ADVERSE REACTIONS
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, suicidal attempt (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 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 1 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 1 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 1. Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-Controlled Clinical Trials* | Clonazepam Maximum Daily Dose |
|---|
Adverse Event by
Body System | <1 mg n=96
% | 1-<2 mg n=129
% | 2-< mg n=113
% | > 3 mg n=235
% | All Clonazepam
Groups
N=574
% | Placebo N=294
% |
| * 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 | 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 | | | | | | |
Commonly Observed Adverse Events:
Table 2. Incidence of Most Commonly Observed Adverse Events* in Acute Therapy in Pool of 6- to 9-Week Trials | Adverse Event | Clonazepam
(N=574) | Placebo
(N=294) |
| *Treatment-emergent events for which the incidence in the clonazepam patients was > 5% and at least twice that in the placebo patients. |
| Somnolence | 37% | 10% |
| Depression | 7% | 1% |
| Coordination Abnormal | 6% | 0% |
| Ataxia | 5% | 0% |
Treatment-Emergent Depressive Symptoms: In the pool of two short-term placebo controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of 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 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 1 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 & 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 & 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
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REPORTS OF SUSPECTED CLONAZEPAM SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Clonazepam. The information is not vetted and should not be considered as verified clinical evidence.
Possible Clonazepam side effects / adverse reactions in 53 year old male
Reported by a pharmacist from United States on 2011-10-03
Patient: 53 year old male weighing 72.7 kg (159.9 pounds)
Reactions: Hypoventilation, Respiratory Failure, Unresponsive TO Stimuli, Mental Status Changes, Somnolence
Adverse event resulted in: hospitalization
Suspect drug(s):
Clonazepam
Possible Clonazepam side effects / adverse reactions in 80 year old female
Reported by a physician from United States on 2011-10-03
Patient: 80 year old female weighing 57.0 kg (125.4 pounds)
Reactions: Road Traffic Accident, Somnambulism, Somnolence
Suspect drug(s):
Clonazepam
Other drugs received by patient: Metoprolol Tartrate; Sertraline Hydrochloride; Hydrochlorthiazid
Possible Clonazepam side effects / adverse reactions in 31 year old female
Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-10-04
Patient: 31 year old female weighing 63.5 kg (139.7 pounds)
Reactions: Contusion, Tinnitus, Pruritus, Tachycardia, Sensory Loss, Schizophrenia, Serotonin Syndrome, Hyperhidrosis, Malaise, Incontinence, Balance Disorder, Emotional Disorder, Feeling of Body Temperature Change, Mood Swings, Back Pain, Drooling, Restlessness, Maternal Exposure During Pregnancy, Delirium, H1n1 Influenza, Premature Labour, Irritability, Sleep Disorder, Dissociation, Hypotonia, Vision Blurred, Parosmia, Pregnancy, Muscle Disorder, LIP Swelling, Drug Interaction, Speech Disorder, Musculoskeletal Stiffness, Depression, Decreased Appetite, Dyspnoea, Vomiting, Gastric PH Decreased, Arthralgia, Visual Impairment, Gait Disturbance, Asthenia, Agitation, Depersonalisation, Hallucination, Auditory, Headache, Pyrexia, Cyanosis, Poisoning, Urinary Retention, Oedema Mouth, Muscle Spasms, Feeling of Despair, Dystonia, Pain in Extremity, General Physical Health Deterioration, Hypoaesthesia, Drug Withdrawal Syndrome, Pupillary Disorder, Paraesthesia, Convulsion, Tremor, Cogwheel Rigidity, Feeling Jittery, Insomnia, Nervous System Disorder, Disturbance in Attention, Confusional State, Restless Legs Syndrome, Aphasia, Disorientation, Pallor, Viith Nerve Paralysis, Suicidal Ideation, Mania, Menstruation Irregular, Myalgia, Fatigue, Road Traffic Accident, Neck Pain, Skin Discolouration, Dizziness, Neuroleptic Malignant Syndrome, Blood Sodium Decreased, Hypersomnia, Nightmare, Swelling Face, Swollen Tongue, Eye Pain, Anxiety, Psychotic Disorder, Feeling Abnormal
Adverse event resulted in: life threatening event, hospitalization, disablity
Suspect drug(s):
Lorazepam
Dosage: 1 mg;po
Administration route: Oral
Indication: Sedative Therapy
Start date: 2011-02-24
End date: 2011-04-10
Mirtazapine
Dosage: 30 mg;po
Administration route: Oral
Indication: Depression
Start date: 2010-10-07
End date: 2010-10-12
Domperidone (Domperidone)
Indication: Product Used FOR Unknown Indication
Codeine Sulfate
Dosage: po
Administration route: Oral
Indication: Analgesic Therapy
Start date: 2011-06-15
End date: 2011-07-23
Phosphorate (Phosphorus)
Indication: Product Used FOR Unknown Indication
Quetiapine Fumarate
Dosage: 300 mg;po
Administration route: Oral
Indication: Psychotic Disorder
Start date: 2011-02-24
End date: 2011-05-06
Omeprazole
Indication: Gastric PH Decreased
Start date: 2011-03-01
Clonazepam
Dosage: po
Administration route: Oral
Indication: Sedative Therapy
Start date: 2011-02-24
End date: 2011-04-10
Procyclidine Hydrochloride 2MG TAB
Dosage: 20 mg;po
Administration route: Oral
Indication: Extrapyramidal Disorder
Start date: 2011-03-24
End date: 2011-05-06
Paroxetine HCL
Dosage: 20 mg;tid;po
Administration route: Oral
Indication: Product Used FOR Unknown Indication
Start date: 1999-01-01
End date: 2011-05-01
Tramadol HCL
Dosage: po
Administration route: Oral
Indication: Analgesic Therapy
Start date: 2008-12-01
End date: 2010-12-10
Amitriptyline HCL
Indication: Product Used FOR Unknown Indication
Paroxetine HCL
Dosage: 40 mg;po
Administration route: Oral
Indication: Depression
Start date: 1999-08-01
End date: 2011-07-06
Paroxetine HCL
Dosage: 40 mg;po
Administration route: Oral
Indication: Post-Traumatic Stress Disorder
Start date: 1999-08-01
End date: 2011-07-06
Other drugs received by patient: Diazepam
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