

Maintenance dosage: May be given as a single dose at night. Usually, 4-8 mg/day.

Max: 20 mg/day

Intravenous

Treatment of status epilepticus.

Adult: Usually, 1 mg by slow IV injection (over at least 2 mins) or infusion; rate must not exceed 0.25 to 0.5 mg per minute.

May repeat dose as required by oral route or slow IV injection or infusion until status is controlled; not exceeding a total dose of 20 mg.

Hepatic Impairment

Mild to moderate hepatic impairment:

Adjust dose based on individual requirements; lower dose may be needed.

Severe hepatic impairment:

  • Contraindicated

Child dosage

Oral

Epilepsy

  • Initial dosage: Total daily doses to be given in 3 divided doses;
  • Alternatively, give the initial dose at night for 4 days; then gradually increase over 2-4 weeks Child (<5 years): 250 micrograms/day

Child (25 years):

  • 500 micrograms/day
  • Maintenance dosage:
    • May be given as a single dose at night.

1 to 5 years:

  • 1 to 3 mg daily

5 to 12 years:

  • 3 to 6 mg daily

Child (<1 year):

  • 0.5 to 1 mg daily

Note: If control of childhood epilepsy ceases to be adequate with clonazepam, the dose may be increased, or treatment interrupted for 2 or 3 weeks. During the interruption in therapy, careful observation and other drugs may be needed.

Intravenous

Treatment of status epilepticus.

Infants and children: 0.5 mg by slow IV injection or infusion

Renal dosage

Safety and efficacy of clonazepam in patients with renal impairment have not been established.

Based on pharmacokinetic considerations, dosage adjustment may not be required however, the pharmacodynamics of probable accumulated clonazepam metabolites may necessitate dosage review in these patients.

Side effects of Klonopin

Most frequently reported adverse reactions are associated with CNS depression; drowsiness (approximately 50%) and ataxia (approximately 30%) occurred in seizure-treated patients; some are transitory and disappear with continued treatment.

Behavior problems reported in approximately 25% of patients.

Other adverse reactions grouped based on body systems:

  • Cardiac disorders: Palpitations, tachycardia (after IV injection).
  • Endocrine disorders: Increased libido, hirsutism.
  • Gastrointestinal disorders: Anorexia, vomiting, dyspepsia, increased appetite, constipation, dysphagia, hyperphagia, hepatomegaly.
  • General disorders and administration site conditions: Ankle and facial oedema, lethargy.
  • Haemic and lymphatic system disorders: Leucopenia, eosinophilia, anaemia, lymphadenopathy.
  • Investigations: Abnormal liver function test.
  • Metabolism and nutrition disorders: Weight gain, weight loss, dehydration.
  • Nervous system disorders: Apathy, aphonia, coma, dysdiadochokinesis (inability to perform rapid, alternating movements), hemiparesis, respiratory depression, tremor.
  • Psychiatric disorders: Dysphoria, forgetfulness, hallucinations, hysteria, insomnia, psychosis, suicidal attempt (the behavioural effects are more likely to occur in patients with a history of psychiatric disturbances).
  • Renal and urinary disorders: Dysuria, enuresis, nocturia, urinary retention.
  • Respiratory, thoracic and mediastinal system disorders: Chest congestion, mucus obstruction of nasopharynx, rhinorrhoea, shortness of breath.

Pharmacovigilance

Warning: Risks from Concomitant Use with Opioids; Abuse, Misuse, and Addiction; Dependence and Withdrawal Reactions

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Recommendations:

  • Reserve concomitant prescribing of these drugs 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.

The use of benzodiazepines, including Clonazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes.

Before prescribing Clonazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.

The continued use of benzodiazepines, including Clonazepam, may lead to clinically significant physical dependence.

The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose.

Abrupt discontinuation or rapid dosage reduction of Clonazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Clonazepam or reduce the dosage.

Administration

For Oral and Intravenous administration.

