DESCRIPTION

Clonazepam Tablets, USP, a benzodiazepine, is available as scored tablet with debossing Λ containing 0.5 mg of clonazepam and unscored tablets with debossing Λ and Λ containing 1 mg or 2 mg of clonazepam respectively. Each tablet also contains lactose monohydrate, polyethylene                                                                                                                                                66                                                                                                                 67       69
glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, with the following colourants: 0.5 mg-FD & C Yellow 6 Al Lake, D & C Yellow 10 Al Lake; 1 mg-FD & C Blue 1 Al lake and FD & C Blue 2 Al lake

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro- 2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula:

CLINICAL PHARMACOLOGY

INDICATIONS AND USAGE

Seizure Disorders:

Clonazepam tablets are useful alone or as an adjunct in the treatment of the Lennox- Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam tablets may be useful.

Some loss of effect may occur during the course of clonazepam treatment (see PRECAUTIONS: Loss of Effect).

Panic Disorder:

Clonazepam tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-V. 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 significant change in behavior related to the attacks.

The efficacy of clonazepam tablets was established in two 6- to 9-week trials  in panic disorder patients whose diagnoses corresponded to the DSM-lIlR category of panic disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).

Panic disorder (DSM-V) is characterized by recurrent unexpected panic attacks, i.e., a discrete  period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness  or tingling  sensations); (13) chills or hot flushes.

The effectiveness of clonazepam tablets in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long- term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Clonazepam tablets are contraindicated in patients with the following conditions:

• History of sensitivity to benzodiazepines
• Clinical or biochemical evidence of significant liver disease
• Acute narrow angle glaucoma (it may be used in patients with open angle glaucoma who are receiving appropriate therapy).

WARNINGS

Risks from Concomitant Use With Opioids:

Concomitant use of benzodiazepines, including clonazepam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids 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 tablets 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 tablets are  used with opioids (see PRECAUTIONS; Information for Patients and PRECAUTIONS: Drug Interactions).

Abuse, Misuse, and Addiction:

The use of benzodiazepines, including clonazepam tablets, exposes  users  to  the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse) .

Before prescribing clonazepam tablets and  throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of clonazepam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clonazepam tablets along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions:

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam tablets or reduce the dosage  (a patient-specific  plan should be  used to  taper  the  dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Clonazepam Tablets) .

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had long durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines, including clonazepam tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of clonazepam tablets after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence).

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months  (see DRUG ABUSE AND DEPENDENCE: Dependence) .

Interference With Cognitive and Motor Performance:

Since clonazepam tablets 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 tablets therapy (see PRECAUTIONS, Drug Interactions and Information for Patients).

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs),including clonazepam tablets, 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 (5-100 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	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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 tablets  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.

PRECAUTIONS

ADVERSE REACTIONS

The adverse experiences for clonazepam tablets are provided separately for patients with seizure disorders and with panic disorder.

Seizure Disorders:

The most frequently occurring side effects of clonazepam tablets 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 tablets 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, hallucinations, 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: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams

Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages

Panic Disorder:

Adverse events during exposure to  clonazepam tablets  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 tablets 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 tablets than that of placebo included the following:

Table 2 Most Common Adverse Events (≥1%) Associated with Discontinuation of Treatment

Adverse Event	Clonazepam Orally Disintegrating Tablets (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 Tablets-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 tablets (doses ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.

The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where  patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the  cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some  basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.

