Clonazepam

Clonazepam may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• drowsiness
• dizziness
• unsteadiness
• problems with coordination
• difficulty thinking or remembering
• increased saliva
• muscle or joint pain
• frequent urination
• blurred vision
• changes in sex drive or ability

Some side effects can be serious. If you experience any of these symptoms call your doctor immediately:

• rash
• hives
• swelling of the eyes, face, lips, tongue, or throat
• difficulty breathing or swallowing
• hoarseness
• difficulty breathing

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to clonazepam.

Do not let anyone else take your medication. Clonazepam is a controlled substance. Prescriptions may be refilled only a limited number of times; ask your pharmacist if you have any questions.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Klonopin^®

• Tablets: 0.5, 1, and 2 mg;
• Disintegrating tablets: 0.125, 0.25, 0.5, 1, and 2 mg.

Tablets should be kept at room temperature, between 15 C and 30 C (59 F and 86 F).

Dosage Forms & Strengths

tablet dispersible: Schedule IV

• 0.125mg
• 0.25mg
• 0.5mg
• 1mg
• 2mg

tablet: Schedule IV

• 0.5mg
• 1mg
• 2mg

Panic Disorder

0.25 mg PO q12hr initially; may increase to 1 mg/day after 3 days (up to 4 mg/day in some patients)

Seizure Disorders

1.5 mg/day PO divided q8hr; increase by 0.5-1 mg q3Days until desired effect achieved; not to exceed 20 mg/day

Maintenance: 2-8 mg PO; not to exceed 20 mg/day  

Essential Tremor (Off-label)

0.5 mg PO at bedtime; increase dose by 0.5 mg q3-4days; not to exceed 6 mg/day

REM Sleep Behavior Disorder (Off-label)

0.25-2 mg PO 30 min prior to bedtime; not to exceed 4 mg

Burning Mouth Syndrome (Off-label)

0.25 mg PO at bedtime for 1 week; increase dose by up to 0.25 mg qweek; not to exceed 3 mg daily in 3 divided doses

Alternatively, 1 mg topirally three times daily after each meal; suck on the tablet, retain salive in mouth near pain sites without swallowing for 3 min, then expectorate saliva

Tardive Dyskinesia (Off-label)

The American Academy of Neurology guidelines includes use of clonazepam for short-term treatment (~3 mo) to decrease tardive dyskinesia symptoms

Initial: 1 mg/day PO; adjust dose based on response and tolerability by 1 mg/day increments q3-4 days; not to exceed 4.5 mg/day

Dosage Modifications

Renal impairment: Supplemental dose in hemodialysis not necessary

Dosing Considerations

Discontinuation of treatment: Withdraw treatment gradually; decrease the dose q3Days by 0.125 mg PO q12hr until completely withdrawn

Hyperekplexia (Orphan)

Orphan indication sponsor

• Hoffmann-La Roche, Inc; 340 Kingsland Street; Nutley, NJ 07110

Recurrent, Acute, Repetitive Seizures (Orphan)

Administration: Intranasal spray

Orphan indication sponsor

• Jazz Pharmaceuticals, Inc; 3180 Porter Drive; Palo Alto, CA 94304

Tardive Dyskinesia (Off-label)

The American Academy of Neurology guidelines includes use of clonazepam for short-term treatment (~3 mo) to decrease tardive dyskinesia symptoms

Initial: 1 mg/day PO; adjust dose based on response and tolerability by 1 mg/day increments q3-4 days; not to exceed 4.5 mg/day

Dosage Forms & Strengths

tablet: Schedule IV

• 0.125mg
• 0.25mg
• 0.5mg
• 1mg
• 2mg

Seizure Disorders

<6 years

• Potential toxic dose: 0.05 mg/kg  

<10 years or <30 kg

• 0.01-0.03 mg/kg/day PO divided q8hr; increase by 0.25-0.5 mg/day q3Days to maximum 0.1-0.2 mg/kg/day PO divided q8hr
• Maintenance dose: 0.1-0.2 mg/kg/day PO divided q8hr; not to exceed 0.2 mg/kg/day

≥10 years or ≥30 kg

• 1.5 mg/day PO divided q8hr; increase by 0.5-1 mg q3Days until desired effect achieved; not to exceed 20 mg/day
• Maintenance: 2-8 mg PO; not to exceed 20 mg/day

Dosing Considerations

Discontinuation of treatment

• <10 years: Treatment should be withdrawn gradually, as necessary
• ≥10 years: Withdraw treatment gradually; decrease the dose q3Days by 0.125 mg PO q12hr until completely withdrawn

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of clonazepam there are no specific foods that you must exclude from your diet when receiving clonazepam.

