VA Class:CN400

VA Class:CN302

AHFS Class:

• Benzodiazepines 28:12.08

Generic Name(s):

• clonazePAM

Associated Monographs

• Benzodiazepines General Statement

Clonazepam is a benzodiazepine derivative that is used both as an anticonvulsant and for the treatment of panic disorder with or without agoraphobia.

Seizure Disorders

Clonazepam is used in the prophylactic management of Lennox-Gastaut syndrome (petit mal variant epilepsy) and akinetic and myoclonic seizures. The drug also may be used in the management of absence (petit mal) seizures in patients who have not responded to succinimides. In some patients, use of clonazepam may permit reduction in dosage or discontinuance of other anticonvulsants; however, paradoxical increases in seizure activity also have occurred. (See Cautions: Precautions and Contraindications.) A decreased response to the drug may occur after several months or years of clonazepam therapy; however, seizures may be less severe than those before clonazepam therapy. In some patients, dosage adjustment may restore efficacy.

Most studies to date on the use of clonazepam have been uncontrolled and have involved patients with seizures refractory to other anticonvulsants. In addition, clonazepam has been used mainly as an adjunct to other drugs. For these reasons, determination of the precise role of clonazepam in the management of seizure disorders must await the results of well-controlled comparative studies.

Clonazepam has been used with some success in other refractory seizures†, including partial seizures with complex symptomatology (psychomotor seizures) and other partial (focal) seizures and some cases of infantile spasms. Clonazepam also has been useful in some patients with tonic-clonic (grand mal) seizures†; however, when used in patients with multiple types of seizure disorders, the drug may increase the frequency of or precipitate tonic-clonic seizures in some patients. If this occurs, addition of another anticonvulsant and/or increase in dosage may be required.

IV clonazepam has been used with good results in the management of status epilepticus†; however, a parenteral dosage form of the drug is not currently commercially available in the US.

Panic Attacks and Disorder

Clonazepam is used in the treatment of panic disorder with or without agoraphobia.1,3 Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a clinically important change in behavior related to the attacks.1,2

According to DSM-IV, panic disorder is characterized by recurrent unexpected panic attacks, which consist of a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; fear of dying; paresthesias (numbness or tingling sensations); and chills or hot flushes.1,2

The efficacy of clonazepam for the management of panic disorder has been established by 2 multicenter, double-blind, placebo-controlled studies of 6-9 weeks' duration in adult outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia.1,3,4 In these studies, clonazepam was found to be superior to placebo on the following measures of efficacy: change from baseline in panic attack frequency, the Clinician's Global Impression Severity of Illness Score, and the Clinician's Global Impression Improvement Score.1,3

The first study was a fixed-dose study of 9 weeks' duration involving clonazepam dosages of 0.5, 1, 2, 3, or 4 mg daily.1,3 This study was conducted in 4 phases: a 1-week placebo run-in phase, a 3-week phase of upward titration of the dosage, a 6-week fixed-dosage maintenance phase, and a 7-week discontinuance phase.1,3 A substantial difference from placebo was observed consistently only in the group receiving 1 mg of clonazepam daily; the difference between the reduction from baseline in the number of full panic attacks was approximately 1 per week in patients receiving clonazepam 1 mg daily compared with placebo.1,3 At the study end point (the end of the fixed-dosage maintenance phase), 74% of patients receiving clonazepam 1 mg daily were free of panic attacks compared to 56% of patients receiving placebo.1,3 Daily dosages exceeding 1 mg were less effective and more commonly associated with adverse effects (e.g., somnolence and ataxia) in this study.1

