Klonopin: Package Insert and Label Information (Page 4 of 5)

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	Clonazepam(N=574)	Placebo(N=294)
* Treatment-emergent events for which the incidence in the clonazepam patients was ≥5% and at least twice that in the placebo patients.
Somnolence	37%	10%
Depression	7%	1%
Coordination Abnormal	6%	0%
Ataxia	5%	0%

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 Klonopin-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 Klonopin-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 Klonopin in Panic Disorder

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

Klonopin contains clonazepam, a Schedule IV controlled substance.

Abuse

Klonopin 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

Klonopin 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 Klonopin or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Klonopin 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 Klonopin 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 Klonopin 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

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Abuse, Misuse, and Addiction). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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 Klonopin 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

Klonopin is 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 Klonopin in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of Klonopin 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 twice daily 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 Klonopin 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 Klonopin in panic disorder patients under 18 years of age.

Geriatric Patients

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

Discontinuation or Dosage Reduction of KLONOPIN

To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue Klonopin 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

Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg, orange (NDC 61269-605-10); and unscored tablets with a K-shaped perforation—1 mg, blue (NDC 61269-610-10); 2 mg, white (NDC 61269-620-10)—bottles of 100.

Imprint on tablets:

0.5 mg	—	1/2 KLONOPIN (front) No imprint (scored side)	(click image for full-size original)
1 mg	—	1 KLONOPIN (front) No imprint (reverse side)	(click image for full-size original)
2 mg	—	2 KLONOPIN (front) No imprint (reverse side)	(click image for full-size original)

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Distributed by:

H2-Pharma, LLC
Montgomery, AL
36117, USA

Licensed by:

CHEPLAPHARM Arzneimittel GmbH
Ziegelhof 24, 17489 GreifswaldGermany

Revised: 1/2023

© 2021 CHEPLAPHARM Arzneimittel GmbH

All rights reserved.

This Medication Guide has been approved by the U.S. Food and Drug Administration.			Revised: 1/2023
MEDICATION GUIDEKLONOPIN (KLON-oh-pin) (clonazepam)tablets, for oral use, CIV
What is the most important information I should know about KLONOPIN? KLONOPIN 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 KLONOPIN and opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including KLONOPIN, 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 KLONOPIN. 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 KLONOPIN as prescribed by your healthcare provider. Take KLONOPIN exactly as your healthcare provider prescribed. Do not share your KLONOPIN with other people. Keep KLONOPIN in a safe place and away from children. Physical dependence and withdrawal reactions. KLONOPIN can cause physical dependence and withdrawal reactions. Do not suddenly stop taking KLONOPIN. Stopping KLONOPIN 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 KLONOPIN than prescribed or take KLONOPIN for longer than prescribed. KLONOPIN 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 KLONOPIN affects you. KLONOPIN 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 KLONOPIN until you talk to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, KLONOPIN may make your sleepiness or dizziness worse. Like other antiepileptic medicines, KLONOPIN 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 new or worse anxiety trouble sleeping (insomnia) acting on dangerous impulses	attempts to commit suicide feeling agitated or restless new or worse irritability an extreme increase in activity and talking (mania)	new or worse depression panic attacks acting aggressive, being angry, or violent 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 KLONOPIN without first talking to a healthcare provider. Stopping KLONOPIN suddenly can cause serious problems. Stopping KLONOPIN suddenly can cause seizures that will not stop (status epilepticus).
What is KLONOPIN? KLONOPIN is a 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 KLONOPIN is a federally controlled substance (C-IV) because it contains clonazepam that can be abused or lead to dependence. Keep KLONOPIN in a safe place to prevent misuse and abuse. Selling or giving away KLONOPIN 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 KLONOPIN is safe or effective in treating panic disorder in children younger than 18 years old.
Who should not take KLONOPIN? Do not take KLONOPIN 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 KLONOPIN, 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.o Taking KLONOPIN 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).o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with KLONOPIN.o If you become pregnant while taking KLONOPIN, 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. KLONOPIN can pass into breast milk.o Breastfeeding during treatment with KLONOPIN may cause your baby to have sleepiness, feeding problems, and decreased weight gain.o Talk to your healthcare provider about the best way to feed your baby while you take KLONOPIN. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking KLONOPIN with certain other medicines can cause side effects or affect how well KLONOPIN or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
How should I take KLONOPIN? Take KLONOPIN exactly as your healthcare provider tells you. If you take KLONOPIN for seizures, your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms. KLONOPIN is available as a tablet. Do not stop taking KLONOPIN without first talking to your healthcare provider. Stopping KLONOPIN suddenly can cause serious problems. KLONOPIN tablets should be taken with water and swallowed whole. If you take too much KLONOPIN, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking KLONOPIN? KLONOPIN can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how KLONOPIN affects you. Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking KLONOPIN until you talk to your healthcare provider. When taken with alcohol or medicines that cause sleepiness or dizziness, KLONOPIN may make your sleepiness or dizziness much worse.
What are the possible side effects of KLONOPIN?See “What is the most important information I should know about KLONOPIN?“KLONOPIN 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 KLONOPIN.The most common side effects of KLONOPIN include:
drowsiness problems with walking and coordination		dizziness depression	fatigue problems with memory
These are not all the possible side effects of KLONOPIN. 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 the Safety Call Center at 1-866-788-3904.
How should I store KLONOPIN? Store KLONOPIN between 59°F to 86°F (15°C to 30°C) Keep KLONOPIN and all medicines out of the reach of children
General Information about the safe and effective use of KLONOPIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KLONOPIN for a condition for which it was not prescribed. Do not give KLONOPIN 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 KLONOPIN that is written for health professionals.
What are the ingredients in KLONOPIN? Active ingredient: clonazepamInactive ingredients: Tablets: 0.5 mg tablets contain lactose, magnesium stearate, microcrystalline cellulose, corn starch, FD&C Yellow No. 6 Lake 1 mg tablets contain lactose, magnesium stearate, microcrystalline cellulose, corn starch, FD&C Blue No. 1 Lake and FD&C Blue No. 2 Lake 2 mg tablets contain lactose, magnesium stearate, microcrystalline cellulose, corn starch Distributed by:H2-Pharma, LLC Montgomery, AL36117, USA Licensed by:CHEPLAPHARM Arzneimittel GmbH Ziegelhof 24, 17489 GreifswaldGermany © 2021 CHEPLAPHARM Arzneimittel GmbH All rights reserved. For additional Medication Guides, go to www.h2-pharma.com/products/klonopin/medicationguide.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):