Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages 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.
Note: Reduce dose or avoid use in patients receiving opioids, with significant chronic disease (eg, respiratory compromise), or at increased risk for accumulation (eg, hepatic impairment). Generally, avoid use in patients with, or at risk for, substance use disorders; if prescribed, closely supervise use.
Anxiety:
Anxiety and agitation, acute (adjunctive therapy or monotherapy) (off-label use):
Oral: Initial: 0.5 mg/day in 2 divided doses; may be given as needed or scheduled (Fang 2012; Marder 2020; Mojtabai 2020; manufacturer's labeling). May increase dose based on response and tolerability up to 4 mg/day in 2 to 4 divided doses (Roy-Byrne 2020b; manufacturer's labeling). In severe agitation due to psychosis, some experts consider further increasing dose, if needed and tolerated, up to a reported maximum of 8 mg/day in divided doses (Fang 2012).
Anxiety disorder (adjunctive therapy or monotherapy) (alternative agent):
Note: While FDA-approved for panic disorder, clinical trials also support use in other anxiety disorders (Pollack 2014; Wang 2016). Generally used short-term for symptom relief until concurrent therapy is effective (eg, ≤12 weeks). Long-term, low-dose therapy may be used for select patients when other treatments are ineffective or poorly tolerated (Katzman 2014; WFSBP [Bandelow 2012]). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may worsen symptoms (VA/DoD 2017).
Oral: Initial: 0.25 to 1 mg/day in 1 to 2 divided doses; may be given as needed or scheduled. If needed, may increase daily dose based on response and tolerability in increments of 0.25 to 0.5 mg every few days (eg, ≥3 days); usual target range: 1 to 3 mg/day; maximum: 4 mg/day in 1 to 4 divided doses. To minimize daytime motor impairment and drowsiness, may be taken as a single dose at bedtime (Bystritsky 2020; Roy-Byrne 2020a; Roy-Byrne 2020b; Stein 2020; manufacturer's labeling).
Myoclonus (monotherapy or adjunctive therapy) (off-label use):
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 (Caviness 2020; Jankovic 1986; Obeso 1989; Tijssen 1997).
Rapid eye movement sleep behavior disorder (monotherapy or adjunctive therapy) (off-label use):
Oral: Initial: 0.25 to 0.5 mg within 30 minutes of bedtime; usual dose range: 0.25 to 2 mg before bedtime (AASM [Aurora 2010]; Howell 2021). In most patients, 0.5 to 1 mg before bedtime is sufficient and better tolerated than doses >1 mg (Howell 2021).
Note: In patients with dementia, gait disorders, or obstructive sleep apnea, avoid use or reduce dose (eg, initial dose: 0.125 to 0.25 mg before bedtime) (AASM [Aurora 2010]; Fernández-Arcos 2016; Li 2016).
Seizure disorders, refractory (adjunctive therapy or monotherapy) (alternative agent):
Note: FDA-approved for Lennox-Gastaut syndrome and resistant absence seizures; however, also used off label as adjunctive or bridge therapy in other seizure types, including myoclonic and atonic seizures and drug-resistant epilepsy syndromes (Bank 2017; Schachter 2020).
Oral:
Monotherapy: Initial: 0.5 to 1.5 mg/day in 1 to 3 divided doses (Brodie 1997; manufacturer's labeling).
Adjunctive therapy: Initial: 0.5 to 1 mg/day in 1 to 3 divided doses (Schachter 2020).
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 (Brodie 1997; Schachter 2020; manufacturer's labeling).
Tardive dyskinesia (alternative agent) (off-label use):
Note: For reduction of dyskinesia and anxiety in milder forms of tardive dyskinesia in conjunction with appropriate therapy modification(s) such as tapering/discontinuing offending drug (Liang 2021).
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 (Liang 2021; Thaker 1990).
Vertigo, acute episodes, treatment (alternative agent) (off-label use):
Note: Reserve use for episodes lasting several hours to days.
Oral: 0.25 to 0.5 mg every 8 to 12 hours as needed for 24 to 48 hours (Furman 2021; Ganança 2002).