The second study was of 6 weeks' duration and used a flexible dosing schedule involving clonazepam dosages ranging from 0.5-4 mg daily.1,4 The study was conducted in 3 phases: a 1-week placebo run-in phase, a 6-week optimal dose-finding phase, and a 6-week discontinuance phase.1,4 The mean clonazepam dosage during the optimal dosing period was 2.3 mg daily.1,4 The difference between the reduction from baseline in the number of full panic attacks was approximately 1 per week in patients receiving clonazepam compared with placebo.1,4 At the study end point, 62% of patients receiving clonazepam were free of panic attacks compared with 37% of patients receiving placebo.1,4

Subgroup analysis from these 2 controlled studies for possible race- or gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the race or gender of the patient.1

The manufacturer states that the efficacy of clonazepam for long-term use (i.e., longer than 9 weeks) has not been systematically evaluated in controlled studies.1 However, limited information from follow-up studies of patients with panic disorder who responded favorably to benzodiazepine therapy indicates that the benefits observed during short-term therapy are usually maintained for longer periods (e.g., up to several years) without increases in dosage.15,16,17,20,21 In an open study in which patients with panic disorder were treated with clonazepam over a 2-year period, clonazepam produced and maintained a therapeutic benefit without evidence of tolerance development (as manifested by dosage escalation or worsening of clinical status).15 The manufacturer states that there is insufficient experience concerning how long patients with panic disorder who are treated with clonazepam should remain on the drug.1 However, some clinicians state that panic disorder is a chronic condition; therefore, it may be reasonable to continue therapy in responding patients.5,10,19,20,21 If clonazepam is used for extended periods, the need for continued therapy with the drug should be reassessed periodically.1 (See Dosage and Administration: Dosage.)

Panic disorder can be treated with cognitive behavioral psychotherapy and/or pharmacologic therapy.5,6,7,8,10,12,26,27,28 Currently, there are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants (e.g., imipramine, clomipramine), monoamine oxidase inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (e.g., venlafaxine), and benzodiazepines (e.g., alprazolam, clonazepam).6,7,8,9,10,11,12,14,26,27,28 When choosing among the available drugs in the treatment of panic disorder, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); their cost; and their ability to prevent relapse during long-term therapy.6,7,8,10,11,12,13,26,27,28

Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines) and the lack of physical dependence problems commonly associated with benzodiazepines, some clinicians currently prefer selective serotonin-reuptake inhibitors as first-line therapy in the management of panic disorder.6,7,9,10,11,12,13,14,28 However, benzodiazepines such as clonazepam have a more rapid onset of action often with immediate reduction of panic symptoms, whereas antidepressants may require several weeks or more for therapeutic effect.8,27,28 Therefore, benzodiazepines can be used for early symptom control (usually in combination with another form of treatment such as cognitive behavioral therapy or antidepressant therapy) and are useful in relieving anticipatory anxiety.27,28 Benzodiazepines also can be used to treat surges of anxiety or panic, although some experts state that this as-needed use of benzodiazepines should not replace the use of adequate daily dosages when clinically necessary.8 In addition, some clinicians consider the anxiolytic effect of benzodiazepines advantageous in reducing anxiety between panic attacks.8 The most serious risk factor associated with benzodiazepines in panic disorder is physical dependence; withdrawal symptoms or a recurrence of panic symptoms may occur during drug tapering or following abrupt discontinuance of therapy.1,8,28 Therefore, gradual discontinuance of clonazepam therapy is advised.1,8 (See Chronic Toxicity and see also Dosage and Administration.) In addition, as with other benzodiazepines, clonazepam can produce sedation and psychomotor impairment and potentially may interact with alcohol if it is not restricted.1,8 (See Cautions: Precautions and Contraindications.)

Schizophrenia

Clonazepam also has been used in patients who experience akathisia† while receiving antipsychotic drugs (e.g., for management of schizophrenia) and for the treatment of acute catatonic reactions†, whether associated with schizophrenia or other conditions.529 (See Uses: Schizophrenia, in the Benzodiazepines General Statement 28:24.08.)

Other Uses

The efficacy of clonazepam as a hypnotic† has not been fully evaluated.

