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Klonopin

Generic Name: Clonazepam
Class: Benzodiazepines
VA Class: CN400
CAS Number: 1622-61-3

Warning

    Concomitant Use with Opiates
  • Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.700 701 703 705 706 707

  • Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.700 703 (See Specific Drugs under Interactions.)

Introduction

Benzodiazepine; anticonvulsant, sedative, and anxiolytic.1 b

Uses for Klonopin

Seizure Disorders

Prophylactic management of Lennox-Gastaut syndrome and akinetic and myoclonic seizures.1 b d

Management of absence seizures in patients unresponsive to succinimides.1 b d

Some evidence of success in the management of refractory seizures, including partial seizures with complex symptomatology and other partial seizures and some cases of infantile spasms.b d

Useful in some patients with tonic-clonic seizures.b d

Panic Disorder

Treatment of panic disorder with or without agoraphobia.1 3

Catatonia

Also has been used for treatment of acute catatonic reactions, whether associated with schizophrenia or other conditions.529

Akathisia

May be helpful in patients experiencing akathisia while receiving antipsychotic drugs (e.g., for management of schizophrenia).529

Klonopin Dosage and Administration

General

  • Adjust dosage carefully and slowly according to individual requirements and response.b

  • Withdraw clonazepam slowly; avoid abrupt discontinuance, especially during long-term, high-dose therapy, to avoid precipitating seizures, status epilepticus, or withdrawal symptoms.b During withdrawal of clonazepam in patients with seizure disorders, simultaneous substitution of another anticonvulsant may be indicated.b

Administration

Oral Administration

Administer orally as conventional or orally disintegrating tablets.a

Administer in 3 equally divided doses for the treatment of seizure disorders; if doses are not equally divided, give the largest dose at bedtime.1 b

Administer in 2 equally divided doses for the management of panic disorder; alternatively, administer the entire dosage at bedtime to reduce the inconvenience of somnolence.1 b

Conventional Tablets

Swallow tablet whole with water.a

Orally Disintegrating Tablets

Just prior to administration, remove blister from aluminum pouch; with dry hands, peel open blister package, place orally disintegrating tablet in mouth to dissolve, and swallow with or without water.a

Dosage

Pediatric Patients

Seizure Disorders
Oral

Infants and children <10 years of age or weighing <30 kg: Initially, 0.01–0.03 mg/kg daily; initial dosage should not exceed 0.05 mg/kg daily given in 2 or 3 divided doses.1

Increase dosage by no more than 0.5 mg every third day until seizure control is achieved with minimal adverse effects.1 Maintenance dosage of 0.1–0.2 mg/kg daily.1

Children ≥10 years of age or weighing ≥30 kg: Initial dosage should not exceed 1.5 mg daily given in 3 divided doses.1 e

Increase dosage in increments of 0.5–1 mg every third day (up to a maximum dosage of 20 mg daily) until seizure control is achieved with minimal adverse effects.1 e

Adults

Seizure Disorders
Oral

Initial dosage should not exceed 1.5 mg daily given in 3 divided doses.1 b Increase dosage in increments of 0.5–1 mg every third day (up to a maximum dosage of 20 mg daily) until seizure control is achieved with minimal adverse effects.1 b

Panic Disorder
Oral

Initially, 0.25 mg twice daily.1 After 3 days, increase dosage to usual maintenance dosage of 1 mg daily.1

Some clinicians recommend dosages of 1–2 mg daily.3 Certain patients may benefit from dosages up to 4 mg daily.1 In such cases, increase dosage by 0.125–0.25 mg twice daily every 3 days until panic disorder is controlled with minimal adverse effects.1

Discontinue therapy gradually by decreasing the dosage in increments of 0.125 mg twice daily every 3 days until the drug is completely withdrawn.1

Prescribing Limits

Pediatric Patients

Seizure Disorders
Oral

Maximum 0.2 mg/kg daily.b

Adults

Seizure Disorders
Oral

Maximum 20 mg daily.1

Panic Disorder
Oral

Maximum 4 mg daily.1

Special Populations

Geriatric Patients

Initiate therapy at low dosage and observe closely.a

Cautions for Klonopin

Contraindications

  • Known hypersensitivity to clonazepam or other benzodiazepines.1

  • Clinical or biochemical evidence of substantial hepatic impairment.1

  • Manufacturer states that clonazepam is contraindicated in patients with acute angle-closure glaucoma but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy;1 however, clinical rationale for this contraindication has been questioned.c

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clonazepam, and opiates may result in profound sedation, respiratory depression, coma, and death.700 701 703 705 706 707 Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.700 701 705 706 707 711

Reserve concomitant use of clonazepam and opiates for patients in whom alternative treatment options are inadequate.700 703 (See Specific Drugs under Interactions.)

