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. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. 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.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Musculoskeletal: Muscle weakness, pains.
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Klonopin is 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.
0.5 mg - 1/2 KLONOPIN (front) ROCHE (scored side) 1 mg - 1 KLONOPIN (front) ROCHE (reverse side) 2 mg - 2 KLONOPIN (front) ROCHE (reverse side).
In some cases, these may diminish with time; behavior problems have been noted in approximay 25% of patients. Experience in treatment of seizures has shown that drowsiness has occurred in approximay 50% of patients and ataxia in approximay 30%. Others, listed by system, including those identified during postapproval use of Klonopin are: Cardiovascular: Palpitations. The most frequently occurring side effects of Klonopin are referable to CNS depression.
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. There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it.
These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients. Events are further categorized by body system and listed in order of decreasing frequency.
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration Vascular (Extracardiac) Disorders: thrombophlebitis leg.
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid -related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is compley withdrawn.
In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.
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 ).
There is no clinical trial experience with Klonopin in panic disorder patients under 18 years of age.
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 clonazepamtreated patients were not experiencing a worsening or emergence of clinical depression. 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.
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages.
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids.
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Klonopin is administered orally. If doses are not equally divided, the largest dose should be given before retiring. 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. Whenever possible, the daily dose should be divided into three equal 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.
The efficacy of Klonopin was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see Clinical Trials ).
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 ).
The physician who elects to use Klonopin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials.
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. Adverse events during exposure to Klonopin were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing.
Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin 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 Klonopin than that of placebo included the following:.
Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums.
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo.
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.
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. 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. 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. The initial dose for adults with panic disorder is 0.25 mg bid. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.
† Indicates that the p-value for the dose-trend test (Cochran-Man-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. 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 n=96 % 1- <2mg n=129 % 2- <3mg n=113 % ≥3mg n=235 % All Klonopin Groups N=574 % Placebo N=294 % Central & Peripheral Nervous System Somnolence† 26 35 50 36 37 10 Dizziness 5 5 12 8 8 4 Coordination Abnormal† Ataxia† Dysarthria† Psychiatric Depression Memory Disturbance Nervousness Inlectual Ability Reduced Emotional Lability Libido Decreased Confusion Respiratory System Upper Respiratory Tract Infection† 10 10 7 6 8 4 Sinusitis Rhinitis Coughing Pharyngitis Bronchitis Gastrointestinal System Constipation† Appetite Decreased Abdominal Pain† Body as a Whole Fatigue Allergic Reaction Musculoskeletal Myalgia Resistance Mechanism Disorders Influenza Urinary System Micturition Frequency Urinary Tract Infection † Vision Disorders Blurred Vision Reproductive Disorders‡ Female Dysmenorrhea Colpitis Male Ejaculation Delayed Impotence * Events reported by at least 1% of patients treated with Klonopin and for which the incidence was greater than that for placebo.
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.
Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, or if you feel agitated, irritable, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia.
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema.
Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.
The adverse experiences for Klonopin are provided separay for patients with seizure disorders and with panic disorder.
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase.
Genitourinary: Dysuria, enuresis, nocturia, urinary retention.
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 Klonopin (doses ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.
Special Senses Other, Disorders: taste loss.
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain.
RISKS FROM CONCOMITANT USE WITH OPIOIDS.
Monitoring of phenytoin concentration is recommended when clonazepam is co-administrated with phenytoin. Clonazepam has the potential to influence concentrations of phenytoin. Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Metabolic and Nutritional Disorders: thirst, gout.
Revised: Oct 2017. Distributed by: Genentech USA,Inc,A member of the Roche group 1DNA way,South san Franciso, CA.
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.
Some loss of effect may occur during the course of clonazepam treatment (see PRECAUTIONS : Loss Of Effect ).
Call your doctor at once if you have a serious side effect such as:
An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. 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.
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy.
6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation containing 1 mg or 2 mg of clonazepam. 2 Lake. Each tablet also contains lactose, magnesium stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5 mg—FD&C Yellow No.
Heart Rate and Rhythm Disorders: palpitation.
Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents (e.g., fluconazole ), should be used cautiously in patients receiving clonazepam because they may impair the metabolism of clonazepam leading to exaggerated concentrations and effects. The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19 inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam. Cytochrome P- 450 inducers, such as phenytoin, carbamazepine, lamotrigine, and phenobarbital induce clonazepam metabolism, causing an approximay 38% decrease in plasma clonazepam levels.
Imprint on tablets:. Klonopin tablets are available as scored tablets with a K-shaped perforation - 0.5 mg, orange ( NDC ; and unscored tablets with a K-shaped perforation - 1 mg, blue ( NDC ; 2 mg, white ( NDC - bottles of 100.
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness.
Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H -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:.
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).
Reproductive Disorders, Male: ejaculation decreased.
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder.
KLONOPIN ( clonazepam ) Tablets, for Oral Use WARNING.
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.
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 Plaet, Bleeding and Clotting Disorders: bleeding dermal.
Reproductive Disorders, Female: breast pain, menstrual irregularity.
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.
Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis.
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia.
Klonopin is 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, Klonopin may be useful.
The following paradoxical reactions have been observed: irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, abnormal dreams, hallucinations.
It is important to emphasize that, although the events occurred during treatment with Klonopin, they were not necessarily caused by it. 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 acuy life-threatening. 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.
Table 2 Most Common Adverse Events (≥1%) Associated with Discontinuation of Treatment Adverse Event Klonopin (N=574) Placebo (N=294) Somnolence 7% 1% Depression 4% 1% Dizziness 1% <1% Nervousness 1% 0% Ataxia 1% 0% Inlectual Ability Reduced 1% 0%
The tablets should be administered with water by swallowing the tablet whole. Clonazepam is available as a tablet.
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS ).
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) 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.
Maximum recommended daily dose is 20 mg. Maintenance dosage must be individualized for each patient depending upon response. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequay controlled or until side effects preclude any further increase. The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses.
Cardiovascular Disorders: chest pain, hypotension postural.
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