Table 3 Treatment-Emergent Adverse Event Incidence in 6- to 9- Week Placebo-Controlled

                                                                                        Clinical Trials*

			Clonazepam Maximum Daily Dose
Adverse Event by Body System	<1mg	1- <2mg	2- <3mg	≥3mg	All Clonazepam Tablets Groups	Placebo
	n=96	n=129	n=113	n=235	N=574	N=294
	%	%	%	%	%	%
Central & Peripheral Nervous System
Somnolence†	26	35	50	36	37	10
Dizziness	5	5	12	8	8	4
Coordination Abnormal†	1	2	7	9	6	0
Ataxia†	2	1	8	8	5	0
Dysarthria†	0	0	4	3	2	0
Psychiatric
Depression	7	6	8	8	7	1
Memory Disturbance	2	5	2	5	4	2
Nervousness	1	4	3	4	3	2
Intellectual Ability Reduced	0	2	4	3	2	0
Emotional Lability	0	1	2	2	1	1
Libido Decreased	0	1	3	1	1	0
Confusion	0	2	2	1	1	0
Respiratory System
Upper Respiratory Tract Infection †	10	10	7	6	8	4
Sinusitis	4	2	8	4	4	3
Rhinitis	3	2	4	2	2	1
Coughing	2	2	4	0	2	0
Pharyngitis	1	1	3	2	2	1
Bronchitis	1	0	2	2	1	1
Gastrointestinal System
Constipation†	0	1	5	3	2	2
Appetite Decreased	1	1	0	3	1	1
Abdominal Pain†	2	2	2	0	1	1
Body as a Whole
Fatigue	9	6	7	7	7	4
Allergic Reaction	3	1	4	2	2	1
Musculoskeletal
Myalgia	2	1	4	0	1	1
Resistance Mechanism Disorders
Influenza	3	2	5	5	4	3
Urinary System
Micturition Frequency	1	2	2	1	1	0
Urinary Tract Infection†	0	0	2	2	1	0
Vision Disorders
Blurred Vision	1	2	3	0	1	1
Reproductive Disorders‡
Female
Dysmenorrhea	0	6	5	2	3	2
Colpitis	4	0	2	1	1	1
Male
Ejaculation Delayed	0	0	2	2	1	0
Impotence	3	0	2	1	1	0

*  Events reported by at least 1% of patients treated with clonazepam tablets and for which the incidence was greater than that for placebo.

† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for adverse event incidence was ≤0.10.

‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102 (placebo) for male, and 334 (clonazepam), 192 (placebo) for female.

Commonly Observed Adverse Events:

Table 4. Incidence of Most Commonly Observed Adverse Events* in Acute Therapy in Pool of 6 to 9-Week Trials

Adverse Event	C lonazepam (N=574)	Placebo (N=294)
Somnolence	37%	10%
Depression	7%	1%
Coordination Abnormal	6%	0%
Ataxia	5%	0%

*Treatment-emergent events for which the incidence in the clonazepam patients was ≥5% and at least twice that in the placebo patients.

Treatment-Emergent Depressive Symptoms:

In the pool of two short-term placebo-controlled trials, adverse events classified under the  preferred term “depression” were reported in 7% of clonazepam tablets-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam tablets-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression.

Other Adverse Events Observed During the Premarketing Evaluation of Clonazepam Tablets in Panic Disorder:

Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam tablets at multiple doses during clinical trials. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with clonazepam tablets, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients.

Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized

Cardiovascular Disorders: chest pain, hypotension postural

Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching

Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids

Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness

Heart Rate and Rhythm Disorders: palpitation

Metabolic and Nutritional Disorders: thirst, gout

Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee

Platelet, Bleeding and Clotting Disorders: bleeding dermal

Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggression, apathy, disturbance in attention, excitement, anger, hunger abnormal, illusion, nightmares, sleep disorder, suicide ideation, yawning

Reproductive Disorders, Female: breast pain, menstrual irregularity

Reproductive Disorders, Male: ejaculation decreased

Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis

Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy

Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder

Special Senses Other, Disorders: taste loss

Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration

Vascular (Extracardiac) Disorders: thrombophlebitis leg

Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class:

Clonazepam tablets contain clonazepam, a Schedule IV controlled substance.

Abuse:

Clonazepam tablet is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to  drug  use  than other  activities  and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse  may  lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).

The following adverse reactions have occurred with benzodiazepine abuse  and/or  misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or  misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing  difficulty, and  death. Death is more often associated with polysubstance use  (especially benzodiazepines  with other  CNS depressants such as opioids and alcohol) .