Discontinuation of therapy: In patients receiving extended or higher-dose benzodiazepine therapy, unless safety concerns require a more rapid withdrawal, gradually withdraw to detect reemerging symptoms and minimize rebound and withdrawal symptoms. Taper total daily dose by 10% to 50% every 1 to 2 weeks based on response and tolerability (Bystritsky 2020; Park 2021; VA/DoD 2015). The optimal taper rate and duration will vary; durations up to 6 months may be necessary for some patients. For patients on high doses, taper more rapidly in the beginning and slow the reduction rate as the taper progresses. For example, reduce the dose weekly by 25% until half of the dose remains. Thereafter, continue to reduce by ~12% every 4 to 7 days (VA/DoD 2015).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Clonazepam metabolites may accumulate in patients with renal 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.
(For additional information see "Clonazepam: Pediatric drug information")
Note: If necessary to discontinue clonazepam therapy, drug should be withdrawn gradually.
Neuroirritability, agitation (palliative care): Limited data available: Infants, Children, and Adolescents: Oral:
Patient weight:
<30 kg: Initial: 0.01 to 0.03 mg/kg/day in divided doses up to 3 to 4 times daily; increase dose to desired effect up to a maximum daily dose: 0.2 mg/kg/day in 3 divided doses (Kliegman 2017; Wustoff 2007)
≥30 kg: Initial: ≤0.25 mg/dose 3 times daily; may increase by 0.5 to 1 mg/day every 3 days up to maintenance dose range: 0.05 to 0.2 mg/kg/day up to maximum daily dose: 20 mg/day (Kliegman 2017)
Seizure disorders:
Infants and Children <10 years or ≤30 kg: Oral:
Initial: 0.01 to 0.03 mg/kg/day in 2 to 3 divided doses; maximum initial daily dose: 0.05 mg/kg/day; increase by ≤0.25 to 0.5 mg every third day until seizures are controlled or adverse effects observed
Maintenance dose: 0.1 to 0.2 mg/kg/day in 3 divided doses; maximum daily dose: 0.2 mg/kg/day
Children ≥10 years or >30 kg and Adolescents: Oral:
Initial: 0.01 to 0.05 mg/kg/day in 2 or 3 divided doses; maximum initial dose: 0.5 mg/dose 3 times daily; may increase dose by 25% or by 0.5 to 1 mg every 3 to 7 days until seizures are controlled or adverse effects observed (Kliegman 2017)
Maintenance dose range: 0.05 to 0.2 mg/kg/day in 2 to 3 divided doses; maximum daily dose: 20 mg/day (Kliegman 2017)
Panic disorder: Adolescents ≥18 years: Oral: Initial: 0.25 mg twice daily; increase in increments of 0.125 to 0.25 mg twice daily every 3 days; target dose: 1 mg/day in divided doses; some patients may require higher doses up to a maximum daily dose: 4 mg/day. To discontinue, treatment should be withdrawn gradually; decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Clonazepam metabolites may accumulate in patients with renal 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.
Refer to adult dosing. Initiate with low doses and observe closely.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
KlonoPIN: 0.5 mg [contains corn starch, fd&c yellow #6 aluminum lake]
KlonoPIN: 0.5 mg [DSC] [scored; contains fd&c yellow #6 aluminum lake]
KlonoPIN: 1 mg [contains corn starch, fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]
KlonoPIN: 1 mg [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]
KlonoPIN: 2 mg [DSC]
KlonoPIN: 2 mg [contains corn starch]
Generic: 0.5 mg, 1 mg, 2 mg
Tablet Disintegrating, Oral:
Generic: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Rivotril: 0.5 mg, 2 mg
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
C-IV
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017533s059lbl.pdf#page=19, must be dispensed with this medication.
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.
Oral: 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 (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Panic disorder: Treatment of panic disorder, with or without agoraphobia.
Seizure disorders: Monotherapy 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.
Anxiety and agitation, acute; Anxiety disorder; Myoclonus; Rapid eye movement sleep behavior disorder; Tardive dyskinesia; Vertigo, acute episodes, treatment
ClonazePAM may be confused with ALPRAZolam, cloBAZam, cloNIDine, clorazepate, cloZAPine, LORazepam
KlonoPIN may be confused with cloNIDine, clorazepate, cloZAPine, LORazepam
Beers Criteria: Clonazepam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. Older adults also have a slower metabolism of long-acting benzodiazepines (eg, clonazepam). However, clonazepam may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).
