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ClonazePAM


General


Pronunciation

(kloe NA ze pam)


Brand Names: U.S.

  • KlonoPIN

Indications


Use: Labeled Indications

Panic disorder: Treatment of panic disorder, with or without agoraphobia.

Seizure disorders: Mono- or adjunctive therapy in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures; absence seizures (petit mal) unresponsive to succinimides.


Contraindications


Hypersensitivity to clonazepam, other benzodiazepines, or any component of the formulation; significant liver disease; acute narrow-angle glaucoma


Dosing and Administration


Dosing: Adult

Panic disorder: Oral: 0.25 mg twice daily; increase in increments of 0.125 to 0.25 mg twice daily every 3 days; target dose: 1 mg daily (maximum: 4 mg daily).

Discontinuation of treatment: To discontinue, treatment should be withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.

Seizure disorders: Oral:

Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5 to 1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg daily).

Usual maintenance dose: 2 to 8 mg daily in 1 to 2 divided doses (Brodie 1997); do not exceed 20 mg daily.

Bipolar disorder, mixed or manic episodes (off-label use): Oral: 2 to 8 mg daily, in 2 to 4 divided doses; total daily doses as high as 16 mg have been studied (Bottai 1995; Chouinard 1983; Clark 1997; Edwards 1991; WFSBP [Grunze 2009]).

Burning mouth syndrome (off-label use):

Oral: Initial: 0.25 at bedtime for 1 week; increase dose by ≤0.25 mg every week; maximum dose: 3 mg daily in 3 divided doses. Note: Use should be limited (Buchanan 2008; Grushka 1998).

Topical: May administer topically with 1 mg 3 times daily (after each meal). Note: Patient should be instructed to suck on the tablet, retain saliva in mouth near the pain sites without swallowing for 3 minutes, and then expectorate saliva (Gremeau-Richard 2004).

Essential tremor (off-label use): Oral: Initial: 0.5 mg at bedtime; increase dose by 0.5 mg every 3 to 4 days; maximum dose: 6 mg daily (Biary 1987; Thompson 1984; Zesiewicz 2005; Zesiewicz 2011).

REM sleep behavior disorder (off-label use): 0.25 to 2 mg 30 minutes prior to bedtime (maximum: 4 mg 30 minutes prior to bedtime). Note: Use with caution in patients with dementia, gait disorders, or obstructive sleep apnea (Aurora 2010).

Restless legs syndrome (off-label use): Oral: Initial: 1 mg 30 minutes before bedtime; increase dose by 0.5 to 1 mg at weekly intervals; doses up to 2 mg/day have been evaluated in clinical trials (Montagna 1984; Peled 1987; Saletu 2001).

Tardive dyskinesia (off-label use): Oral: Initial: 1 mg/day; adjust dosage based on response and tolerability by 1 mg/day every 3 to 4 days up to a maximum dose of 4.5 mg/day (Thaker 1990).

Tic disorders (off-label use): Oral: Initial: 0.5 mg at bedtime; adjust dose by 0.5 mg every 2 weeks based on response and tolerability. Dosing range in clinical studies was 1 to 12 mg/day (Merikangas 1985; Troung 1988).


Dosing: Geriatric

Refer to adult dosing. Initiate with low doses and observe closely.


Dosing: Pediatric

Seizure disorders: Oral:

Children <10 years or <30 kg:

Initial daily dose: 0.01 to 0.03 mg/kg/day (maximum: 0.05 mg/kg/day) given in 2 to 3 divided doses; increase by no more than 0.25 to 0.5 mg every third day until seizures are controlled or adverse effects seen.

Usual maintenance dose: 0.1 to 0.2 mg/kg/day divided 3 times daily; not to exceed 0.2 mg/kg/day.

Children >10 years or ≥30 kg and Adolescents: Refer to adult dosing.


Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer 's labeling; use with caution. Clonazepam metabolites may accumulate in patients with renal impairment.


Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer 's labeling; use with caution. Clonazepam undergoes hepatic metabolism. Contraindicated in patients with significant hepatic impairment.


Administration

To reduce somnolence, administration of one dose at bedtime may be desirable.

Orally-disintegrating tablet: Open pouch and peel back foil on the blister; do not push tablet through foil. Use dry hands to remove tablet and place in mouth. May be swallowed with or without water. Use immediately after removing from package.

