ADVERSE REACTIONS
The adverse experiences for Klonopin are providedseparately for patients with seizure disorders and with panic disorder.
Seizure Disorders
The most frequently occurring side effects of Klonopinare referable to CNS depression. Experience in treatment of seizureshas shown that drowsiness has occurred in approximately 50% of patientsand ataxia in approximately 30%. In some cases, these may diminishwith 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 patientswith a history of psychiatric disturbances). The following paradoxicalreactions have been observed: excitability, irritability, aggressivebehavior, 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 andfacial 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 elevationsof serum transaminases and alkaline phosphatase
Panic Disorder
Adverse events during exposure to Klonopin were obtainedby spontaneous report and recorded by clinical investigators usingterminology of their own choosing. Consequently, it is not possibleto provide a meaningful estimate of the proportion of individualsexperiencing adverse events without first grouping similar types ofevents into a smaller number of standardized event categories. Inthe tables and tabulations that follow, CIGY dictionary terminologyhas been used to classify reported adverse events, except in certaincases in which redundant terms were collapsed into more meaningfulterms, as noted below.
The stated frequenciesof 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 thefirst time or worsened while receiving therapy following baselineevaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials
Adverse Events Associated With Discontinuationof Treatment
Overall, the incidence of discontinuation due toadverse events was 17% in Klonopin compared to 9% for placebo in thecombined data of two 6- to 9-week trials. The most common events (≥1%)associated with discontinuation and a dropout rate twice or greaterfor Klonopin than that of placebo included the following:
Table 2Most Common Adverse Events(≥1%) Associated with Discontinuation of Treatment | Adverse Event | Klonopin (N=574) | Placebo (N=294) |
| Somnolence | 7% | 1% |
| Depression | 4% | 1% |
| Dizziness | 1% | <1% |
| Nervousness | 1% | 0% |
| Ataxia | 1% | 0% |
| Intellectual Ability Reduced | 1% | 0% |
Adverse Events Occurring at an Incidenceof 1% or More Among Klonopin-Treated Patients
Table 3 enumeratesthe incidence, rounded to the nearest percent, of treatment-emergentadverse events that occurred during acute therapy of panic disorderfrom a pool of two 6- to 9-week trials. Events reported in 1% or moreof patients treated with Klonopin (doses ranging from 0.5 to 4 mg/day)and for which the incidence was greater than that in placebo-treatedpatients are included.
The prescriber shouldbe aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the courseof usual medical practice where patient characteristics and otherfactors differ from those that prevailed in the clinical trials. Similarly,the cited frequencies cannot be compared with figures obtained fromother clinical investigations involving different treatments, usesand investigators. The cited figures, however, do provide the prescribingphysician with some basis for estimating the relative contributionof drug and nondrug factors to the side effect incidence in the populationstudied.
Table3 Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-ControlledClinical TrialsEvents reported by at least 1% of patientstreated with Klonopin and for which the incidence was greater thanthat for placebo. | ClonazepamMaximum Daily Dose |
| Adverse Event by Body System | <1mg
n=96
% | 1-<2mg
n=129
% | 2-<3mg
n=113
% | ≥3mg
n=235
% | All Klonopin Groups
N=574
% | Placebo
N=294
% |
| Central & Peripheral Nervous System | | | | | | |
| Somnolence
| 26 | 35 | 50 | 36 | 37 | 10 |
| Dizziness | 5 | 5 | 12 | 8 | 8 | 4 |
| Coordination Abnormal | 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 DisordersDenominatorsfor events in gender-specific systems are: n=240 (clonazepam), 102(placebo) for male, and 334 (clonazepam), 192 (placebo) for female. | | | | | | |
| 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 Incidenceof Most Commonly Observed Adverse EventsTreatment-emergentevents for which the incidence in the clonazepam patients was ≥5%and at least twice that in the placebo patients. in AcuteTherapy in Pool of 6- to 9-Week Trials Adverse Event
(Roche PreferredTerm) | Clonazepam
(N=574) | Placebo
(N=294) |
| 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-controlledtrials, adverse events classified under the preferred term "depression"were reported in 7% of Klonopin-treated patients compared to 1% ofplacebo-treated patients, without any clear pattern of dose relatedness.In these same trials, adverse events classified under the preferredterm "depression" were reported as leading to discontinuation in 4%of Klonopin-treated patients compared to 1% of placebo-treated patients.While these findings are noteworthy, Hamilton Depression Rating Scale(HAM-D) data collected in these trials revealed a larger decline inHAM-D scores in the clonazepam group than the placebo group suggestingthat clonazepam-treated patients were not experiencing a worseningor emergence of clinical depression.
Other Adverse Events Observed Duringthe Premarketing Evaluation of Klonopin in Panic Disorder
Following is a list of modified CIGY terms that reflecttreatment-emergent adverse events reported by patients treated withKlonopin at multiple doses during clinical trials. All reported eventsare included except those already listed in Table 3 or elsewhere in labeling, those events for whicha drug cause was remote, those event terms which were so general asto be uninformative, and events reported only once and which did nothave a substantial probability of being acutely life-threatening.It is important to emphasize that, although the events occurred duringtreatment with Klonopin, they were not necessarily caused by it.
Events are further categorized by body system and listedin order of decreasing frequency. These adverse events were reportedinfrequently, 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: abdominaldiscomfort, gastrointestinal inflammation, stomach upset, toothache,flatulence, pyrosis, saliva increased, tooth disorder, bowel movementsfrequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolicand Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, painnape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swellingknee
Platelet,Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreamingexcessive, libido loss, appetite increased, libido increased, reactionsdecreased, aggressive reaction, apathy, attention lack, excitement,feeling mad, hunger abnormal, illusion, nightmares, sleep disorder,suicide ideation, yawning
Reproductive Disorders, Female: breastpain, menstrual irregularity
Reproductive Disorders, Male: ejaculationdecreased
ResistanceMechanism Disorders: infection mycotic, infection viral,infection streptococcal, herpes simplex infection, infectious mononucleosis,moniliasis
RespiratorySystem Disorders: sneezing excessive, asthmatic attack,dyspnea, nosebleed, pneumonia, pleurisy
Skin and Appendages Disorders: acneflare, alopecia, xeroderma, dermatitis contact, flushing, pruritus,pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
UrinarySystem Disorders: dysuria, cystitis, polyuria, urinary incontinence,bladder dysfunction, urinary retention, urinary tract bleeding, urinediscoloration
Vascular(Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes,visual field defect, xerophthalmia
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