DRUG ABUSE AND DEPENDENCE SECTION

DRUG ABUSE AND DEPENDENCE

Controlled Substance:

Clonazepam is a Schedule IV controlled substance.

Abuse:

Clonazepam 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 of benzodiazepines 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 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 or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Clonazepam 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 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 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.

ADVERSE REACTIONS SECTION

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, 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:

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 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.

Commonly Observed Adverse Events:

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-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-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 in Panic Disorder:

Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam 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, 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

SPL MEDGUIDE SECTION

MEDICATION GUIDE

Dispense with Medication Guide available at:

www.solcohealthcare.com/medguide/clonazepam- tablets.pdf

Clonazepam Tablets

for oral use

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

•

**Clonazepam tablets are 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 clonazepamtablets and opioids affects you. 

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

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**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.**

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**You can develop an addiction even if you take clonazepam tablets as prescribed by your healthcare provider.**

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**Take clonazepam tablets exactly as your healthcare provider prescribed.**

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Do not share your clonazepamtablets with other people. 

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Keep clonazepam tablets in a safe place and away from children. 

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**Physical dependence and withdrawal reactions.**Clonazepam tablets can cause physical dependence and withdrawal reactions.

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**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.**

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**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. 

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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. 

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Do not take more clonazepam tablets than prescribed or take clonazepam tablets for longer than prescribed. 

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**Clonazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.**

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Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affect you. 

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Clonazepam tablets may cause problems with your coordination, especially when you are walking or picking things up.

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**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. 

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**Like other antiepileptic drugs, clonazepam tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.**
**Call a 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

attempts 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?

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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.

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**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 a prescription medicine used alone or with other medicines to treat: 

•

certain types of seizure disorders (epilepsy) in adults and children 

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panic disorder with or without fear of open spaces (agoraphobia) in adults 

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**Clonazepam tablets are 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:

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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:

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have liver or kidney problems 

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have lung problems (respiratory disease) 

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have or have had depression, mood problems, or suicidal thoughts or behavior 

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have any other medical problems 

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are pregnant or plan to become pregnant. 

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Taking clonazepam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). 

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Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with clonazepam tablets.

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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.

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are breastfeeding or plan to breastfeed. Clonazepam can pass into breast milk. 

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Breastfeeding during treatment with clonazepam tablets may cause your baby to have sleepiness, feeding problems, and decreased weight gain. 

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Talk to your healthcare provider about the best way to 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?

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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. 

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Clonazepam is available as a tablet. 

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Do not stop taking clonazepam tablets without first talking to your healthcare provider. Stopping clonazepam tablets suddenly can cause serious problems. 

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Clonazepam tablets should be taken with water and swallowed whole. 

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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?

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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 affect you. 

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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 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. You may also report side effects to Solco Healthcare US, LLC at 1-866-257-2597.

How should I store clonazepam tablets?

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Store clonazepam tablets at room temperature, between 68°F to 77°F (20°C to 25°C). 

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**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.

What are the ingredients in clonazepam tablets?

**Active ingredient:**clonazepam

**Inactive ingredients:**colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose, with the following colorants: 0.5 mg – D&C Yellow #10 aluminum lake; 1 mg – FD&C Blue #1 aluminum lake.

Manufactured by:
Prinston Laboratories
Charlotte, NC 28206, USA

Distributed by:
Solco Healthcare US, LLC
Somerset, NJ 08873, USA

Packaged and Distributed By:

MAJOR® PHARMACEUTICALS

Indianapolis, IN 46268 USA

Refer to package label for Distributor's NDC Number

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

Revised: 04/2023