Tablet: Swallow whole with water.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).


Storage

Tablets: Store at 20 � �C to 25 � �C (68 � �F to 77 � �F).

Orally disintegrating tablets: Store at 25 � �C (77 � �F); excursions permitted between 15 � �C and 30 � �C (59 � �F and 80 � �F)


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

KlonoPIN: 0.5 mg [scored; contains fd&c yellow #6 aluminum lake]

KlonoPIN: 1 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]

KlonoPIN: 2 mg

Generic: 0.5 mg, 1 mg, 2 mg

Tablet Dispersible, Oral:

Generic: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg


Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

A 0.1 mg/mL oral suspension may be made with tablets and one of three different vehicles (cherry syrup; a 1:1 mixture of Ora-Sweet � � and Ora-Plus � �; or a 1:1 mixture of Ora-Sweet � � SF and Ora-Plus � �). Crush six 2 mg tablets in a mortar and reduce to a fine powder. Add 10 mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well " � and "protect from light " �. Stable for 60 days when stored in amber prescription bottles in the dark at room temperature or refrigerated.

Allen LV Jr and Erickson MA 3rd, Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm 1996, 53(16):1944-9.[PMID: 8862208]

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of ClonazePAM. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Cosyntropin: May enhance the hepatotoxic effect of ClonazePAM. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vigabatrin: May enhance the CNS depressant effect of ClonazePAM. Vigabatrin may increase the serum concentration of ClonazePAM. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Monitor therapy

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. Consider therapy modification


Monitoring Parameters

CBC, liver and renal function tests (periodically with long-term therapy) suicidality (eg, suicidal thoughts, depression, behavioral changes)


Adverse Reactions


Reactions reported in patients with seizure disorder, unless otherwise noted. Frequency not always defined.

>10%: Central nervous system: Drowsiness (seizure disorder: ~50%; panic disorder: 26% to 50%), ataxia (seizure disorder: ~30%; panic disorder: 1% to 9%), behavioral problems (seizure disorder: ~25%), dizziness (panic disorder: 5% to 12%)

1% to 10%:

Central nervous system: Fatigue (panic disorder: 6% to 9%), depression (panic disorder: 6% to 8%), memory impairment (panic disorder: 4% to 5%), nervousness (panic disorder: 3% to 4%), dysarthria (panic disorder: ≤4%), reduced intellectual ability (panic disorder: ≤4%), emotional lability (panic disorder: 2%), confusion (panic disorder: ≤2%), delayed ejaculation (panic disorder ≤2%)

Endocrine & metabolic: Decreased libido (panic disorder: ≤3%)

Gastrointestinal: Constipation (panic disorder: 3% to 5%), decreased appetite (panic disorder: 3%), abdominal pain (panic disorder: 2%)

Genitourinary: Dysmenorrhea (panic disorder: 3% to 6%), vaginitis (panic disorder: 2% to 4%), impotence (panic disorder: ≤3%), urinary tract infection (panic disorder: ≤2%), urinary frequency (panic disorder: 1% to 2%)

Hypersensitivity: Hypersensitivity (panic disorder: 2% to 4%)

Neuromuscular & skeletal: Myalgia (panic disorder: 2% to 4%)

Ophthalmic: Blurred vision (panic disorder: 2% to 3%)

Respiratory: Upper respiratory tract infection (panic disorder: 6% to 10%), sinusitis (panic disorder: 4% to 8%), influenza (panic disorder: 4% to 5%), cough (panic disorder: ≤4%), rhinitis (panic disorder: 2% to 4%), pharyngitis (panic disorder: 2% to 3%), bronchitis (panic disorder: 2%)

Frequency not defined:

Cardiovascular: Edema (ankle or facial), palpitations

Central nervous system: Amnesia, aphonia, choreiform movements, coma, glassy-eyed appearance, hallucination, headache, hemiparesis, hypotonia, hysteria, insomnia, myasthenia, psychosis, slurred speech, vertigo

Dermatologic: Alopecia, skin rash

Endocrine & metabolic: Dehydration, hirsutism, increased libido, weight gain, weight loss

Gastrointestinal: Anorexia, coated tongue, diarrhea, encopresis, gastritis, gingival pain, increased appetite, nausea, xerostomia

