ients whose diagnoses corresponded to the dsm-iiir category of panic disorder (see cllnical pharmacology: clinical trials ). panic disorder (dsm-iv) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. the effectiveness of clonazepam in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. the physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see dosage and administration ).

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 to100 years) in the clinical trials analyzed. table 1 shows absolute and relative risk by indication for all evaluated aeds. table 1 risk by indication for antiepileptic drugs in the pooled analysis indication placebo patients drug patients with relative risk: risk difference: with events per events per 1000 incidence of events additional drug 1000 patients patients in drug patients with events patients/incidence per 1000 patients in placebo patients epilepsy 1 3.4 3.5 2.4 psychiatric 5.7 8.5 1.5 2.9 other 1 1.8 1.9 0.9 total 2.4 4.3 1.8 1.9 the relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. anyone considering prescribing clonazepam 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. 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 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/m2 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/m2 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 drug abuse and dependence ).

doses. dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. whenever possible, the daily dose should be divided into three equal doses. if doses are not equally divided, the largest dose should be given before retiring. geriatric patients: there is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older. in general, elderly patients should be started on low doses of clonazepam and observed closely (see precautions: geriatric use ). panic disorder: adults: the initial dose for adults with panic disorder is 0.25 mg bid. an increase to the target dose for most patients of 1 mg/day may be made after 3 days. the recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. to reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable. treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn. there is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. therefore, the physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. pediatric patients: there is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age. geriatric patients: there is no clinical trial experience with clonazepam in panic disorder patients 65 years of age and older. in general, elderly patients should be started on low doses of clonazepam and observed closely (see precautions: geriatric use ).

rbances). 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 twice or greater for clonazepam than that of placebo included the following: table 2 most common adverse events (≥1%) associated with discontinuation of treatment adverse event clonazepam(n=574) placebo (n=294) somnolence 7% 1% depression 4% 1% dizziness 1% <1% nervousness 1% 0% ataxia 1% 0% intellectual ability reduced 1% 0% adverse events occurring at an incidence of 1% or more among clonazepam-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. table 3. treatment-emergent adverse event incidence in 6- to 9-week placebo-controlled clinical trials* clonazepam maximum daily dose all clonazepam <1 mg 1-<2 mg 2-< 3mg >3 mg groups placebo adverse event by n=96 n=129 n=113 n=235 n=574 n=294 body system % % % % % % * 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. central & peripheral nervous system somnolence† 26 35 50 36 37 10 dizziness 5 5 12 8 8 4 coordination abnormal† 1 2 7 9 6 0 ataxia† 2 1 8 8 5 0 dysarthria† 0 0 4 3 2 0 psychiatric depression 7 6 8 8 7 1 memory disturbance 2 5 2 5 4 2 nervousness 1 4 3 4 3 2 intellectual ability reduced 0 2 4 3 2 0 emotional lability 0 1 2 2 1 1 libido decreased 0 1 3 1 1 0 confusion 0 2 2 1 1 0 respiratory system upper respiratory tract infection† 10 10 7 6 8 4 sinusitis 4 2 8 4 4 3 rhinitis 3 2 4 2 2 1 coughing 2 2 4 0 2 0 pharyngitis 1 1 3 2 2 1 bronchitis 1 0 2 2 1 1 gastrointestinal system constipation† 0 1 5 3 2 2 appetite decreased 1 1 0 3 1 1 abdominal pain† 2 2 2 0 1 1 body as a whole fatigue 9 6 7 7 7 4 allergic reaction 3 1 4 2 2 1 musculoskeletal myalgia 2 1 4 0 1 1 resistance mechanism disorders influenza 3 2 5 5 4 3 urinary system micturition frequency 1 2 2 1 1 0 urinary tract infection† 0 0 2 2 1 0 vision disorders blurred vision 1 2 3 0 1 1 reproductive disorders‡ female dysmenorrhea 0 6 5 2 3 2 colpitis 4 0 2 1 1 1 male ejaculation delayed 0 0 2 2 1 0 impotence 3 0 2 1 1 0 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 placebo (preferred term) (n=574) (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 clonazepam-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. in these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam-treated patients compared to 1% of placebo-treated patients. while these findings are noteworthy, hamilton depression rating scale (ham-d) data collected in these trials revealed a larger decline in ham-d scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression. other adverse events observed during the premarketing evaluation of clonazepam in panic disorder: following is a list of modified cigy terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam at multiple doses during clinical trials. all reported events are included except those already listed in table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. it is important to emphasize that, although the events occurred during treatment with clonazepam, they were not necessarily caused by it. events are further categorized by body system and listed in order of decreasing frequency. these adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients. body as a whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized cardiovascular disorders: chest pain, hypotension postural central and peripheral nervous system disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching gastrointestinal system disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids hearing and vestibular disorders: vertigo, otitis, earache, motion sickness heart rate and rhythm disorders: palpitation metabolic and nutritional disorders: thirst, gout musculoskeletal system disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee platelet, bleeding and clotting disorders: bleeding dermal psychiatric disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, 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, 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

azepam are reached within 1 to 4 hours after oral administration. clonazepam is approximately 85% bound to plasma proteins. clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. this derivative can be acetylated, hydroxylated and glucuronidated. cytochrome p-450 including cyp3a, may play an important role in clonazepam reduction and oxidation. the elimination half-life of clonazepam is typically 30 to 40 hours. clonazepam pharmacokinetics are dose-independent throughout the dosing range. there is no evidence that clonazepam induces its own metabolism or that of other drugs in humans. pharmacokinetics in demographic subpopulations and in disease states: controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. thus, caution should be exercised when administering clonazepam to these patients. clinical trials: panic disorder: the effectiveness of clonazepam in the treatment of panic disorder was demonstrated in two double-blind, placebo-controlled studies of adult outpatients who had a primary diagnosis of panic disorder (dsm-iiir) with or without agoraphobia. in these studies, clonazepam was shown to be significantly more effective than placebo in treating panic disorder on change from baseline in panic attack frequency, the clinician’s global impression severity of illness score and the clinician’s global impression improvement score. study 1 was a 9-week, fixed-dose study involving clonazepam doses of 0.5, 1, 2, 3 or 4 mg/day or placebo. this study was conducted in four phases: a 1-week placebo lead-in, a 3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. a significant difference from placebo was observed consistently only for the 1 mg/day group. the difference between the 1 mg dose group and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. at endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic attacks, compared to 56% of placebo-treated patients. study 2 was a 6-week, flexible-dose study involving clonazepam in a dose range of 0.5 to 4 mg/day or placebo. this study was conducted in three phases: a 1-week placebo lead-in, a 6-week optimal-dose and a 6-week discontinuance phase. the mean clonazepam dose during the optimal dosing period was 2.3 mg/day. the difference between clonazepam and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. at endpoint, 62% of patients receiving clonazepam were free of full panic attacks, compared to 37% of placebo-treated patients. subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of race or gender.