SIDE EFFECTS
Commonly Observed
The most commonly observed adverse events associated with
the use of Anafranil and not seen at an equivalent incidence among
placebo-treated patients were gastrointestinal complaints, including dry mouth,
constipation, nausea, dyspepsia, and anorexia; nervous system complaints,
including somnolence, tremor, dizziness, nervousness, and myoclonus;
genitourinary complaints, including changed libido, ejaculatory failure, impotence,
and micturition disorder; and other miscellaneous complaints, including
fatigue, sweating, increased appetite, weight gain, and visual changes.
Leading To Discontinuation Of Treatment
Approximately 20% of 3616 patients who received Anafranil
in U.S. premarketing clinical trials discontinued treatment because of an
adverse event. Approximately one-half of the patients who discontinued (9% of
the total) had multiple complaints, none of which could be classified as
primary. Where a primary reason for discontinuation could be identified, most
patients discontinued because of nervous system complaints (5.4%), primarily
somnolence. The second-most-frequent reason for discontinuation was digestive
system complaints (1.3%), primarily vomiting and nausea.
There was no apparent relationship between the adverse
events and elevated plasma drug concentrations.
Incidence In Controlled Clinical Trials
The following table enumerates adverse events that
occurred at an incidence of 1% or greater among patients with OCD who received
Anafranil in adult or pediatric placebo-controlled clinical trials. The
frequencies were obtained from pooled data of clinical trials involving either
adults receiving Anafranil (N=322) or placebo (N=319) or children treated with
Anafranil (N=46) or placebo (N=44). The prescriber should be aware that these
figures cannot be used to predict the incidence of side effects in the course
of usual medical practice, in which 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, provide the physician with a basis for estimating the
relative contribution of drug and nondrug factors to the incidence of side
effects in the populations studied.
Incidence of Treatment-Emergent Adverse Experience in
Placebo- Controlled Clinical Trials (Percentage of Patients Reporting Event)
Body System/ Adverse Event* |
Adults |
Children and Adolescents |
Anafranil
(N=322) |
Placebo
(N=319) |
Anafranil
(N=46) |
Placebo
(N=44) |
Nervous System |
Somnolence |
54 |
16 |
46 |
11 |
Tremor |
54 |
2 |
33 |
2 |
Dizziness |
54 |
14 |
41 |
14 |
Headache |
52 |
41 |
28 |
34 |
Insomnia |
25 |
15 |
11 |
7 |
Libido change |
21 |
3 |
- |
- |
Nervousness |
18 |
2 |
4 |
2 |
Myoclonus |
13 |
- |
2 |
- |
Increased appetite |
11 |
2 |
- |
2 |
Paresthesia |
9 |
3 |
2 |
2 |
Memory impairment |
9 |
1 |
7 |
2 |
Anxiety |
9 |
4 |
2 |
- |
Twitching |
7 |
1 |
4 |
5 |
Impaired concentration |
5 |
2 |
- |
- |
Depression |
5 |
1 |
- |
- |
Hypertonia |
4 |
1 |
2 |
- |
Sleep disorder |
4 |
- |
9 |
5 |
Psychosomatic disorder |
3 |
- |
- |
- |
Yawning |
3 |
- |
- |
- |
Confusion |
3 |
- |
2 |
- |
Speech disorder |
3 |
- |
- |
- |
Abnormal dreaming |
3 |
- |
- |
2 |
Agitation |
3 |
- |
- |
- |
Migraine |
3 |
- |
- |
- |
Depersonalization |
2 |
- |
2 |
- |
Irritability |
2 |
2 |
2 |
- |
Emotional lability |
2 |
- |
- |
2 |
Panic reaction |
1 |
- |
2 |
- |
Aggressive reaction |
- |
- |
2 |