Dependence:

Physical Dependence

Clonazepam tablets may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or  rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions)

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Clonazepam tablets and WARNINGS: Dependence and Withdrawal Reactions).

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle  pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have  included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g.,  weakness,  tremor,  muscle twitches), paresthesia, and tinnitus that persists beyond 4 to  6  weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more  than 12 months . As  a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to clonazepam tablets  may  develop  from continued  therapy.  Tolerance is a physiological state characterized by a reduced response to  a drug  after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of clonazepam tablets may  develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

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.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.

Seizure Disorders:

The use of multiple anticonvulsants may result in an increase of CNS depressant adverse effects. This should be considered before adding clonazepam tablets to an existing anticonvulsant regimen.

Adults:

The initial dose  for adults  with seizure  disorders should not exceed 1.5 mg/day divided into  three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any  further  increase. Maintenance  dosage  must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

Pediatric Patients:

Clonazepam tablets are administered orally. In order to minimize  drowsiness, the initial 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 two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg  every third day until  a daily maintenance  dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into  three  equal doses. If  doses are not equally divided, the largest dose should be given before retiring.

Geriatric Patients:

There is no clinical trial experience with clonazepam tablets in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely (see PRECAUTIONS, Geriatric Use) .

Panic Disorder:

Adults:

The initial dose for adults with panic disorder is 0.25 mg twice daily. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the  optimal effect was  seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. Nevertheless, it is possible that some  individual  patients  may  benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the  dose may be increased in increments of 0.125 to 0.25 mg bid every 3 days until  panic  disorder is  controlled or until  side  effects  make  further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.

Treatment should be discontinued gradually, with a decrease of 0.125 mg twice daily every 3 days, until the drug is completely withdrawn.

There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of  the drug for the individual patient.

Pediatric Patients:

There is no clinical trial experience with clonazepam tablets in panic disorder patients under 18 years of age.

Geriatric Patients:

There is no clinical trial experience with clonazepam tablets in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS, Geriatric Use) .

Discontinuation or Dosage Reduction of clonazepam tablets:

To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clonazepam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence) .

HOW SUPPLIED

Clonazepam Tablets USP, 0.5 mg are mottled orange, round, flat-faced, beveled edge tablet, debossed with Λ on one side and scored on the other side. They are supplied as follows:
                                                                                                                                                                            66 

NDC 72888-152-30, bottles of 30.

NDC 72888-152-01, bottles of 100.

NDC 72888-152-05, bottles of 500.

NDC 72888-152-00, bottles of 1000.

Clonazepam Tablets USP, 1 mg are mottled blue, round, flat-faced, beveled edge tablet, debossed with Λ on one side and plain on the other side. They are supplied as follows:
                                                                                                                                                                     67

NDC 72888-153-30, bottles of 30.

NDC 72888-153-01, bottles of 100.

NDC 72888-153-05, bottles of 500.

NDC 72888-153-00, bottles of 1000.

Clonazepam Tablets USP, 2 mg are white to off-white, round, flat-faced, beveled edge tablets, debossed with Λ on one side and plain on the other side. They are supplied as follows:
                                                                                                                                                                               69

NDC 72888-154-30, bottles of 30.

NDC 72888-154-01, bottles of 100.

NDC 72888-154-05, bottles of 500.

NDC 72888-154-00, bottles of 1000.

Store at 20°C to 25°C (68°F -77°F) [See USP Controlled Room Temperature].

All trademarks are the property of their respective owners.

Dispense with Medication Guide available at:

www.advagenpharma.com/medguide/clonazepamtablets

Manufactured by:

Rubicon Research Private Limited

Ambernath, Dist: Thane, 421506 India

Distributed by:

Advagen Pharma Ltd

666 Plainsboro Road

Suite 605 Plainsboro, NJ  08536, US

Revision: 09/22

MEDICATION GUIDECLONAZEPAM (kloe NAZ e pam)
tablet, for oral use, C-IV

What is the most important information I should know about clonazepam tablets?