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.1

Concurrent use of other CNS depressants may potentiate CNS depression.1 (See Concomitant Use with Opiates under Cautions and also see (See Specific Drugs under Interactions.)

Withdrawal Effects

Abrupt discontinuance may result in symptoms of withdrawal (similar to barbiturates or alcohol).1 8 Symptoms may be relieved by tapering the dosage.1

General Precautions

Seizure Disorders

May increase the incidence or precipitate the onset of generalized tonic-clonic seizures in patients with multiple types of seizure disorders.1 Consider addition of appropriate anticonvulsants or an increase in their dosages.1

Abrupt withdrawal, particularly in patients receiving long-term, high-dose therapy, may result in status epilepticus.1

Concomitant use with valproic acid may produce absence status.1

Laboratory Testing

Perform blood counts and liver function tests periodically during long-term therapy.1

Hypersalivation

May increase salivation; use with caution in patients who have difficulty tolerating or clearing secretions.1

Respiratory Effects

Possible hypersalivation and respiratory depression in patients with chronic respiratory disease; use with caution in such patients.1 b

Abuse Potential

Psychologic and physical dependence may occur following prolonged use.1

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.1

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.c Prescribe drug in the smallest feasible quantity.c

Psychiatric Indications

Do not use in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.c

Specific Populations

Pregnancy

Category D.1

Lactation

Distributed into milk;c discontinue nursing or the drug.1

Pediatric Use

Effects of long-term administration on physical and mental development have not been established.1 b Administer to children with seizure disorders only if potential benefits outweigh possible risks.1 b

Safety and efficacy for treatment of panic disorder not established in children <18 years of age;1 however, clonazepam has been effective in a limited number of adolescents with panic disorder.22

Geriatric Use

Insufficient experience from clinical studies to determine whether patients ≥65 years of age respond differently than younger adults.a Other clinical experience has not identified age-related differences in responses. Potential increased sensitivity (increased risk of oversedation and confusion) to sedatives.a

Select dosage carefully, generally initiating therapy at low dosage; observe closely.a Consider the increased incidence of hepatic and renal impairment, decreased cardiac function, and concomitant disease and drug therapy in the geriatric population.a May be useful to assess hepatic and/or renal function when selecting dosage.a

Hepatic Impairment

Prolonged elimination.1 c Contraindicated in patients with clinical or biochemical evidence of substantial liver disease.1

Renal Impairment

Elimination of metabolites may be decreased; use with caution.1

Common Adverse Effects

Sedation/drowsiness, ataxia/hypotonia, behavioral disturbances (principally in children) including aggressiveness, irritability, agitation, hyperkinesis.b

Interactions for Klonopin

Metabolized by CYP enzymes, including CYP3A.1

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered plasma concentrations of clonazepam) with CYP inducers or inhibitors.1

No evidence that clonazepam induces metabolism of other drugs.a

Specific Drugs

Drug

Interaction

Comments

Antifungal agents, azole-type (e.g., itraconazole, ketoconazole)

Possible increase in plasma clonazepam concentrationsa

Use with caution1

Carbamazepine

Decreased plasma clonazepam concentrations; carbamazepine pharmacokinetics not affecteda

CNS depressants (e.g., barbiturates, sedatives, anticonvulsants, alcohol)

Additive CNS effects1 b

Use caution to avoid overdosageb

Avoid alcohol use1 700

Disulfiram

Possible increase in plasma clonazepam concentrations 200

Reduce clonazepam dosage as necessary 200

Fluoxetine

Clonazepam pharmacokinetics not affecteda

Opiate agonists and partial agonists

Risk of profound sedation, respiratory depression, coma, or death700 701 703 705 706 707