Administration

Clonazepam is administered orally.

Clonazepam conventional tablets should be administered with water and swallowed whole. The orally disintegrating tablets should be administered immediately after opening the pouch and peeling back the blister; do not push the tablet through the foil. The orally disintegrating tablet should be removed with a dry hand and placed on the tongue, where it disintegrates rapidly in saliva, and then subsequently can be swallowed with or without water.

In the treatment of seizure disorders, the manufacturer states that daily dosage usually is given in 3 equally divided doses. The largest dose should be given at bedtime if doses are not equally divided.

In the treatment of panic disorder, the daily dosage of clonazepam may be given in 2 equally divided doses.1,28 Alternatively, the drug may be given as one dose at bedtime to reduce the inconvenience of somnolence.1,28

Clonazepam also has been administered IV†, but a parenteral dosage form is not currently commercially available in the US.

Patients who are currently receiving or beginning therapy with clonazepam and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.23,24,25,29,30 (See Cautions: CNS Effects and Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.)

Dosage

Dosage of clonazepam must be carefully and slowly adjusted according to individual requirements and response. Clonazepam should be withdrawn slowly, and abrupt discontinuance of the drug should be avoided, especially during long-term, high-dose therapy to avoid precipitating seizures, status epilepticus, or withdrawal symptoms. If clonazepam is to be discontinued in patients who have received prolonged therapy with the drug, it is recommended that dosage be tapered gradually. Addiction-prone patients (e.g., alcoholic patients, individuals known to have been dependent on other drugs) should be carefully monitored while receiving clonazepam or other psychotropic therapy because of the predisposition of these patients to habituation and addiction. During clonazepam withdrawal, simultaneous substitution of another anticonvulsant may be indicated.

Seizure Disorders

Various clonazepam dosage regimens have been used in published studies. The manufacturer states that the usual initial dosage for infants and children up to 10 years of age or weighing up to 30 kg is 0.01-0.03 mg/kg daily. Initial pediatric dosage should not exceed 0.05 mg/kg daily given in 2 or 3 divided doses. Dosage may be increased by no more than 0.5 mg every third day until seizure control is achieved with minimal adverse effects. Pediatric maintenance dosage should not exceed 0.2 mg/kg daily.

Initial adult dosage of clonazepam should not exceed 1.5 mg daily given in 3 equally divided doses. Dosage may be increased in increments of 0.5-1 mg every third day until seizure control is achieved with minimal adverse effects. Adult maintenance dosage should not exceed 20 mg daily.

Panic Disorder

For the management of panic disorder in adults, the recommended initial dosage of clonazepam is 0.25 mg twice daily.1 An increase to the target dose for most patients of 1 mg daily may be made after 3 days.1 The manufacturer states that the recommended dosage of 1 mg daily is based on the results of a fixed-dose study in which the optimal therapeutic effect was seen at this dosage.1,3 In this study, higher dosages of 2, 3, and 4 mg daily were found to be less effective than the 1 mg daily dosage and more commonly associated with adverse effects (e.g., somnolence and ataxia).1,3 Some clinicians recommend a dosage of 1-2 mg daily in patients with panic disorder3,28 and the manufacturer states that certain individual patients may benefit from dosages up to a maximum of 4 mg daily.1 In such cases, the dosage of clonazepam may be increased in increments of 0.125-0.25 mg twice daily every 3 days until panic disorder is controlled or until adverse effects make further increases in dosage undesirable.1

