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Clonazepam
Overview
What is Clonazepam?
Clonazepam a benzodiazepine, is available for oral administration as scored tablets containing 0.5 mg, 1 mg or 2 mg of clonazepam. In addition, each tablet also contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 0.5 mg tablet also contains D&C Red #30 aluminum lake. The 1 mg tablet also contains D&C Yellow #10HT aluminum lake.
Chemically, clonazepam is 5-(-Chlorophenyl)-1,3-dihydro-7-nitro-2-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder insoluble in water, sparingly soluble in acetone and chloroform and slightly soluble in alcohol. It has a molecular weight of 315.72 and the following structural formula:
What does Clonazepam look like?
What are the available doses of Clonazepam?
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What should I talk to my health care provider before I take Clonazepam?
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How should I use Clonazepam?
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 may be useful.
In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.
Clonazepam tablets should be administered with water by swallowing the tablet whole.
What interacts with Clonazepam?
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.
What are the warnings of Clonazepam?
Interference With Cognitive And Motor Performance:
Since clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam therapy (see and ).
Suicidal Behavior and Ideation:
Antiepileptic drugs (AEDs), including clonazepam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
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 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.
| 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 |
Pregnancy Risks:
Data from several sources raise concerns about the use of clonazepam during pregnancy.
Animal Findings:
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5, or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended daily human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m basis).
General Concerns And Considerations About Anticonvulsants:
Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors ( eg, genetic factors or the epileptic condition itself) may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus.
General Concerns About Benzodiazepines:
An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.
There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.
Advice Regarding The Use Of Clonazepam In Women Of Childbearing Potential:
In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women.
Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.
Withdrawal Symptoms:
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see ).
What are the precautions of Clonazepam?
General
When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.
Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.
The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.
Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.
Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, clonazepam should be used with caution in patients with chronic respiratory diseases.
Information for Patients
Patients should be instructed to take clonazepam only as prescribed. Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam:
Dose ChangesTo assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.
Interference With Cognitive And Motor PerformanceBecause benzodiazepines have the potential to impair judgement, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.
Suicidal Thinking and Behavior:
Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with clonazepam (see ). Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see ).
Nursing: Patients should be advised not to breastfeed an infant if they are taking clonazepam.
Concomitant MedicationPatients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
AlcoholPatients should be advised to avoid alcohol while taking clonazepam.
Drug Interactions
Effect Of Clonazepam On The Pharmacokinetics Of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Effect Of Other Drugs On The Pharmacokinetics Of Clonazepam: Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.
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 C of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. 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, should be used cautiously in patients receiving clonazepam.
Pharmacodynamic InteractionsThe CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/m basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.
Pregnancy
Pregnancy Category D
To provide information regarding the effects of in utero exposure to clonazepam, physicians are advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on this registry can also be found at the website http://www.aedpregnancyregistry.org/.
Labor and Delivery
The effect of clonazepam on labor and delivery in humans has not been specifically studied however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena (see ).
Nursing Mothers
Mothers receiving clonazepam should not breastfeed their infants.
Pediatric Use
Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder (see and ).
Safety and effectivess in pediatric patients with panic disorder below the age of 18 have not been established.
Geriatric Use
Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by kidneys; to avoid their excess accumulation, caution should be excercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal functions at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patient generally should be started on low doses of clonazepam and observed closely.
What are the side effects of Clonazepam?
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, are:
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.
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.
Musculoskeletal: Muscle weakness, pains.
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain.
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia.
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase.
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 approximately 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.
| Adverse Event | Clonazepam | Placebo | |||||||||||
| (N=574) | (N=294) | ||||||||||||
| Somnolence | 7% | 1% | |||||||||||
| Depression | 4% | 1% | |||||||||||
| Dizziness | 1% | <1% | |||||||||||
| Nervousness | 1% | 0% | |||||||||||
| Ataxia | 1% | 0% | |||||||||||
| Intellectual Ability Reduced | 1% | 0% | |||||||||||
| * Events reported by at least 1% of patients treated with clonazepam 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. | |||||||||||||
| All Clonazepam | |||||||||||||
| Adverse Event by | <1 mg | 1-<2 mg | 2-< mg | Groups | Placebo | ||||||||
| Body System | 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 | 1 | 2 | 2 | 1 | 1 | 0 | |||||||
| Micturition Frequency | 0 | 0 | 2 | 2 | 1 | 0 | |||||||
| Urinary Tract Infection† | |||||||||||||
| Vision Disorders | 1 | 2 | 3 | 0 | 1 | 1 | |||||||
| Blurred Vision | |||||||||||||
| Reproductive Disorders‡ | |||||||||||||
| Female | 0 | 6 | 5 | 2 | 3 | 2 | |||||||
| Dysmenorrhea | 4 | 0 | 2 | 1 | 1 | 1 | |||||||
| Colpitis | |||||||||||||
| Male | 0 | 0 | 2 | 2 | 1 | 0 | |||||||
| Ejaculation Delayed | 3 | 0 | 2 | 1 | 1 | 0 | |||||||
| Impotence | |||||||||||||
| *Treatment-emergent events for which the incidence in the clonazepam patients was 5% and at least twice that in the placebo patients. | |||||||||||||
| Adverse Event | Clonazepam | Placebo | |||||||||||
| (N=574) | (N=294) | ||||||||||||
| Somnolence | 37% | 10% | |||||||||||
| Depression | 7% | 1% | |||||||||||
| Coordination Abnormal | 6% | 0% | |||||||||||
| Ataxia | 5% | 0% |
Other Adverse Events Observed During Tthe 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, aggressive reaction, apathy, attention lack, excitement, feeling mad, 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, pruritis, 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
What should I look out for while using Clonazepam?
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.
What might happen if I take too much Clonazepam?
How should I store and handle Clonazepam?
Store at controlled room temperature, 20º to 25ºC (68º to 77ºF) [ USP]. The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF); that results in a mean kinetic temperature calculated to be not more than 25ºC; and that allows for excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, and warehouses.Clonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJWClonazepam Tablets, USP are available as follows: 0.5 mg — Each pink, round tablet imprinted and 33 on one side and scored on the other side contains 0.5 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-915-30). 1 mg — Each yellow, round tablet imprinted and 34 on one side and scored on the other side contains 1 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-917-30). 2 mg — Each white, round tablet imprinted and 35 on one side and scored on the other side contains 2 mg of clonazepam USP. Tablets are supplied in blisters of 30 (NDC 67046-919-30).Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).Dispense in tight, light-resistant containers as defined in the USP.Manufactured by: Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8804Revised — June 2009Repackaged by: Contract Pharmacy Services-PA125 Titus Ave Suite 200Warrington, PA 18976 USAOriginal--07/2010--NJW
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.
Non-Clinical Toxicology
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.Effect Of Clonazepam On The Pharmacokinetics Of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Effect Of Other Drugs On The Pharmacokinetics Of Clonazepam: Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.
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 C of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. 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, should be used cautiously in patients receiving clonazepam.
Pharmacodynamic InteractionsThe CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.
The adverse experiences for clonazepam are provided separately for patients with seizure disorders and with panic disorder.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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