Benzodiazepines can impair explicit memory and produce anterograde amnesia (ie, memory of information or events after drug administration). Retrograde amnesia (ie, events or information prior to drug administration) is unaffected. However, the magnitude of the amnesic effect from benzodiazepines differs among the various agents, depending on their pharmacokinetic/pharmacodynamic properties, route of administration, and dose. Anterograde amnesia is associated with higher doses, IV administration, and benzodiazepines with faster absorption and higher potency (Ref).
Mechanism: Dose-related (Ref). Benzodiazepines, including clonazepam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. The GABA-A receptor complex has subunits, including a benzodiazepine-binding site, which is classified into several types. The BZ1 receptor type, specifically, which is highly concentrated in the cortex, thalamus, and cerebellum, is responsible for benzodiazepine-associated anterograde amnesia (Ref). Of note, clonazepam has a relatively weaker binding affinity for GABA-A receptors compared to other high-potency benzodiazepines (Ref).
Onset: Rapid; during chronic benzodiazepine administration, tolerance appears to develop, and memory impairment is limited to a window of 90 minutes following each dose (Ref)
Risk factors:
• Specific benzodiazepine: Clonazepam, despite its high potency, is less likely to cause anterograde amnesia due to its low lipid solubility (resulting in slower absorption) (Ref)
Clonazepam can cause significant drowsiness and fatigue. Tolerance usually develops to its sedative effects. In addition, clonazepam has been shown to cause ataxia (usually transient) and psychomotor impairment (Ref). Benzodiazepines, in general, are associated with an increased risk of motor vehicle accidents and falls (particularly in older adults) (Ref).
Mechanism: Sedation is dose-dependent (Ref); benzodiazepines, including clonazepam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. The GABA-A receptor complex has subunits, including a benzodiazepine-binding site, which is classified into several types. The BZ1 receptor, specifically, which is highly concentrated in the cortex, thalamus, and cerebellum, is responsible for benzodiazepine-associated sedation (Ref).
Risk factors:
Sedating effects:
• Older adults (Ref)
• Higher doses (Ref)
• Titrating the initial dose too rapidly (gradual titration and dividing the dosing is preferred) (Ref)
• Concomitant use of other CNS depressants (Ref)
Paradoxical reactions, sometimes referred to as disinhibitory reactions or behavioral disinhibition, have been reported in children, adults, and older adults with benzodiazepine use, particularly in those with risk factors. Reactions are relatively uncommon and have been characterized in a number of ways, including increased talkativeness, excitement, restlessness, hyperactivity, sleep disturbances, hostility, rage, agitation, and/or aggressive behavior (Ref). In children, paradoxical reactions to benzodiazepines, particularly midazolam, have been most commonly described as agitation, restlessness, inconsolable crying, screaming, disorientation, and/or excitement (Ref).
Mechanism: Dose-related (potentially, although may also be idiosyncratic); exact mechanism is unclear due to limited evidence (Ref). One hypothesis has suggested that increased GABAergic activity in the brain from benzodiazepines causes a decrease in the restraining influence of the frontal cortex, thereby causing excitement, hostility, and rage. An additional proposed mechanism is that benzodiazepines can reduce 5HT (serotonin) neurotransmission, subsequently causing aggressive behavior. Another mechanism is that in select patients with genetic variations in the gamma-aminobutyric acid (GABA) receptor, there is decreased GABA transmission with benzodiazepines which results in neuronal overexcitation manifested clinically as a paradoxical reaction (Ref).