- |
Paresis |
|
|
2 |
|
Skin and Appendages |
Increased sweating |
29 |
3 |
9 |
- |
Rash |
8 |
1 |
4 |
2 |
Pruritus |
6 |
- |
2 |
2 |
Dermatitis |
2 |
- |
- |
2 |
Acne |
2 |
2 |
- |
5 |
Dry skin |
2 |
- |
- |
5 |
Urticaria |
1 |
- |
- |
- |
Abnormal skin odor |
- |
- |
2 |
- |
Digestive System |
Dry mouth |
84 |
17 |
63 |
16 |
Constipation |
47 |
11 |
22 |
9 |
Nausea |
33 |
14 |
9 |
11 |
Dyspepsia |
22 |
10 |
13 |
2 |
Diarrhea |
13 |
9 |
7 |
5 |
Anorexia |
12 |
- |
22 |
2 |
Abdominal pain |
11 |
9 |
13 |
16 |
Vomiting |
7 |
2 |
7 |
- |
Flatulence |
6 |
3 |
- |
2 |
Tooth disorder |
5 |
- |
- |
- |
Gastrointestinal disorder |
2 |
- |
- |
2 |
Dysphagia |
2 |
- |
- |
- |
Esophagitis |
1 |
- |
- |
- |
Eructation |
- |
- |
2 |
2 |
Ulcerative stomatitis |
- |
- |
2 |
- |
Body as a Whole |
Fatigue |
39 |
18 |
35 |
9 |
Weight increase |
18 |
1 |
2 |
- |
Flushing |
8 |
- |
7 |
- |
Hot flushes |
5 |
- |
2 |
- |
Chest pain |
4 |
4 |
7 |
- |
Fever |
4 |
- |
2 |
7 |
Allergy |
3 |
3 |
7 |
5 |
Pain |
3 |
2 |
4 |
2 |
Local edema |
2 |
4 |
- |
- |
Chills |
2 |
1 |
- |
- |
Weight decrease |
- |
- |
7 |
- |
Otitis media |
- |
- |
4 |
5 |
Asthenia |
- |
- |
2 |
- |
Halitosis |
- |
- |
2 |
- |
Cardiovascular System |
Postural hypotension |
6 |
- |
4 |
- |
Palpitation |
4 |
2 |
4 |
- |
Tachycardia |
4 |
- |
2 |
- |
Syncope |
- |
- |
2 |
- |
Respiratory System |
Pharyngitis |
14 |
9 |
- |
5 |
Rhinitis |
12 |
10 |
7 |
9 |
Sinusitis |
6 |
4 |
2 |
5 |
Coughing |
6 |
6 |
4 |
5 |
Bronchospasm |
2 |
- |
7 |
2 |
Epistaxis |
2 |
- |
- |
2 |
Dyspnea |
- |
- |
2 |
- |
Laryngitis |
- |
1 |
2 |
- |
Urogenital System Male and Female Patients Combined |
Micturition disorder |
14 |
2 |
4 |
2 |
Urinary tract infection |
6 |
1 |
- |
- |
Micturition frequency |
5 |
3 |
- |
- |
Urinary retention |
2 |
- |
7 |
- |
Dysuria |
2 |
2 |
- |
- |
Cystitis |
2 |
- |
- |
- |
Female Patients Only |
(N=182) |
(N=167) |
(N=10) |
(N=21) |
Dysmenorrhea |
12 |
14 |
10 |
10 |
Lactation (nonpuerperal) |
4 |
- |
- |
- |
Menstrual disorder |
4 |
2 |
- |
- |
Vaginitis |
2 |
- |
- |
- |
Leukorrhea |
2 |
- |
- |
- |
Breast enlargement |
2 |
- |
- |
- |
Breast pain |
1 |
- |
- |
- |
Amenorrhea |
1 |
- |
- |
- |
Male Patients Only |
(N=140) |
(N=152) |
(N=36) |
(N=23) |
Ejaculation failure |
42 |
2 |
6 |
- |
Impotence |
20 |
3 |
- |
- |
Special Senses |
Abnormal vision |
18 |
4 |
7 |
2 |
Taste perversion |
8 |
- |
4 |
- |
Tinnitus |
6 |
- |
4 |
- |
Abnormal lacrimation |
3 |
2 |
- |
- |
Mydriasis |
2 |
- |
- |
- |
Conjunctivitis |
1 |
- |
- |
- |
Anisocoria |
- |
- |
2 |
- |
Blepharospasm |
- |
- |
2 |
- |
Ocular allergy |
- |
- |
2 |
- |
Vestibular disorder |
- |
- |
2 |
2 |
Musculoskeletal |
Myalgia |
13 |
9 |
- |
- |
Back pain |
6 |
6 |
- |
- |
Arthralgia |
3 |
5 |
- |
- |
Muscle weakness |
1 |
- |
2 |
- |
Hemic and Lymphatic |
Purpura |
3 |
- |
- |
- |
Anemia |
- |
- |
2 |
2 |
Metabolic and Nutritional |
Thirst |
2 |
2 |
- |
2 |
*Events reported by at least 1% of Anafranil patients are
included. |
Other Events Observed During The Premarketing Evaluation Of
Anafranil
During clinical testing in the U.S., multiple doses of
Anafranil were administered to approximately 3600 subjects. Untoward events
associated with this exposure were 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 untoward events into a smaller number of
standardized event categories.