The manufacturer states that the efficacy of clonazepam for long-term use (i.e., longer than 9 weeks) has not been systematically evaluated in controlled studies.1 However, limited information from follow-up studies of patients with panic disorder who responded favorably to benzodiazepine therapy indicate that the benefits observed during short-term therapy usually are maintained for longer periods without increases in dosage.15,16,17,20,21 In an open study in which patients with panic disorder were treated with clonazepam over a 2-year period, clonazepam produced and maintained a therapeutic benefit without evidence of tolerance development (as manifested by dosage escalation or worsening of clinical status).15 The manufacturer states that there is insufficient experience concerning how long patients with panic disorder who are treated with clonazepam should remain on the drug.1 However, some clinicians state that panic disorder is a chronic condition; therefore, it may be reasonable to continue therapy in responding patients.5,10,19,20,21 If clonazepam is used for extended periods, the need for continued therapy with the drug should be reassessed periodically.1

When clonazepam therapy is to be discontinued in patients with panic disorder, the manufacturer states that therapy should be gradually discontinued by decreasing the dosage by 0.125 mg twice daily every 3 days until the drug is completely withdrawn.1

Dosage in Renal and Hepatic Impairment

The effect of renal impairment on clonazepam elimination is not known.

The possibility that clonazepam dosage adjustment may be necessary in patients with hepatic impairment should be considered.

A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900

Nervous System Effects

The most frequent adverse effects of clonazepam are sedation or drowsiness, ataxia or hypotonia, and behavioral disturbances (principally in children) including aggressiveness, irritability, agitation, and hyperkinesis. In one study, some patients experienced euphoria that was followed by dysphoria. Tolerance to clonazepam varies considerably among patients and is not necessarily dose related. Behavioral disturbances are most likely to occur in patients with preexisting brain damage and/or mental retardation or a history of behavioral or psychiatric disturbances; however, the precise role of clonazepam in inducing behavioral changes in these patients is difficult to assess. It has been suggested that methylphenidate or amphetamines may be useful to control behavioral disturbances if they occur. Drowsiness, ataxia, and behavioral disturbances are most severe during initial therapy and frequently decrease or disappear during continued therapy. It has been suggested that these adverse effects may be minimized by starting with low dosages and gradually increasing dosage over a 2-week period and by administering the drug in divided doses daily. In some patients, however, these adverse effects have necessitated discontinuance of clonazepam.

Adverse neurologic effects of clonazepam include abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, glassy-eyed appearance, headache, hemiparesis, nystagmus, respiratory depression, slurred speech, tremor, dizziness, and vertigo. Clonazepam also may cause confusion, mental depression, forgetfulness, hallucinations, hysteria, increased libido, insomnia, psychosis, or suicidal tendencies. (See Cautions: Precautions and Contraindications.) Muscle weakness and pains also may occur.

Respiratory Effects

Increased salivation, hypersecretion in upper respiratory passages, chest congestion, rhinorrhea, and shortness of breath may occur in patients receiving clonazepam. In one study, increased salivation, mucous obstruction of the nasopharynx and bronchi, and difficulty in swallowing occurred in infants receiving the drug. The investigator reported that these effects occurred most frequently when clonazepam was used in conjunction with phenobarbital.

Dermatologic Effects

Dermatologic reactions, including hair loss, hirsutism, skin rash, and ankle and facial edema, have been reported in patients receiving clonazepam. Rarely, abnormal skin pigmentation has been reported in patients receiving clonazepam and phenytoin.

GI Effects

Adverse GI effects of clonazepam include constipation, diarrhea, encopresis, gastritis, increased or decreased appetite, weight gain or loss, dyspepsia, nausea, coated tongue, dry mouth, abnormal thirst, and sore gums.

Genitourinary Effects

Adverse genitourinary effects of clonazepam include dysuria, enuresis, nocturia, and urinary retention.

Hematologic Effects

Adverse hematologic effects of clonazepam include anemia, leukopenia, thrombocytopenia, and eosinophilia.

Hepatic Effects

Hepatomegaly and transient elevations of serum aminotransferase and alkaline phosphatase concentrations may occur in patients receiving clonazepam.

Other Adverse Effects

Other reported adverse effects include palpitations, dehydration, general deterioration, fever, and lymphadenopathy. Abnormal retinal vascularization without visual impairment was reported in one patient who received clonazepam and other anticonvulsants.