• Take clonazepam exactly as your doctor tells you. Clonazepam is available as a tablet or as an orally disintegrating tablet (wafer).
• Do not stop taking clonazepam without first talking to your doctor. Stopping clonazepam suddenly can cause serious problems.
• Clonazepam immediate-release tablets should be taken with water and swallowed whole.
• Clonazepam disintegrating tablets can be taken with or without water.
  • Do not open the pouch until you are ready to take clonazepam.
  • After opening the pouch, peel back the foil on the blister pack.
  • Do not push the wafer through the foil.
  • After opening the blister pack, with dry hands, take the disintegrating tablet and place it in your mouth.
  • The disintegrating tablet will melt quickly. It can be taken with or without water.
• If you take too much clonazepam, call your healthcare provider or local Poison Control Center right away.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Klonopin (regular-release tablet) and orally disintegrating tablets:

• The recommended dose for adults with seizure disorders should not exceed 1.5 mg/day divided into 3 doses. Maximum recommended daily dose is 20 mg.
• In order to minimize drowsiness, the starting dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in 2 or 3 divided doses. Whenever possible, the daily dose should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before going to bed.

General

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

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

Administration

Oral Administration

Administer orally as conventional or orally disintegrating tablets.a

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

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

Swallow tablet whole with water.a

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

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

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

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

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

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

Adults

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

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

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

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

Prescribing Limits

Pediatric Patients

Maximum 0.2 mg/kg daily.b

Adults

Maximum 20 mg daily.1

Maximum 4 mg daily.1

Special Populations

Geriatric Patients

Initiate therapy at low dosage and observe closely.a

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

• Potential for psychologic or physiologic dependence.1

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

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

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

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

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

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

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines, including Clonazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Clonazepam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Clonazepam is used with opioids (see PRECAUTIONS, Information for Patients and PRECAUTIONS, Drug Interactions).

Interference With Cognitive and Motor Performance

Since Clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during Clonazepam therapy (see PRECAUTIONS, Drug Interactions and PRECAUTIONS, Information for Patients).

Antiepileptic drugs (AEDs), including Clonazepam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Clonazepam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Pregnancy Risks

Data from several sources raise concerns about the use of Clonazepam during pregnancy.

In three studies in which Clonazepam was administered orally to pregnant rabbits at doses of 0.2 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).

Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, (e.g., genetic factors or the epileptic condition itself) may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus.

An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.

There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.

In general, the use of Clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.

The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women.

Because of experience with other members of the benzodiazepine class, Clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.

Withdrawal Symptoms

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

Controlled Substance Class

Clonazepam is a Schedule IV controlled substance.

Physical and Psychological Dependence

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of Clonazepam. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving Clonazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see CLINICAL PHARMACOLOGY, Clinical Trials), patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well-controlled long-term Clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.

Human Experience

Symptoms of Clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes.

Overdose Management

Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Dialysis is of no known value.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

~20 to 40 minutes (Hanson 1972)

Time to Peak

Serum: 1 to 4 hours

Seizure disorders: Oral:

Infants, Children ≤10 years or ≤30 kg:

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

Usual maintenance dose: 0.1 to 0.2 mg/kg/day divided 3 times daily.

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

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

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

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

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

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

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

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

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

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

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

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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

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

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

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

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

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

Melatonin: May enhance the sedative effect of Benzodiazepines. Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

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

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

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

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

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

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

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

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

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

You should not use clonazepam if you have narrow-angle glaucoma or severe liver disease, or if you are allergic to Valium or a similar medicine.

Call your doctor if you have any new or worsening symptoms of depression, unusual changes in behavior, or thoughts about suicide or hurting yourself.

Do not drink alcohol while taking this medicine. Clonazepam may be habit-forming. Never share clonazepam with another person. Keep the medication in a place where others cannot get to it. Selling or giving away clonazepam is against the law.

You should not take clonazepam if you have:

• narrow-angle glaucoma;

• severe liver disease; or

• a history of allergic reaction to any benzodiazepine, such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan), chlordiazepoxide, flurazepam, and others.