Risk factors:
Benzodiazepines, in general:
Age-related (extremes of age):
• Children (Ref)
• Older adults (Ref)
Disease- or condition-related:
• Past history of aggressive behavior or violence (Ref)
• Alcoholism or history of alcohol use (Ref)
• Psychiatric or personality disorders, including affective disorder (Ref)
• Dementia (Ref)
Patient-related:
• Genetic predisposition (potential risk factor) (ie, variability in the density of the GABA-benzodiazepine receptors throughout the brain, a persistence of a juvenile pattern of benzodiazepine response in adulthood, or multiple allelic forms of the receptors with varying affinities for benzodiazepines have all been suggested as potentially playing a role) (Ref)
Other potential risk factors: Note: No established risk factors since evidence is limited (Ref)
• Higher doses (likely a risk, but not firmly established) (Ref)
• Parenteral benzodiazepine administration (potential risk) (Ref)
• Specific benzodiazepines (potential risk): Benzodiazepines with a higher potency (eg, clonazepam) and/or a short half-life (eg, alprazolam) are believed to carry an increased risk; however, it has also been suggested that there is no difference in risk among the various benzodiazepines (Ref) Of note, clonazepam is considered to have a relatively long half-life (usually reported at >24 hours for adults) (Ref)
Therapeutic use of benzodiazepines, including clonazepam, is associated with a withdrawal syndrome in children and adults, particularly following abrupt or overly rapid discontinuation following regular use. Benzodiazepine-associated withdrawal symptoms can include new withdrawal symptoms or rebound symptoms, both of which are typically transient, short-lasting, and reversible. A persistent post-withdrawal disorder, which can be long-lasting, severe, and potentially irreversible, has also been described. In general, withdrawal symptoms are typically mild and characterized as anxiety, panic attacks, restlessness, insomnia and other sleep disturbances, irritability, poor concentration, confusion, nausea/vomiting, weight loss, tremor, diaphoresis, tachycardia, and muscle pain/stiffness. Severe symptoms such as seizure and psychosis may also rarely occur following abrupt discontinuation. Severe withdrawal may be fatal. Data are limited on persistent post-withdrawal disorders, but cognitive impairment; depression; anxiety; sensory disturbances (eg, tinnitus, paresthesia, skin sensations); motor disturbances (eg, muscle pain, weakness, spasms); and GI disturbances have been described (Ref). For clonazepam specifically, there are also rare case reports of new-onset withdrawal catatonia occurring after abrupt withdrawal of chronic therapy (Ref). Severity, onset, and duration of any benzodiazepine withdrawal syndrome varies based on several factors, such as specific benzodiazepine administered (and its half-life), dose, and duration of use. However, in general, new withdrawal symptoms typically resolve within 2 to 4 weeks and rebound symptoms may last 3 weeks, but persistent post-withdrawal symptoms may last >6 weeks and take 6 to 12 months to completely resolve, and in some cases, persist for years (Ref).
Mechanism: Withdrawal; exact mechanisms are complex and unclear, but chronic exposure to benzodiazepines alters GABAergic neurotransmission (up/down regulation of gamma-aminobutyric acid [GABA]-A receptor subunits) and rapid or abrupt withdrawal results in underactivity of inhibitory GABA functions subsequently increasing excitatory nervous activity and likely contributing to symptoms associated with withdrawal (Ref). A role of glutamate receptors, including N-methyl-D aspartate (NMDA)-, non-NMDA-receptors, and metabotropic glutamate (mGlu) receptors, has also been suggested. In mice and rat studies, antagonists for NMDA, non-NMDA, and group 1 mGluRs have shown the ability to potently suppress the withdrawal signs caused by chronic benzodiazepine administration (Ref).
Onset: Varied; onset of symptoms usually occurs within the first day following abrupt withdrawal of short- or intermediate-acting benzodiazepines (such a lorazepam). Long-acting benzodiazepines (such as diazepam) are usually associated with an initial onset of withdrawal symptoms 5 days following abrupt discontinuation (Ref). Due to clonazepam’s longer half-life (range in adults: 17 to 60 hours) and slower elimination, clonazepam is usually associated with withdrawal symptoms that are more delayed in onset; in a small number of patients receiving clonazepam for seven consecutive nights for insomnia, significant rebound insomnia was observed on the third withdrawal night following abrupt discontinuation (Ref). In general, persistent post-withdrawal disorder associated with psychotropic medications (eg, benzodiazepines) have an onset ranging from 24 hours to 6 weeks following a decrease, discontinuation, or switch (Ref).
Risk factors:
Benzodiazepines, in general:
• Abrupt discontinuation (rather than gradual dosage reduction) of a benzodiazepine used long-term (Ref)
• Higher doses (Ref)
• Chronic dosing (ie, intermittent dosing may reduce the risk of withdrawal symptoms) (Ref)
• Withdrawal-associated seizure: Predisposed patients (eg, brain damage, alcohol abuse, history of seizure, or those taking medications that lower the seizure threshold) (Ref)
Clonazepam specifically:
• Specific benzodiazepine: Benzodiazepines with a relatively longer half-life (usually reported at >24 hours in adults), such as clonazepam, are usually associated with fewer (and potentially less severe) rebound and withdrawal symptoms, particularly if tapered appropriately. High-potency benzodiazepines with short and intermediate half-lives generally have a higher risk for rebound, withdrawal reactions, and dependence compared to long-acting agents (Ref)
• Ultraslow acetylation of the clonazepam metabolite by the N-acetyltransferase (NAT2) enzyme (potential risk factor; single case report) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reactions reported in patients with panic disorder, unless otherwise noted.