Precautions and Contraindications

Clonazepam shares the toxic potential of other benzodiazepines, and the usual cautions, precautions, and contraindications of benzodiazepine therapy should be followed. (See Cautions in the Benzodiazepines General Statement 28:24.08.)

Concomitant use of benzodiazepines, including clonazepam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,703,705,706,707 Patients receiving clonazepam and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines and opiates.700,703 (See Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Depressants.)

Benzodiazepines have the potential to impair judgment, thinking, or motor skills.1 Therefore, patients receiving clonazepam should be cautioned that the drug may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they experience how the drug affects them.1

Patients receiving clonazepam should be advised to avoid alcohol while receiving the drug.1 In addition, they should be advised to notify their clinician if they are taking or plan to take nonprescription (over-the-counter) or prescription medications or alcohol-containing beverages or preparations.1

Clinicians should inform patients, their families, and caregivers about the potential for an increased risk of suicidal thinking and behavior (suicidality) associated with anticonvulsant therapy.23,30 For a complete discussion, see Cautions: CNS Effects and Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.

When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic (grand mal) seizures.1 This may require the addition of appropriate anticonvulsants or an increase in their dosages.1 The concomitant use of valproic acid and clonazepam may produce absence status.1

Because clonazepam may increase salivation, it should be used with caution in patients in whom increased secretions might be harmful. The manufacturer states that the drug also should be used with caution in patients with chronic respiratory disease or impaired renal function. Periodic blood counts and liver function tests should be performed in patients receiving long-term clonazepam therapy.

The manufacturer states that clonazepam is contraindicated in patients with clinical or biochemical evidence of significant hepatic impairment or a history of sensitivity to benzodiazepines. The manufacturer states that the drug is contraindicated in patients with acute angle-closure glaucoma, but it may be used with caution in patients with open-angle glaucoma who are receiving appropriate therapy.

Pediatric Precautions

The effect of long-term administration of clonazepam on physical and mental development in children has not been established. Therefore, the drug should not be administered to pediatric patients with seizure disorders unless the potential benefits outweigh the possible risks.

The manufacturer states that the safety and efficacy of clonazepam in pediatric patients with panic disorder younger than 18 years of age have not been established.1 Clonazepam has been effective in a limited number of adolescents with panic disorder; however, controlled studies are needed to confirm these preliminary findings.22

Pregnancy and Lactation

Pregnancy

Safe use of clonazepam during pregnancy has not been established. Adverse fetal effects have been observed in reproduction studies in rats and rabbits. Although several reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women, a causal relationship to many of these drugs has not been established. The manufacturer states that the majority of women receiving anticonvulsant therapy deliver normal infants. Clonazepam should be used in pregnant women or women who might become pregnant only if the drug is considered essential in the management of their seizures. Anticonvulsants should not be discontinued in pregnant women in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases, when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drugs may be considered prior to and during pregnancy; however, it cannot be said with any certainty that even minor seizures do not pose some hazard to the fetus. The clinician should carefully weigh these considerations in treating or counseling epileptic women of childbearing potential.

Lactation

Safe use of clonazepam during lactation has not been established. The manufacturer states that it is inadvisable for women receiving clonazepam to nurse infants.

CNS Depressants

Additive CNS depression may occur when clonazepam is administered concomitantly with other CNS depressants, including alcohol, opiate agonists, barbiturates, anxiolytics, sedatives and hypnotics, some antipsychotic agents, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, and other anticonvulsants.30 If clonazepam is used concomitantly with other CNS depressants, caution should be used to avoid excessive CNS depression.30 Patients also should be advised to avoid alcohol while receiving clonazepam therapy.30