To make sure clonazepam is safe for you, tell your doctor if you have:

• kidney or liver disease;

• glaucoma;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

• asthma, emphysema, bronchitis, chronic obstructive pulmonary disorder (COPD), or other breathing problems;

• a history of depression or suicidal thoughts or behavior;

• a history of mental illness, psychosis, or addiction to drugs or alcohol; or

• if you use a narcotic (opioid) medication.

Some people have thoughts about suicide when taking seizure medication. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Follow your doctor's instructions about taking seizure medication if you are pregnant. Do not start or stop taking this medicine without your doctor's advice, and tell your doctor right away if you become pregnant. Clonazepam may cause harm to an unborn baby, and may cause breathing or feeding problems in a newborn. But having seizures during pregnancy could harm both mother and baby.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of clonazepam on the baby.

Clonazepam can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Do not give this medicine to a child without medical advice. Clonazepam is not approved to treat panic disorder in anyone younger than 18 years old.

The sedative effects of clonazepam may last longer in older adults. Accidental falls are common in elderly patients who take benzodiazepines. Use caution to avoid falling or accidental injury while you are taking clonazepam.

Take clonazepam exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Clonazepam may be habit-forming. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

Misuse of habit-forming medicine can cause addiction, overdose, or death. Selling or giving away this medicine is against the law.

Clonazepam should be used for only a short time. Do not take this medication for longer than 9 weeks without your doctor's advice.

Swallow the tablet whole, with a full glass of water.

If you use this medicine long-term, you may need frequent medical tests.

Do not stop using clonazepam suddenly or you could have unpleasant withdrawal symptoms, including a seizure (convulsions). Ask your doctor how to safely stop using this medicine.

Call your doctor if this medicine seems to stop working as well in treating your seizures or anxiety symptoms.

Seizures are often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store clonazepam at room temperature away from moisture, heat, and light.

Keep track of the amount of medicine used from each new bottle. Clonazepam is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

Taking this medicine with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Other drugs may interact with clonazepam, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to clonazepam: oral solution, oral tablet, oral tablet disintegrating

Along with its needed effects, clonazepam may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking clonazepam:

• Body aches or pain
• chills
• cough
• difficulty breathing
• discouragement
• dizziness
• ear congestion
• feeling sad or empty
• fever
• headache
• irritability
• lack of appetite
• loss of interest or pleasure
• loss of voice
• nasal congestion
• poor coordination
• runny nose
• shakiness and unsteady walk
• sleepiness or unusual drowsiness
• sneezing
• sore throat
• tiredness
• trouble concentrating
• trouble sleeping
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual tiredness or weakness

• Being forgetful
• bladder pain
• bloody or cloudy urine
• change in speech
• diarrhea
• difficult, burning, or painful urination
• frequent urge to urinate
• general feeling of discomfort or illness
• joint pain
• loss of appetite
• lower back or side pain
• mood or mental changes
• muscle aches and pains
• nausea
• nervousness
• problems in urination or increase in the amount of urine
• shivering
• slurred speech
• sore throat
• sweating
• trouble speaking
• vomiting

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• changes in skin color
• chest pain or discomfort
• cold sweats
• colds
• confusion
• cough or hoarseness
• difficulty with sleeping
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• excessive dreaming
• excessive muscle tone
• excitement
• falling
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling mad
• feeling of unreality
• flu-like symptoms
• headache, severe and throbbing
• lack of feeling or emotion
• lack or loss of self-control
• muscle stiffness
• muscle tension or tightness
• nightmares
• pain, inflammation, or swelling in the calves, shoulders, or hands
• pain or swelling in the arms or legs without any injury
• pain, tenderness, or swelling of the foot or leg
• partial or slight paralysis
• scaling
• sense of detachment from self or body
• shakiness in the legs, arms, hands, or feet
• skin rash
• swelling around the eyes
• swelling of the face, ankle, foot, or knees
• thoughts of killing oneself changes in behavior
• tightness in the chest
• trembling or shaking of the hands or feet
• uncaring
• vision changes

• Abdominal pain or fullness
• anxiety
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• change in consciousness
• chest congestion
• difficulty with coordination
• double vision
• drowsiness
• dry mouth
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• feeling, seeing, or hearing things that are not there
• hyperventilation
• irregular, fast, slow, or shallow breathing
• irregular, twisting uncontrolled movement of the face, hands, arms, or legs
• loss of interest or pleasure
• loss of memory
• loss of strength or energy
• loss of voice
• muscle weakness
• pale or blue lips, fingernails, or skin
• pinpoint red spots on the skin
• problems with memory
• restlessness
• severe mood or mental changes
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• troubled breathing with exertion
• uncontrolled eye movements
• unusual behavior
• unusual bleeding or bruising
• unusual weakness
• vivid dreams
• weight loss or gain