• Clonazepam tablet is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death. Get emergency help right away if any of the following happens:

• shallow or slowed breathing
• breathing stops (which may lead to the heart stopping)
• excessive sleepiness (sedation)

Do not drive or operate heavy machinery until you know how taking clonazepam tablets with opioids affects you.

• Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including clonazepam tablet which can lead to overdose and serious side effects including coma and death.

• Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including clonazepam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.
• You can develop an addiction even if you take clonazepam tablets as prescribed by your healthcare provider.
• Take clonazepam tablets exactly as your healthcare provider prescribed.
• Do not share your clonazepam tablets with other people.
• Keep clonazepam tablets in a safe place and away from children.

• Physical dependence and withdrawal reactions. Clonazepam tablets  can cause physical dependence and withdrawal reactions.
  • Do not suddenly stop taking clonazepam tablets. Stopping clonazepam tablets suddenly can cause serious and life-threatening side  effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts  or actions. Call your  healthcare  provider or go to the nearest hospital emergency room right away if you get any of these symptoms.   
  • Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more  than 12 months, including, anxiety, trouble  remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.
  • Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.   
  • Do not take more clonazepam tablets than prescribed or take clonazepam tablets for longer than prescribed.

• Clonazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affects you.
  • Clonazepam tablets may cause problems with your coordination, especially when you are walking or picking things up.

• Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clonazepam tablets until you talk to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, clonazepam tablets may make your sleepiness or dizziness worse.
• Like other antiepileptic drugs, clonazepam tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying                                                      ◦ attempt to commit suicide                                                      ◦ new or worse depression
• new or worse anxiety                                                                      ◦ feeling agitated or restless                                                      ◦ panic attacks
• trouble sleeping (insomnia)                                                             ◦ new or worse irritability                                                        ◦ acting aggressive, being angry, or violent
• acting on dangerous impulses                                                          ◦ an extreme  increase  in activity and  talking (mania)          ◦ other unusual  changes  in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Do not stop clonazepam tablets without first talking to a healthcare provider.

• Stopping clonazepam tablets suddenly can cause  serious  problems. Stopping clonazepam tablets
• suddenly can cause seizures that will not stop (status epilepticus).

What are clonazepam tablets?

• Clonazepam tablets are prescription medicine used alone or with other medicines to treat:
  • certain types of seizure disorders (epilepsy) in adults and children
  • panic disorder with or without fear of open spaces (agoraphobia) in adults

Clonazepam tablet is a federally controlled substance (C-IV) because it  contains clonazepam that can be  abused or lead to  dependence. Keep clonazepam tablets in a safe place to prevent misuse and  abuse. Selling  or giving  away clonazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs.

It is not known if clonazepam tablets are safe or effective in treating panic disorder in children younger than 18 years old.

Who should not take clonazepam tablets?

Do not take clonazepam tablets if you:

• are allergic to benzodiazepines
• have significant liver disease
• have an eye disease called acute narrow angle glaucoma

Ask your healthcare provider if you are not sure if you have any of the problems listed above.

Before you take clonazepam tablets, tell your healthcare provider if you:

• have liver or kidney problems
• have lung problems (respiratory disease)
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical problems
• are pregnant or plan to become pregnant. It is not known if clonazepam tablets can harm your unborn baby.

Tell your healthcare provider right away if you become pregnant while taking clonazepam tablets. You and

your healthcare provider will decide if you should take clonazepam tablets while you are pregnant.

• Studies in pregnant animals have shown harmful effects of benzodiazepine medications (including the active ingredient in clonazepam tablets) on the developing fetus.
• Children born to mothers receiving benzodiazepine medications (including clonazepam tablets) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, hypothermia, and withdrawal symptoms.