In the tabulations that follow, a modified World Health
Organization dictionary of terminology has been used to classify reported
adverse events. The frequencies presented, therefore, represent the proportion
of the 3525 individuals exposed to Anafranil who experienced an event of the
type cited on at least one occasion while receiving Anafranil. All events are
included except those already listed in the previous table, those reported in terms
so general as to be uninformative, and those in which an association with the
drug was remote. It is important to emphasize that although the events reported
occurred during treatment with Anafranil, they were not necessarily caused by
it.
Events are further categorized by body system and listed
in order of decreasing frequency according to the following definitions:
frequent adverse events are those occurring on one or more occasions in at
least 1/100 patients; infrequent adverse events are those occurring in 1/100 to
1/1000 patients; rare events are those occurring in less than 1/1000 patients.
Body as a Whole - Infrequent - general
edema, increased susceptibility to infection, malaise. Rare - dependent edema,
withdrawal syndrome.
Cardiovascular System - Infrequent -
abnormal ECG, arrhythmia, bradycardia, cardiac arrest, extrasystoles, pallor. Rare
- aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral
hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral
ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.
Digestive System - Infrequent - abnormal
hepatic function, blood in stool, colitis, duodenitis, gastric ulcer, gastritis,
gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis,
increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage,
tongue ulceration, tooth caries. Rare - cheilitis, chronic enteritis, discolored
feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction,
oral/pharyngeal edema, paralytic ileus, salivary gland enlargement.
Endocrine System - Infrequent -
hypothyroidism. Rare - goiter, gynecomastia, hyperthyroidism.
Hemic and Lymphatic System - Infrequent -
lymphadenopathy. Rare - leukemoid reaction, lymphoma-like disorder,
marrow depression.
Metabolic and Nutritional Disorder - Infrequent - dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia,
hyperuricemia, hypokalemia. Rare - fat intolerance, glycosuria.
Musculoskeletal System - Infrequent -
arthrosis. Rare - dystonia, exostosis, lupus erythematosus rash, bruising,
myopathy, myositis, polyarteritis nodosa, torticollis.
Nervous System - Frequent - abnormal
thinking, vertigo. Infrequent - abnormal coordination, abnormal EEG, abnormal
gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia,
dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations,
hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps,
manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory
disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt,
teeth-grinding. Rare - anticholinergic syndrome, aphasia, apraxia,
catalepsy, cholinergic syndrome, choreoathetosis, generalized spasm,
hemiparesis, hyperesthesia, hyperreflexia, hypoesthesia, illusion, impaired
impulse control, indecisiveness, mutism, neuropathy, nystagmus, oculogyric crisis,
oculomotor nerve paralysis, schizophrenic reaction, stupor, suicide.
Respiratory System - Infrequent - bronchitis,
hyperventilation, increased sputum, pneumonia. Rare - cyanosis, hemoptysis,
hypoventilation, laryngismus.
Skin and Appendages - Infrequent - alopecia,
cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular
rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration. Rare
- chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin
hypertrophy, skin ulceration.
Special Senses - Infrequent - abnormal
accommodation, deafness, diplopia, earache, eye pain, foreign body sensation,
hyperacusis, parosmia, photophobia, scleritis, taste loss. Rare - blepharitis,
chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis,
labyrinth disorder, night blindness, retinal disorder, strabismus, visual field
defect.
Urogenital System - Infrequent - endometriosis,
epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain,
polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder,
urinary incontinence, uterine hemorrhage, vaginal hemorrhage. Rare - albuminuria,
anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia,
endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst,
uterine inflammation, vulvar disorder.
Postmarketing Experience
The following adverse drug reaction has been reported
during post-approval use of Anafranil. Because this reaction is reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate frequency.
Eye Disorders - Angle-closure glaucoma.
Immune System Disorders - Drug Rash with
Eosinophilia and Systemic Symptoms (DRESS).
Metabolism and Nutrition Disorders - Hyponatremia.
Endocrine Disorders - Syndrome of inappropriate
antidiuretic hormone secretion (SIADH).