>10%: Nervous system: Ataxia (seizure disorder: ~30%; panic disorder: 1% to 9%) (table 1), behavioral problems (seizure disorder: ~25%), dizziness (5% to 12%), drowsiness (seizure disorder: ~50%; panic disorder: 26% to 50%) (table 2)
|
Drug (Clonazepam) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Clonazepam) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|
|
8% |
0% |
Adults |
≥3 mg/day |
Panic disorder |
235 |
294 |
N/A |
|
8% |
0% |
Adults |
2 to <3 mg/day |
Panic disorder |
113 |
294 |
N/A |
|
2% |
0% |
Adults |
<1 mg/day |
Panic disorder |
96 |
294 |
N/A |
|
1% |
0% |
Adults |
1 to <2 mg/day |
Panic disorder |
129 |
294 |
N/A |
|
9% |
0% |
Adults |
≥3 mg/day |
Panic disorder |
235 |
294 |
Defined as "coordination abnormal" |
|
7% |
0% |
Adults |
2 to <3 mg/day |
Panic disorder |
113 |
294 |
Defined as "coordination abnormal" |
|
2% |
0% |
Adults |
1 to <2 mg/day |
Panic disorder |
129 |
294 |
Defined as "coordination abnormal" |
|
1% |
0% |
Adults |
<1 mg/day |
Panic disorder |
96 |
294 |
Defined as "coordination abnormal" |
|
~30% |
N/A |
N/A |
N/A |
Seizure disorder |
N/A |
N/A |
N/A |
|
Drug (Clonazepam) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Clonazepam) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
50% |
10% |
Adults |
2 to <3 mg/day |
Panic disorder |
113 |
294 |
|
36% |
10% |
Adults |
≥3 mg/day |
Panic disorder |
235 |
294 |
|
35% |
10% |
Adults |
1 to <2 mg/day |
Panic disorder |
129 |
294 |
|
26% |
10% |
Adults |
<1 mg/day |
Panic disorder |
96 |
294 |
|
~50% |
N/A |
N/A |
N/A |
Seizure disorder |
N/A |
N/A |
1% to 10%:
Endocrine & metabolic: Decreased libido (1% to 3%)
Gastrointestinal: Abdominal pain (2%), constipation (3% to 5%), decreased appetite (3%)
Genitourinary: Dysmenorrhea (3% to 6%), impotence (≤3%), urinary frequency (1% to 2%), urinary tract infection (2%), vaginitis (2% to 4%)
Hypersensitivity: Hypersensitivity reaction (2% to 4%)
Infection: Influenza (4% to 5%)
Nervous system: Confusion (1% to 2%), delayed ejaculation (1% to 2%), depression (6% to 8%), dysarthria (2% to 4%), emotional lability (2%), fatigue (6% to 9%), (table 3) memory impairment (4% to 5%), nervousness (3% to 4%), reduced intellectual ability (2% to 4%)
|
Drug (Clonazepam) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Clonazepam) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
9% |
4% |
Adults |
<1 mg/day |
Panic disorder |
96 |
294 |
|
7% |
4% |
Adults |
≥3 mg/day |
Panic disorder |
235 |
294 |
|
7% |
4% |
Adults |
2 to <3 mg/day |
Panic disorder |
113 |
294 |
|
6% |
4% |
Adults |
1 to <2 mg/day |
Panic disorder |
129 |
294 |
Neuromuscular & skeletal: Myalgia (2% to 4%)
Ophthalmic: Blurred vision (2% to 3%)
Respiratory: Bronchitis (2%), cough (2% to 4%), pharyngitis (2% to 3%), rhinitis (2% to 4%), sinusitis (4% to 8%), upper respiratory tract infection (6% to 10%)
<1% (all indications):
Cardiovascular: Ankle edema, chest pain, edema, flushing, leg thrombophlebitis, orthostatic hypotension, palpitations, pedal edema
Dermatologic: Acne flare, alopecia, burning sensation of skin, cellulitis, contact dermatitis, dermal hemorrhage, dermatological reaction, excoriation of skin, pruritus, pustular rash, xeroderma
Endocrine & metabolic: Gout, increased libido, increased thirst, loss of libido, weight gain, weight loss
Gastrointestinal: Abdominal distress, ageusia, dyspepsia, flatulence, frequent bowel movements, gastric distress, gastrointestinal inflammation, heartburn, hemorrhoids, hunger, increased appetite, motion sickness, sialorrhea, toothache
