Clonazepam .5 mg Tablet, 30-count — NDC 58118-0832-8 (Billing 58118-0832-08)

WARNINGS 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 ). Suicidal Behavior and Ideation 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. Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5

2.4Psychiatric 5.7 8.5 1.5

2.9Other 1.0 1.8 1.9

0.9Total 2.4 4.3 1.8

1.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epileps… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The adverse experiences for clonazepam are provided separately for patients with seizure disorders and with panic disorder. Seizure Disorders The most frequently occurring side effects of clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%.

In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, including those identified during postapproval use of clonazepam are: Cardiovascular: Palpitations Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums Genitourinary: Dysuria, enuresis, nocturia, urinary retention Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase Musculoskeletal: Muscle weakness, pains Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, “glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo Psychiatric: Confusion, depression, amnesia, hysteria, increased libido, insomnia, psychosis (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances).

The following paradoxical reactions have been observed: irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, abnormal dreams and hallucinations. Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages Panic Disorder Adverse events during exposure to clonazepam were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories.

In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials Adverse Events Associated with Discontinuation of Treatment Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam compared to 9% for placebo in the combined data of two 6 to 9 week trials. The most common events (≥ 1%) associated with discontinuation and a dropout rate twice or greater for clonazepam than that of placebo included the following: Table 2: Most Common Adverse Events (≥ 1%) Associated With Discontinuation of Treatment Adverse Event Clonazepam (N = 574) Placebo (N = 294) Somnolence 7% 1% Depression 4% 1% Dizziness 1% < 1% Nervousness 1% 0% Ataxia 1% 0% Intellectual Ability Reduced 1% 0% Adverse Events Occurring at an Incidence of 1% or More among Clonazepam-Treated Patients Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6 to 9 week trials.

Events reported in 1% or more of patients treated with clonazepam (doses ranging from 0.5 to 4 mg/day) and for which the inciden… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Worsening of Seizures 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 seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.

Loss of Effect : In some studies, up to 30% of patients who initially responded have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy. Laboratory Testing During Long-Term Therapy Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.

Psychiatric and Paradoxical Reactions : Paradoxical reactions, such as agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations, and psychoses are known to occur when using benzodiazepines (see ADVERSE REACTIONS: Psychiatric ). Should this occur, the use of the drug should be discontinued gradually (see PRECAUTIONS: Risks of Abrupt Withdrawal and DRUG ABUSE AND DEPENDENCE: Physical and Psychological Dependence ). Paradoxical reactions are more likely to occur in children and in the elderly.

Risks of Abrupt Withdrawal The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.

Caution in Renally Impaired Patients Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Hypersalivation Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions.

Respiratory Depression Clonazepam may cause respiratory depression and should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, sleep apnea). Porphyria Clonazepam may have a porphyrogenic effect and should be used with care in patients with porphyria. Information for Patients A clonazepam tablets Medication Guide must be given to the patient each time clonazepam tablets are dispensed, as required by law.

Patients should be instructed to take clonazepam only as prescribed. Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam: Risks from Concomitant Use with Opioids Inform patients and caregivers that potentially fatal additive effects may occur if clonazepam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS, Risks from Concomitant Use With Opioids and PRECAUTIONS, Drug Interactions ). Dose Changes To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

Interference with Cognitive and Motor Performance Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely. Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including clonazepam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the… [Excerpted — this section continues on DailyMed.]

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, mood changes, 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.

Controlled Substance Class Clonazepam is a Schedule IV controlled substance.