May administer with or without food; to be swallowed whole with water. Efficacy by the intramuscular (IM) route has not been established

IV administration:

Administer by IV injection very slowly using a vein of sufficient calibre and with continuous monitoring of EEG, respiration and blood pressure.

Rapid IV injection and/or injection into the vein with insufficient calibre will increase the risk of thrombophlebitis, which may in turn lead to thrombosis

Advice to patients

Benzodiazepines have the potential to impair judgment, thinking or motor skills; caution patient about driving, operating machinery and other hazardous activities until it is known that they do not become drowsy or dizzy from the medication especially when starting treatment or making dosage changes.

Advise patient to avoid drinking alcohol while on the medication as alcohol can provoke epileptic seizures in addition to potentiating the CNS depressant effects of clonazepam.

Advise patient to report immediately the emergence or worsening of the signs and symptoms of depression, suicidal ideation or behaviour.

Inform patient that potentially fatal additive effects may occur if clonazepam is used with opioids and to avoid such combination unless under medical supervision.

Inform patient about the risks of abuse, misuse, and addiction associated with clonazepam; teach them how to recognize the risks and to report such signs or symptoms.

Advise patient to avoid abrupt discontinuation of drug due to potential for acute withdrawal reactions, which can be life-threatening.

Contraindications of Klonopin

Hypersensitivity to Klonopin, other benzodiazepines, or any of the excipients. Avoid use in patients with chronic obstructive airways disease with incipient respiratory failure; acute pulmonary insufficiency; myasthenia gravis; severe hepatic impairment as benzodiazepines may precipitate hepatic encephalopathy.

Clonazepam must not be used in patients in a coma, or in patients known to be dependent on drugs of abuse and CNS depressants including alcohol. Acute narrow angle glaucoma (it may be used in patients with open angle glaucoma who are receiving appropriate therapy) 

Precautions

Risks from Concomitant Use with Opioids; Abuse, Misuse, and Addiction; Dependence and Withdrawal Reactions – see under Pharmacovigilance

Worsening of seizures: When used in patients with coexisting different types of seizure disorders, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages.

Hypersalivation: Clonazepam may cause increased salivation, and this will necessitate appropriate precautions when used in patients who have difficulty handling secretions.

Respiratory depression: Benzodiazepines may cause respiratory depression and should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease (COPD), sleep apnea).

Concurrent use with alcohol and other CNS depressants: This may increase the effects of clonazepam including the potential for severe sedation that could result in coma or death, respiratory and/or cardiovascular depression.

Advise patient to avoid drinking alcohol while on the medication as alcohol can provoke epileptic seizures in addition to potentiating the CNS depressant effects of clonazepam.

Amnesia: Benzodiazepines are associated with transient amnesia or memory impairment especially at higher doses. Psychiatric and paradoxical reactions: Benzodiazepines are associated with paradoxical reactions (such as restlessness, agitation, irritability, aggressiveness, nervousness, hostility, anxiety, delusion, sleep disturbances, nightmares, hallucinations, psychoses, vivid dreams, acute rage, stimulation or excitement, inappropriate behaviour and other adverse behavioural effects); incidence usually higher in children and elderly. Discontinue treatment gradually if such reactions occur.

Hepatic impairment: Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair its elimination and should therefore be used with caution in this population.

Renal impairment: Some of the metabolites are excreted renally and to avoid their excess accumulation, caution is advised in this population.

Elderly: The sedative effects of clonazepam may last longer in older adults. Accidental falls are common in elderly patients who take benzodiazepines. Advise caution while on the medication to minimize the risk of falling or accidental injury.

Porphyria: Caution in patients with porphyria due to its porphyrogenic potential.

IV administration: Administer by IV injection very slowly using a vein of sufficient calibre and with continuous monitoring of EEG, respiration and blood pressure.

Rapid IV injection and/or injection into the vein with insufficient calibre will increase the risk of thrombophlebitis, which may in turn lead to thrombosis.

Effects on ability to drive and use machines: As with other CNS depressants, patients should be warned to avoid driving, operating machinery and other hazardous activities until it is known that they do not become drowsy or dizzy from Clonazepam therapy.