Genitourinary: Bladder dysfunction, cystitis, dysuria, ejaculatory disorder, irregular menses, mastalgia, pelvic pain, urinary incontinence, urinary retention, urinary tract hemorrhage, urine discoloration
Hypersensitivity: Tongue edema
Infection: Candidiasis, fungal infection, herpes simplex infection, infectious mononucleosis, streptococcal infection, viral infection
Local: Local inflammation
Nervous system: 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
Neuromuscular & skeletal: 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
Ophthalmic: Diplopia, eye irritation, hordeolum, periorbital edema, visual disturbance, visual field defect, xerophthalmia
Otic: Otalgia, otitis
Renal: Polyuria
Respiratory: Dyspnea, epistaxis, exacerbation of asthma, hoarseness, pleurisy, pneumonia, sneezing
Miscellaneous: Accidental injury, burn, fever, wound
Frequency not defined (all indications):
Nervous system: Drug dependence, suicidal tendencies, withdrawal syndrome
Miscellaneous: Paradoxical reaction (including, agitation, hallucination, hostility, irritability, sleep disturbance, vivid dreams)
Postmarketing (all indications):
Cardiovascular: Facial edema
Dermatologic: Skin rash (Munoli 2012)
Endocrine & metabolic: Dehydration, hirsutism
Gastrointestinal: Anorexia, coated tongue, diarrhea, encopresis, gastritis, gingival pain, nausea, xerostomia
Genitourinary: Nocturia
Hematologic & oncologic: Anemia, eosinophilia, leukopenia, lymphadenopathy, pancytopenia (Bautista-Quach 2010), thrombocytopenia (Veall 1975)
Hepatic: Hepatomegaly, increased serum alkaline phosphatase (transient), increased serum transaminases (transient)
Nervous system: Abnormal behavior (increased oppositional behavior) (Waslick 2006), anterograde amnesia, aphonia, catatonia (with withdrawal) (Oldham 2016), choreiform movements, coma, glassy-eyed appearance, headache, hemiparesis, hypotonia, hysteria, myasthenia, parasomnias (sleep-related eating disorder) (Ghosh 2018), psychomotor impairment (Wilden 1990), psychosis, slurred speech
Neuromuscular & skeletal: Dysdiadochokinesia, muscle injury (myotoxicity) (Han 2019)
Ophthalmic: Abnormal eye movements, nystagmus disorder
Respiratory: Chest congestion, respiratory depression (Channing 2012), rhinorrhea, upper respiratory system symptoms (hypersecretion)
Miscellaneous: Physical health deterioration
Hypersensitivity to clonazepam, other benzodiazepines, or any component of the formulation; significant liver disease; acute narrow-angle glaucoma
Canadian labeling: Additional contraindications (not in US labeling): Severe respiratory insufficiency; sleep apnea syndrome; myasthenia gravis
Concerns related to adverse effects:
• 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 (Dolder 2008).
• 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 health care provider immediately if symptoms occur.
Disease-related concerns:
• Depression: Use caution in patients with depression, particularly if suicidal risk may be present.
• 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 (eg, chronic obstructive pulmonary disease, sleep apnea) and in patients who have difficulty handling secretions.
Concurrent drug therapy issues:
• Flumazenil: Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Special populations:
• Debilitated patients: Use with caution in debilitated patients.
• Elderly patients: Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls.
Dosage form specific issues:
• Phenylalanine: Some products contain phenylalanine.