Some side effects of clonazepam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Decreased interest in sexual intercourse
• difficulty with swallowing
• dryness or soreness of the throat
• heavy bleeding
• hives
• inability to have or keep an erection
• longer than usual time to ejaculation of semen
• loss in sexual ability, desire, drive, or performance
• pain or tenderness around the eyes and cheekbones
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• voice changes

• Acid or sour stomach
• ankle, knee, or great toe joint pain
• belching
• bleeding after defecation
• blistering, burning, crusting, dryness, or flaking of the skin
• bloated
• blurred or loss of vision
• change in color perception
• cracks in the skin at the corners of the mouth
• decrease or change in vision
• difficulty moving
• double vision
• dryness of the eyes
• earache
• excess air or gas in stomach or intestines
• feeling of constant movement of self or surroundings
• feeling of warmth
• frequent bowel movements
• full feeling
• hair loss or thinning of the hair
• halos around lights
• heartburn
• increased watering of the mouth
• indigestion
• irregularities in menstruation
• itching in the genital or other skin areas
• itching, scaling, severe redness, soreness, or swelling of the skin
• joint stiffness or swelling
• leg or muscle cramps
• loss of taste
• night blindness
• nosebleeds
• overbright appearance of lights
• pain in the breasts or pelvic area
• pain in the leg, nape, or back
• passing gas
• red, sore eyes
• redness of the face, neck, arms, and occasionally, upper chest
• redness or swelling in the ear
• sensation of spinning
• smaller amount of semen ejaculated than usual
• sore on the edge of the eyelid
• soreness or redness around the fingernails and toenails
• stomach discomfort, upset, or pain
• thickening of the tongue
• thirst
• tooth disorder
• toothache
• tunnel vision
• twitching of the eyes
• uncomfortable swelling around the anus
• worsening of acne

• Burning feeling in the chest or stomach
• difficulty having a bowel movement (stool)
• increased appetite
• increased hair growth, especially on the face
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• sore gums
• tenderness in the stomach area

• Take exactly as directed by your doctor. Do not increase or decrease the dosage without his or her advice. If you have been taking clonazepam for a long period of time do not stop suddenly as withdrawal reactions (blurred vision, insomnia, sweating, rarely seizures) may occur. Your doctor will advise you how to taper off the dose. Keep out of sight of potential drug seekers.
• Swallow regular-release tablets whole with water.
• For orally disintegrating tablets, open the pouch and peel back the foil on the blister; do not push the tablet through the foil. Use dry hands to remove the tablet and place it in the mouth; it will dissolve rapidly in saliva.
• Clonazepam may cause sleepiness and affect your ability to drive or perform other complex tasks. Avoid doing these activities if clonazepam has this effect on you.
• Avoid drinking alcohol while taking clonazepam as it may enhance the side effects of sedation and respiratory depression.
• Clonazepam may make you feel dizzy, increasing your risk of falls. Be careful when sitting or standing up after lying down.
• If you think you have become dependant on clonazepam or addicted to it, talk with your doctor.
• Do not take any other medications with clonazepam including those bought over the counter without first checking with your pharmacist or doctor that they are compatible.
• If your mood changes, or you experience depression or a worsening of depression, talk with your doctor.
• Do not use clonazepam if you are allergic to it or other benzodiazepines like alprazolam, lorazepam, or oxazepam.
• Do not start or discontinue clonazepam during pregnancy without speaking to your provider first.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. AU TGA pregnancy category: C US FDA pregnancy category: D Comments: -The child born to a mother taking benzodiazepines may be at risk for withdrawal symptoms. -The patient should be warned of the potential risks to the fetus and instructed to discontinue the drug prior to becoming pregnant. -There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been taking benzodiazepines late in pregnancy.

Animal studies have shown reproductive toxicity. There are no adequate studies in pregnant women. US: To provide information regarding the effects of in utero exposure to this drug, healthcare providers are advised to recommend that pregnant patients taking this drug enroll in the North American Anti-epileptic Drug (NAAED) Pregnancy Registry. Patients can call the toll-free number 1-888-233-2334. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.