Opiate Agonists and Opiate Partial Agonists

Concomitant use of benzodiazepines, including clonazepam, and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,703,705,706,707 Whenever possible, such concomitant use should be avoided.708,709,710,711 Opiate antitussive agents should be avoided in patients receiving benzodiazepines,700,704 and concomitant use of opiate analgesics and benzodiazepines should be reserved for patients in whom alternative treatment options are inadequate.700,703 The lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703

If clonazepam is required for any indication other than epilepsy in a patient receiving opiate therapy, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700 If an opiate analgesic is required in a patient receiving clonazepam, the opiate analgesic should be initiated at a reduced dosage and titrated based on clinical response.700 For further information on potential interactions between benzodiazepines and opiates, see Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Agents, in the Benzodiazepines General Statement 28:24.08.

Phenytoin

In one study, increased serum phenytoin concentrations were reported to occur when clonazepam and phenytoin were administered concomitantly. In another study, plasma clonazepam concentrations decreased when the two drugs were administered. Although the clinical importance of these reports has not been established, it may be desirable to monitor serum concentrations of both drugs during initial concomitant therapy, making dosage adjustments as necessary.

Acute Toxicity

Manifestations

Overdosage of clonazepam may produce somnolence, confusion, ataxia, diminished reflexes, or coma.

Treatment

Treatment of clonazepam intoxication consists of general supportive therapy. Flumazenil, a benzodiazepine antagonist, can be used in the management of benzodiazepine overdosage, but the drug is an adjunct to, not a substitute for, appropriate supportive and symptomatic therapy. (See Flumazenil 28:92.) The possibility that the antagonist could precipitate withdrawal in benzodiazepine-dependent individuals should be weighed carefully against the possible benefits. Clinicians should be aware of the risk of seizure in association with flumazenil administration, particularly in patients receiving long-term benzodiazepine therapy or following tricyclic antidepressant overdosage. The risks of flumazenil therapy should be weighed carefully when multiple-drug overdosage is possible. Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine's effects in such patients may provoke seizures.

If ingestion of the benzodiazepine is recent and the patient is fully conscious, emesis should be induced. If the patient is comatose, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Activated charcoal and a saline cathartic may be administered after gastric lavage and/or emesis to remove any remaining drug. The patient's heart rate, blood pressure, and respiration should be monitored and the patient closely observed. IV fluids should be administered and an adequate airway maintained. Hypotension may be controlled, if necessary, by IV administration of norepinephrine or metaraminol. Although some manufacturers of benzodiazepines recommend use of caffeine and sodium benzoate to combat CNS depression, most authorities believe caffeine and other analeptic agents should not be used, because these drugs have questionable benefit and transient action. Instead, administration of flumazenil, if indicated, generally would be preferred. As in overdosage with other benzodiazepines, dialysis is of no known value in clonazepam overdosage.

Chronic Toxicity

The possibility of physical or psychological dependence should be considered, particularly when clonazepam is administered to alcoholic patients or to those known to have been dependent on other drugs. Abrupt withdrawal of clonazepam following prolonged administration has resulted in severe withdrawal symptoms including seizures, psychosis, hallucinations, behavioral disturbances, tremors, abdominal and muscle cramps, vomiting, sweating, irritability, restlessness, sleeplessness, and hand tremors. In one study, patients who experienced some of these withdrawal symptoms had plasma 7-aminoclonazepam concentrations 3-4 times greater than those who did not have withdrawal symptoms. In addition, milder withdrawal symptoms such as dysphoria and insomnia have been reported following abrupt discontinuance of benzodiazepines in patients receiving therapeutic dosages for several months. Because clonazepam has a long half-life, withdrawal symptoms may not occur until several days after the drug has been discontinued.

Pharmacology

The pharmacologic actions of clonazepam are qualitatively similar to those of other benzodiazepine derivatives.

