See also:
What is the most important information I should know about Epitril?
You should not use this medication if you have severe liver disease, of if you are allergic to Epitril or to other benzodiazepines, such as alprazolam (Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), or oxazepam (Serax).
Epitril may cause harm to an unborn baby, and may cause breathing or feeding problems in a newborn. But having seizures during pregnancy could harm both mother and baby. Do not start or stop taking Epitril during pregnancy without medical advice.
You may have thoughts about suicide while taking this medication. Your doctor will need to check you at regular visits. Do not miss any scheduled appointments. Call your doctor at once if you have any new or worsening symptoms 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.
Before you take Epitril, tell your doctor if you have kidney or liver disease, glaucoma, any breathing problems, or a history of depression, suicidal thoughts, or addiction to drugs or alcohol.
Do not drink alcohol while taking Epitril. This medication can increase the effects of alcohol.
Epitril may be habit-forming and should be used only by the person it was prescribed for. Keep the medication in a secure place where others cannot get to it.
See also:
What are the possible side effects of Epitril?
The adverse experiences for Epitril are provided separately for patients with seizure disorders and with panic disorder.
Seizure DisordersThe most frequently occurring side effects of Epitril are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, including those identified during postapproval use of Epitril are:
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums
Genitourinary: Dysuria, enuresis, nocturia, urinary retention
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase
Musculoskeletal: Muscle weakness, pains
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, ''glassy-eyed'' appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
Psychiatric: Confusion, depression, amnesia, 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
Panic DisorderAdverse events during exposure to Epitril 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 TrialsAdverse Events Associated With Discontinuation Of TreatmentOverall, the incidence of discontinuation due to adverse events was 17% in Epitril 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 Epitril than that of placebo included the following:
Table 2 : Most Common Adverse Events ( ≥ 1%) Associated with Discontinuation of Treatment
| Adverse Event | Epitril (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% |
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 6to 9-week trials. Events reported in 1% or more of patients treated with Epitril (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 9Week Placebo-Controlled Clinical Trials*
| Adverse Event by Body System | Epitril Maximum Daily Dose | |||||
| < 1mg n=96 % | 1- < 2mg n=129 % | 2- < 3mg n=113 % | > 3mg n=235 % | All Epitril 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† | 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 MechanismDisorders | ||||||
| Influenza Urinary System | 3 | 2 | 5 | 5 | 4 | 3 |
| 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 |
| * Events reported by at least 1% of patients treated with Epitril 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 (Epitril), 102 (placebo) for male, and 334 (Epitril), 192 (placebo) for female. |
Table 4 : Incidence of Most Commonly Observed Adverse Events* in Acute Therapy in Pool of 6-to 9-Week Trials
| Adverse Event (Genentech Preferred Term) | Epitril (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 Epitril patients was ≥ 5% and at least twice that in the placebo patients. |
In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of Epitril-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 Epitril-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 Epitril group than the placebo group suggesting that clonazepamtreated patients were not experiencing a worsening or emergence of clinical depression.
Other Adverse Events Observed During The Premarketing Evaluation Of Epitril In Panic DisorderFollowing is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with Epitril 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 Epitril, 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
Drug Abuse And DependenceControlled Substance ClassEpitril is a Schedule IV controlled substance.
Physical And Psychological DependenceWithdrawal symptoms, similar in character to those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations, behavioral disorder, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of Epitril. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving Epitril or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
Following the short-term treatment of patients with panic disorder in Studies 1 and 2, 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 Epitril studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.
Epitril
Orally Disintegrating Tablets USP 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, Epitril
Orally Disintegrating Tablets USP 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.
Panic Disorder
Epitril
Orally Disintegrating Tablets USP are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. 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.
The efficacy of Epitril was established in two 6 to 9 week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder.
Panic disorder (DSM-IV) 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.
The effectiveness of Epitril 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 Epitril
Orally Disintegrating Tablets USP for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Epitril (Epitril) is a benzodiazepine. Epitril affects chemicals in the brain that may be unbalanced. Epitril is also a seizure medicine, also called an anti-epileptic drug.
Epitril is used to treat certain seizure disorders (including absence seizures or Lennox-Gastaut syndrome) in adults and children.
Epitril is also used to treat panic disorder (including agoraphobia) in adults.
Epitril is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one.
Use Epitril orally disintegrating tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Epitril orally disintegrating tablets.
There are specific as well as general uses of a drug or medicine. A medicine can be used to prevent a disease, treat a disease over a period or cure a disease. It can also be used to treat the particular symptom of the disease. The drug use depends on the form the patient takes it. It may be more useful in injection form or sometimes in tablet form. The drug can be used for a single troubling symptom or a life-threatening condition. While some medications can be stopped after few days, some drugs need to be continued for prolonged period to get the benefit from it.Use: Labeled IndicationsPanic disorder: Treatment of panic disorder, with or without agoraphobia.
Seizure disorders: Mono- or adjunctive therapy in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures; absence seizures (petit mal) unresponsive to succinimides.
Off Label UsesBipolar disorder, manic or mixed episodes
Data from a meta-analysis of 5 randomized, controlled trials supports the use of Epitril in the treatment of acute bipolar mania. Additional data may be necessary to further define the role of Epitril in this condition.
Based on the American Academy of Neurology guideline for the treatment of tardive syndromes, Epitril given for tardive dyskinesia is probably effective in decreasing tardive dyskinesia symptoms in the short-term (approximately 3 months) and is suggested for the short-term treatment of tardive dyskinesia.
Tic disordersData from a limited number of patients studied in a single-blind and two retrospective studies suggest that Epitril may be beneficial for multifocal tic disorder or Tourette disorder. Additional data may be necessary to further define the role of Epitril in these conditions.
Epitril is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.
Seizure DisordersAdultsThe 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.
The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding Epitril to an existing anticonvulsant regimen.
Pediatric PatientsEpitril 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 PatientsThere is no clinical trial experience with Epitril in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of Epitril and observed closely.
Panic DisorderAdultsThe 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 Epitril should remain on it. Therefore, the physician who elects to use Epitril for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Pediatric PatientsThere is no clinical trial experience with Epitril in panic disorder patients under 18 years of age.
Geriatric PatientsThere is no clinical trial experience with Epitril in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of Epitril and observed closely.
How suppliedEpitril tablets are available as scored tablets with a K-shaped perforation—0.5 mg, orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg, blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.
Imprint on tablets:
0.5 mg — ½ Epitril (front) ROCHE (scored side)
1 mg — 1 Epitril (front) ROCHE (reverse side)
2 mg — 2 Epitril (front) ROCHE (reverse side)
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Distributed by: Genentech USA, Inc., A Member of the Roche Group 1 DNA Way, South San Francisco, CA 94080-4990. Revised: March 2016
See also:
What other drugs will affect Epitril?
Effect of Epitril on the Pharmacokinetics of Other Drugs: Epitril does not appear to alter the pharmacokinetics of phenytoin, carbamazepine, or phenobarbital. The effect of Epitril on the metabolism of other drugs has not been investigated.
Effect of Other Drugs on the Pharmacokinetics of Epitril: Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter Epitril pharmacokinetics.
In a study in which the 2 mg Epitril 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 Epitril was 10% lower and the Cmax of Epitril 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 Epitril. Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital, induce Epitril metabolism, causing an approximately 30% decrease in plasma Epitril levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in Epitril metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving Epitril.
Pharmacodynamic Interactions: The 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.