Even when adequately controlled on clonazepam, increases in dosage or alteration in timings of dosage may modify patients’ reactions, depending on individual susceptibility.

Clonazepam can slow reaction to such an extent that the ability to drive a vehicle or operate machinery is impaired.

This effect is aggravated by consumption of alcohol. Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment.

Klonopin use in pregnancy and lactation

Pregnancy:

Benzodiazepines including Clonazepam, are known to cross the placenta and appear in the foetus.

Continuous administration during pregnancy may give rise to hypotonia, reduced respiratory function and hypothermia in the newborn child.

Withdrawal symptoms in newborn infants have occasionally been reported with this class of medicines.

Animal data involving oral administration of clonazepam during the period of organogenesis show evidence of malformations in rabbits (cleft palate, open eyelids, fused sternebrae, limb defects) and mice (exencephaly, CNS defects) at doses less than maximum recommended human dose (MRHD).

These effects were not observed in rats at oral doses more than 20-fold MRHD. Clinical significance of these findings is unknown.

Anticonvulsant use during pregnancy:

Recommendations

  • The risk of a mother with epilepsy giving birth to a baby with an abnormality is about three times that of the normal population.
  • Some of this risk is due to the anticonvulsant medicines taken.
  • Mothers taking more than one anticonvulsant medicine might have a higher risk of having a baby with a malformation than mothers taking one medicine.
  • Overall, the risk of having an abnormal child is far outweighed by the dangers to the mother and foetus of uncontrolled convulsions.

It is therefore recommended that:

  • women on anticonvulsant medicines receive pre-pregnancy counselling with regard to the risk of foetal abnormalities
  • anticonvulsant should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose;
  • folic acid supplement (5 mg) should be commenced 4 weeks prior to and continue for 12 weeks after conception;
  • specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

Lactation:

Clonazepam passes into the maternal milk in small amounts and may cause drowsiness and feeding difficulties in the infant. If there is a compelling reason for use, breastfeeding should be discontinued.

Drugs interactions with Klonopin

Opioids:

  • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.
  • If the combination is necessary, limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Alcohol and other CNS depressants (e.g., barbiturates, nonbarbiturate hypnotics, anxiolytics, phenothiazines, thioxanthene and butyrophenone, MAOIS and TCAS):

  • Concurrent use may increase the CNS-depressant action of clonazepam including the potential for severe sedation that could result in coma or death, respiratory and/or cardiovascular depression.
  • Advise patient to avoid drinking alcohol while on the medication as alcohol can provoke epileptic seizures in addition to potentiating the CNS depressant effects of clonazepam

Other anticonvulsants:

  • Some benzodiazepines are known to interact with other anticonvulsants.
  • When clonazepam is used with other anticonvulsants, patients should be observed for altered responses and serum levels of both medications should be monitored more frequently; dosage adjustments should be made as needed.

Interactions involving Clonazepam combinations with specific anticonvulsants:

  1. Hydantoins, Phenobarbital: May increase the risk of side-effects such as sedation and apathy, and toxicity, especially at the start of treatment.
  2. Valproic acid (Sodium valproate): Rare occurrence of absence status epilepticus associated with the combination; concurrent use of both drugs also shown to be safe and effective in some patients.
  3. CYP450 inducers (e.g., Phenytoin, Carbamazepine, Lamotrigine, and Phenobarbital): Clonazepam is extensively metabolised in the liver. Concurrent use with any of these agents may induce clonazepam metabolism, causing an increase in its clearance and a decrease in its plasma levels. Pharmacokinetics of carbamazepine or phenobarbital is not altered by clonazepam. CYP450 inhibitors (e.g., Fluconazole): Concurrent use may impair the metabolism of clonazepam leading to its elevated plasma levels and thus, the risk of adverse reactions.

How to store Klonopin

Tablets:

Store below 30°C. Keep tablets in original packaging to protect from light and moisture.

Oral liquid:

Store below 25°C.

Concentrated injection solution:

Store below 25°C. Keep ampoules in the outer carton to protect from light

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