Other warnings/precautions:
• Abuse, misuse, and addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Worsening of seizures may occur when added to patients with multiple seizure types. Loss of anticonvulsant activity may occur (typically within 3 months of initiation); dose adjustment may be necessary. 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.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cosyntropin: May enhance the hepatotoxic effect of ClonazePAM. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of ClonazePAM. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of ClonazePAM. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or 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. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy
Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Vigabatrin: May enhance the CNS depressant effect of ClonazePAM. Vigabatrin may increase the serum concentration of ClonazePAM. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: 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. Risk D: Consider therapy modification
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 pregnant females 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). When treating pregnant females with panic disorder, psychosocial interventions should be considered prior to pharmacotherapy (APA 2009).
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.
Clonazepam is present in breast milk.
The relative infant dose (RID) of clonazepam is 2.8% when calculated using the highest breast milk concentration from a case report and compared to a weight-adjusted maternal dose of 4 mg/day.
In general, breastfeeding is considered acceptable when an RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).
The RID of clonazepam was calculated using a milk concentration of 0.0107 mcg/mL, providing an estimated daily infant dose via breast milk of 1.6 mcg/kg/day. This milk concentration was obtained following maternal administration of clonazepam 2 mg twice daily during pregnancy and after delivery; milk samples were obtained on days 2 to 4 postpartum (Söderman 1988). Slightly higher milk concentrations (0.013 mcg/mL) were noted in a second report. The mother was taking clonazepam throughout pregnancy (dose not specified); milk sampling began 72 hours after delivery (Fisher 1985). Clonazepam was detected in the serum of the breastfeeding infants (Fisher 1985; Söderman 1988) and concentrations may have been influenced not only by breast milk but also by in utero exposure.
Apnea, CNS depression, hypotonia, and somnolence have been reported in infants exposed to clonazepam via breast milk (Fisher 1985; Kelly 2012; Soussan 2014). In a review of females taking various doses of clonazepam (range: 0.5 to 2 mg/day) during pregnancy and postpartum (n=10) or only postpartum (n=1), clonazepam was measurable in the serum of two infants; however, adverse events were not reported (Birnbaum 1999).
Clonazepam has a long half-life and may accumulate in the breastfed infant, especially preterm infants or those exposed to chronic maternal doses (Davanzo 2013). A single maternal dose may be compatible with breastfeeding (WHO 2002). If chronic use of a benzodiazepine is needed in breastfeeding females, use of shorter acting agents is preferred (Davanzo 2013; Veiby 2015; WHO 2002). Infants of females using medications for seizure disorders should be monitored for drowsiness, decreased feeding, and poor weight gain (Veiby 2015). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Some products may contain phenylalanine.
Mental alertness, CBC, liver and renal function tests (periodically with long-term therapy), suicidality (eg, suicidal thoughts, depression, behavioral changes).
Relationship between serum concentration and dose is not well established. Therapeutic doses have been associated with serum concentrations of ~20 to 70 ng/mL (Patsalos 2018).
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.
Onset of action: ~20 to 40 minutes (Hanson 1972).
Duration: Infants and young children: 6 to 8 hours (Hanson 1972); Adults: ≤12 hours (Hanson 1972).
Absorption: Rapidly and completely absorbed.
Distribution: Children: Vd: 1.5 to 3 L/kg (Walson 1996); Adults: Vd: 1.5 to 6.4 L/kg (Walson 1996).
Protein binding: ~85%.
Metabolism: Extensively hepatic via glucuronide and sulfate conjugation; undergoes nitroreduction to 7-aminoclonazepam, followed by acetylation to 7-acetamidoclonazepam; nitroreduction and acetylation are via CYP3A4; metabolites undergo glucuronide and sulfate conjugation (Patsalos 2018).
Bioavailability: ~90%.
Half-life elimination: Neonates: 22 to 81 hours (Patsalos 2018); Children: 22 to 33 hours (Walson 1996); Adults: 17 to 60 hours (Walson 1996).
Time to peak, serum: 1 to 4 hours.
Excretion: Urine (<2% as unchanged drug); metabolites excreted as glucuronide or sulfate conjugates.
Tablet, orally-disintegrating (clonazePAM Oral)
0.125 mg (per each): $1.30
0.25 mg (per each): $1.30
0.5 mg (per each): $1.30
1 mg (per each): $1.48
2 mg (per each): $2.05
Tablets (clonazePAM Oral)
0.5 mg (per each): $0.75
1 mg (per each): $0.86
2 mg (per each): $1.18
Tablets (KlonoPIN Oral)
0.5 mg (per each): $3.06
1 mg (per each): $3.49
2 mg (per each): $4.84
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