In animal studies, clonazepam has been shown to protect against seizures induced by pentylenetetrazol and, to a lesser extent, electrical stimulation.1 Clonazepam also appears to antagonize seizures produced by photic stimulation in animals.1 In humans, clonazepam can suppress the spike and wave discharge in absence seizures (petit mal) and can decrease the frequency, amplitude, duration, and spread of discharge in minor motor seizures.1 Clonazepam also has been shown to produce a taming effect, muscle weakness, and hypnosis in animals.1

The exact mechanism(s) by which clonazepam exerts its anticonvulsant, sedative, and antipanic effects is unknown.1 However, it is believed to be related at least in part to the drug's ability to enhance the activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the central nervous system.1

Pharmacokinetics

Absorption

Clonazepam is rapidly and well absorbed from the GI tract. The absolute bioavailability is approximately 90%.1 In one study, peak blood concentrations of 6.5-13.5 ng/mL were usually reached within 1-2 hours following a single 2-mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4-8 hours. Although the plasma concentration of clonazepam required for anticonvulsant effects has not been definitely established, some studies indicate it may be 20-80 ng/mL. Plasma concentrations in this range have been reported to be maintained in adults receiving 6 mg of clonazepam daily in 3 divided doses and in children 6-13 years of age receiving 1.5-4 mg of the drug daily in 3 divided doses. The onset of anticonvulsant action usually occurs within 20-60 minutes, and the duration of action usually is 6-8 hours in infants and young children and up to 12 hours in adults.

Distribution

There is little information on the distribution of clonazepam. Clonazepam is approximately 85% bound to plasma proteins.1 Like other benzodiazepines, the drug apparently crosses the blood-brain barrier and the placenta.

Elimination

The elimination half-life of clonazepam has been reported to be 18.7-39 hours.

Clonazepam is extensively metabolized in the liver to several metabolites including 7-aminoclonazepam, 7-acetaminoclonazepam, and 3-hydroxy derivatives of these metabolites and clonazepam. Clonazepam metabolites are excreted in urine by first-order kinetics, principally as their glucuronide and/or sulfate conjugates. Only very small amounts of the drug (less than 2%) are excreted unchanged.

Chemistry and Stability

Chemistry

Clonazepam is a benzodiazepine derivative that is used both as an anticonvulsant and for the treatment of panic disorder with or without agoraphobia. The drug is structurally and pharmacologically related to diazepam and other benzodiazepines. Clonazepam occurs as an off-white to light yellow, crystalline powder with a faint odor and is insoluble in water and slightly soluble in alcohol. Clonazepam has pK_as of 1.5 and 10.5.

Stability

Clonazepam tablets and orally disintegrating tablets should be stored in air-tight, light-resistant containers at 25°C, but may be exposed to temperatures ranging from 15-30°C. The commercially available conventional tablets have an expiration date of 5 years following the date of manufacture.

Additional Information

For further information on uses, cautions, and dosage and administration of clonazepam, see the Anticonvulsants General Statement 28:12 and the Benzodiazepines General Statement 28:24.08.

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. [PubMed 3209726]

23. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

24. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

25. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

26. Ballenger MC, Davison JRT, Lucribier Y et al. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry . 1998; 59(Suppl 8):47-54.

27. Campbell-Sills L, Stein MB: Guideline watch: Practice guideline for the treatment of patients with panic disorder. American Psychiatric Association. Arlington, VA; 2006 Apr. From the American Psychiatric Association website. [Web]

28. American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. Am J Psychiatry . 1998; 155(5 Suppl):1-34.

29. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2009 Oct 11. [Web]

30. Roche Laboratories Inc. Klonopin^® (clonazepam) tablets and Klonopin^® Wafers (clonazepam) orally disintegrating tablets prescribing information. Nutley, NJ; 2009 Apr.

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. [Web]

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. [Web]

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. [Web]

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. [PubMedCentral][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. [Web]

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

900. US Food and Drug Administration. Drug safety communication: FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class Includes potential for abuse, addiction, and other serious risks. Silver Spring, MD; 2020 Sep 23. From FDA website. [Web]