Whenever possible, avoid concomitant use708 709 710 711

Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation700 703

In patients receiving clonazepam, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response700

In patients receiving an opiate analgesic, initiate clonazepam, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700

Opiate antitussives: Avoid concomitant use700 704

Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly709 712

Phenobarbital

Decreased plasma clonazepam concentrations; phenobarbital pharmacokinetics not affecteda

Phenytoin

Decreased plasma clonazepam concentrations; phenytoin pharmacokinetics not affecteda

Propantheline

Possible decrease in plasma clonazepam concentrationsa

Klonopin Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak concentrations achieved within 1–4 hours.1 Absolute bioavailability is approximately 90%.1

Onset

Anticonvulsant action occurs within 20–60 minutes following oral administration.b

Duration

Duration of anticonvulsant action is 6–8 hours in infants and young children and up to 12 hours in adults.b

Distribution

Extent

Apparently crosses the blood-brain barrier and the placenta.b

Plasma Protein Binding

Approximately 85%.1

Elimination

Metabolism

Extensively metabolized in the liver to several metabolites.b

Elimination Route

Excreted in urine (<2% as unchanged drug).b 1

Half-life

18–50 hours.1 b c

Stability

Storage

Oral

Conventional or Orally Disintegrating Tablets

25°C (may be exposed to 15–30°C).a

Actions

  • Exact mechanism of anticonvulsant, sedative, and antipanic effects is unknown;1 however, mechanism appears to be related to the drug’s ability to enhance the activity of GABA, the principal inhibitory neurotransmitter in the CNS.1 b

Advice to Patients

  • Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly.700 703 Avoid concomitant use of opiate antitussives;700 704 also avoid concomitant use of opiate analgesics unless use is supervised by clinician.700 703

  • Importance of taking only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.1

  • Importance of not abruptly discontinuing therapy; consult clinician about discontinuing use.1

  • Potential for psychologic or physiologic dependence.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and concomitant illnesses, particularly depression.1

  • Importance of avoiding alcohol-containing beverages or products.1

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1

  • Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

clonazePAM

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg*

clonazePAM Tablets (C-IV)

KlonoPIN ( C-IV; scored)

Genentech

1 mg*

clonazePAM Tablets (C-IV)

KlonoPIN ( C-IV)

Genentech

2 mg*

clonazePAM Tablets (C-IV)

KlonoPIN ( C-IV)

Genentech

Tablets, orally disintegrating

0.125 mg*

clonazePAM Orally Disintegrating Tablets ( C-IV)

0.25 mg*

clonazePAM Orally Disintegrating Tablets ( C-IV)

0.5 mg*

clonazePAM Orally Disintegrating Tablets ( C-IV)

1 mg*

clonazePAM Orally Disintegrating Tablets ( C-IV)

2 mg*

clonazePAM Orally Disintegrating Tablets ( C-IV)

AHFS DI Essentials. © Copyright 2017, Selected Revisions November 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

1. Roche Laboratories Inc. Klonopin (clonazepam) tablets prescribing information. Nutley, NJ; 1997 Oct.

2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV™. 4th ed. Washington, DC: American Psychiatric Association; 1994:393-444.

3. Rosenbaum JF, Moroz G, Bowden CL for the Clonazepam Panic Disorder Dose-Response Group. Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. J Clin Psychopharmacol. 1997; 17:390-400. [PubMed 9315990]

4. Moroz G, Rosenbaum JF. Clonazepam efficacy in the treatment of panic disorder: results of a multicenter placebo-controlled trial. Data on file. Hoffmann-La Roche Inc., Nutley, NJ.

5. Oehrberg S, Christiansen PE, Behnke K et al. Paroxetine in the treatment of panic disorder: a randomised, double-blind, placebo-controlled study. Br J Psychiatry. 1995; 167:374-9. [PubMed 7496647]

6. Westenberg HG. Developments in the drug treatment of panic disorder: what is the place of the selective serotonin reuptake inhibitors? J Affect Dis. 1996; 40:85-93.

7. deh Boer JA. Pharmacotherapy of panic disorder: differential efficacy from a clinical standpoint. J Clin Psychiatry. 1998; 59:30-6; discussion 37-8.