• If you become pregnant while taking clonazepam tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy
• are breastfeeding or plan to breastfeed. Clonazepam can pass into breast milk. You and your healthcare provider should decide how you will feed your baby while you take clonazepam tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking clonazepam tablets with certain other medicines can cause side effects or affect how well clonazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take clonazepam tablets?

• Take clonazepam tablets exactly as your healthcare provider tells you. If you take clonazepam tablets for seizures, your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms.
• Clonazepam is available as a tablet.
• Do not stop taking clonazepam tablets without first talking to your healthcare provider. Stopping clonazepam tablets suddenly can cause serious problems.
• Clonazepam tablets should be taken with water and swallowed whole.
• If you take too much clonazepam tablets, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking clonazepam tablets?

• Clonazepam tablets can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affects you.
• Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking clonazepam tablets  until  you talk to  your  healthcare  provider. When taken with alcohol or medicines that cause sleepiness or dizziness, clonazepam tablets may make your sleepiness or dizziness much worse.

What are the possible side effects of clonazepam tablets?

See “What is the most important information I should know about clonazepam tablets?”

Clonazepam tablets can also make your seizures happen more often or make them worse. Call your healthcare provider right away if your seizures get worse while taking clonazepam tablets.

The most common side effects of clonazepam tablets include:

• drowsiness                                                                     • dizziness                                                   • fatigue
• problems with walking and coordination                      • depression                                                • problems with memory

These are not all the possible  side  effects of  clonazepam tablets.  Call  your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or contact Advagen Pharma Ltd, at 866-488-0312.

How should I store clonazepam tablets?

• Store clonazepam tablets at 20°C to 25°C (68°F -77°F) [See USP Controlled Room Temperature].
• Keep clonazepam tablets and all medicines out of the reach of children.

General Information about the safe and effective use of clonazepam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clonazepam tablets for a condition for which it was not prescribed. Do not give clonazepam tablets to other people, even if they have the same  symptoms  that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about clonazepam tablets that is written for health professionals.

For more information, contact Advagen Pharma Ltd, at 866-488-0312.

What are the ingredients in clonazepam tablets?

Active ingredient: clonazepam

Inactive ingredients:

• 0.5 mg tablets contain lactose monohydrate, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, FD & C Yellow 6 Al Lake, D & C Yellow 10 Al Lake
• 1 mg tablets contain lactose monohydrate, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, FD & C Blue 1 Al lake and FD & C Blue 2 Al lake
• 2 mg tablets contain lactose monohydrate, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Rubicon Research Private Limited

Ambernath, Dist: Thane, 421506 India

Distributed by:

Advagen Pharma Ltd

666 Plainsboro Road

Suite 605 Plainsboro, NJ  08536, US

Revision: 04/22

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL

Clonazepam Tablets USP, 0.5 mg - NDC 72888-152-01 - 30 Tablets Label

Clonazepam Tablets USP, 0.5 mg - NDC 72888-152-01 - 100 Tablets Label

Clonazepam Tablets USP, 0.5 mg - NDC 72888-152-05 - 500 Tablets Label

Clonazepam Tablets USP, 0.5 mg - NDC 72888-152-00 - 1000 Tablets Label

Clonazepam Tablets USP, 1 mg - NDC 72888-153-30 - 30 Tablets Label

Clonazepam Tablets USP, 1 mg - NDC 72888-153-01 - 100 Tablets Label

Clonazepam Tablets USP, 1 mg - NDC 72888-153-05 - 500 Tablets Label

Clonazepam Tablets USP, 1 mg - NDC 72888-153-00 - 1000 Tablets Label

Clonazepam Tablets USP, 2 mg - NDC 72888-154-30 - 30 Tablets Label

Clonazepam Tablets USP, 2 mg - NDC 72888-154-01 - 100 Tablets Label

Clonazepam Tablets USP, 2 mg - NDC 72888-154-05 - 500 Tablets Label

Clonazepam Tablets USP, 2 mg - NDC 72888-154-00 - 1000 Tablets Label