Genitourinary: Dysuria, nocturia, urinary incontinence, urinary retention

Hematologic & oncologic: Anemia, eosinophilia, leukopenia, lymphadenopathy, thrombocytopenia

Hepatic: Hepatomegaly, increased serum alkaline phosphatase (transient), increased serum transaminases (transient)

Neuromuscular & skeletal: Dysdiadochokinesia, tremor

Ophthalmic: Abnormal eye movements, diplopia, nystagmus

Respiratory: Chest congestion, dyspnea, respiratory depression, rhinorrhea, upper respiratory complaint (hypersecretion)

Miscellaneous: Fever, paradoxical reactions (including aggressive behavior, agitation, anxiety excitability, hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams), physical health deterioration

<1% (Limited to important or life-threatening; any indication): Bone fracture, candidiasis, cellulitis, chest pain, cystitis, depersonalization, disinhibition (organic), exacerbation of asthma, fungal infection, gout, herpes simplex infection, infectious mononucleosis, migraine, orthostatic hypotension, pleurisy, pneumonia, streptococcal infection, suicidal ideation, suicidal tendencies, viral infection, visual field defect


Warnings/Precautions


Concerns related to adverse effects:

- Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).

- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

- Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients (Mancuso 2004).

- Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 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; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

- Depression: Use caution in patients with depression, particularly if suicidal risk may be present.

- Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

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

- Hepatic impairment: Use with caution in patients with hepatic impairment; accumulation likely to occur. Contraindicated in patients with significant hepatic impairment.

- Porphyria: Use with caution in patients with porphyria; may have a porphyrogenic effect.

- Renal impairment: Use with caution in patients with renal impairment; clonazepam metabolites are renally eliminated.

- Respiratory disease: Clonazepam may cause respiratory depression and may produce an increase in salivation; use with caution in patients with compromised respiratory function and in patients who have difficulty handling secretions.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

- Debilitated patients: Use with caution in debilitated patients.

- Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

Special handling:

- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

- Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Worsening of seizures may occur when added to patients with multiple seizure types. Periodically reevaluate the long-term usefulness of clonazepam for the individual patient.

- Tolerance: Clonazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the anticonvulsant effects. It does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

- Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy (Brogden 1988).


Pregnancy Risk Factor

D


Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Clonazepam crosses the placenta. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and "floppy infant syndrome " � (which also includes withdrawal symptoms) has been reported with some benzodiazepines, including clonazepam (Bergman 1992; Iqbal 2002; Wikner 2007). A combination of factors influences the potential teratogenicity of anticonvulsant therapy. When treating women with epilepsy, monotherapy with the lowest effective dose and avoidance medications known to have a high incidence of teratogenic effects is recommended (Harden 2009; Wlodarczyk 2012).

Patients exposed to clonazepam during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.


Actions


Pharmacology

The exact mechanism is unknown, but believed to be related to its ability to enhance the activity of GABA; suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex.


Absorption

Rapidly and completely absorbed


Distribution

Children: Vd: 1.5 to 3 L/kg (Walson 1996); Adults: Vd: 1.5 to 64.4 L/kg (Walson 1996)


Metabolism

Extensively hepatic via glucuronide and sulfate conjugation; undergoes nitroreduction to 7-aminoclonazepam, followed by acetylation to 7-acetamidoclonazepam; nitroreduction and acetylation are via cytochrome P450 enzyme system; metabolites undergo glucuronide and sulfate conjugation


Excretion

Urine (<2% as unchanged drug); metabolites excreted as glucuronide or sulfate conjugates


Onset of Action

~20 to 40 minutes (Hanson 1972)


Time to Peak

Serum: 1 to 4 hours


Duration of Action

Infants and young children: 6 to 8 hours (Hanson 1972); Adults: ≤12 hours (Hanson 1972)


Half-Life Elimination

Children: 22 to 33 hours (Walson 1996); Adults: 17 to 60 hours (Walson 1996)


Protein Binding

~85%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience fatigue, constipation, drooling, or dizziness. Have patient report immediately to prescriber shortness of breath, change in balance, confusion, severe loss of strength and energy, memory impairment, seizures, signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), agitation, irritability, panic attacks, or mood changes (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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