8. Treatment of panic disorder. NIH Consensus Statement Online 1991 Sep 25-27; 9(2):1-24.

9. Reviewers’ comments (personal observations) on sertraline hydrochloride 28:16.04.

10. Davidson JR. The long-term treatment of panic disorder. J Clin Psychiatry. 1998; 59(Suppl. 8):17-23. [PubMed 9707158]

11. Baldwin DS, Birtwistle J. The side effect burden associated with drug treatment of panic disorder. J Clin Psychiatry. 1998; 59(Suppl. 8):39-46. [PubMed 9707161]

12. Gorman JM. The use of newer antidepressants for panic disorder. J Clin Psychiatry. 1997; 58(Suppl. 14):54-9. [PubMed 9418747]

13. Sheehan DV, Harnett-Sheehan K. The role of SSRIs in panic disorder. J Clin Psychiatry. 1996; 57(Suppl. 10):51-60. [PubMed 8917132]

14. Lecrubier Y, Bakker A, Dunbar G et al. A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder: Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand. 1997; 95:145-52. [PubMed 9065680]

15. Worthington JJ III, Pollack MH, Otto MW et al. Long-term experience with clonazepam in patients with a primary diagnosis of panic disorder. Psychopharmacol Bull. 1998; 34:199-205. [PubMed 9641001]

16. Sheehan DV. Benzodiazepines in panic disorder and agoraphobia. J Affect Disord. 1987; 13:169-81. [PubMed 2890678]

17. Nagy LM, Krystal JH, Woods SW et al. Clinical and medication outcome after short-term alprazolam and behavioral group treatment of panic disorder. Arch Gen Psychiatry. 1989; 46:993-9. [PubMed 2818144]

18. Davidson JR. Use of benzodiazepines in panic disorder. J Clin Psychiatry. 1997; 58(Suppl. 2):26-31. [PubMed 9078991]

19. Lecrubier Y, Judge R for Collaborative Paroxetine Panic Study Investigators. Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Acta Psychiatr Scand. 1997; 95:153-60. [PubMed 9065681]

20. Pollack MH, Otto MW, Tesar GE et al. Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder. J Clin Psychopharmacol. 1993; 13:257-63. [PubMed 8376613]

21. Burrows GD, Judd FK, Norman TR. Long-term drug treatment of panic disorder. J Psychiatr Res. 1993; 27(Suppl. 1):111-25. [PubMed 7908330]

22. Kutcher SP, MacKenzie S. Successful clonazepam treatment of adolescents with panic disorder. J Clin Psychopharmacol. 1988; 8:299-301. Letter. [PubMed 3209726]

200. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985:276-7, 393-4.

529. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(2 Suppl):1-56.

700. US Food and Drug Administration. Drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Silver Spring, MD; 2016 Aug 31. From FDA website.

701. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013; 309:657-9. [PubMed 23423407]

703. Hughes A. Letter to manufacturers of benzodiazepines: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20.

704. Seymour S. Letter to manufacturers of opioid antitussives: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20.

705. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015; 350:h2698. [PubMed 26063215]

706. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med. 2015; 49:493-501. [PubMed 26143953]

707. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med. 2016; 17:85-98. [PubMed 26333030]

708. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med. 2014; 160:38-47. [PubMed 24217469]

709. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016; 65:1-49. [PubMed 26987082]

710. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician. 2012; 15(3 Suppl):S67-116.

711. New York City Department of Health and Mental Hygiene. New York City emergency department discharge opioid prescribing guidelines. From NYC Health website. 2013 Jan.

712. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun.

a. Roche Laboratories Inc. Klonopin (clonazepam) tablets and Klonopin Wafers (clonazepam) orally disintegrating tablets prescribing information. Nutley, NJ; 2001 Jul.

b. AHFS drug information 2003. McEvoy GK, ed. Clonazepam. Bethesda, MD: American Society of Hospital Pharmacists; 2003:2106-9.

c. AHFS drug information 2003. McEvoy GK, ed. Benzodiazepine general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2003:2353-60.

d. AHFS drug information 2003. McEvoy GK, ed. Anticonvulsants general statement. Bethesda, MD: American Society of Hospital Pharmacists; 2003:2097-102.

e. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby; 2002:643-4.

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