CYPROHEPTADINE HYDROCHLORIDE- cyproheptadine hydrochloride_tablet

CLINICAL PHARMACOLOGY
Cyproheptadine is a serotonin and histamine antagonist with anticholinergic and sedative effects. Antiserotonin and antihistamine drugs appear to compete with serotonin and histamine, respectively, for receptor sites. After a single 4 mg oral dose of 14C-labelled cyproheptadine HCl in normal subjects, given as tablets, 2 to 20% of the radioactivity was excreted in the stools. Only about 34% of the stool radioactivity was unchanged drug, corresponding to less than 5. 7% of the dose. At least 40% of the administered radioactivity was excreted in the urine. No detectable amounts of unchanged drug were present in the urine of patients on chronic 12 to 20 mg daily doses. The principle metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine. Elimination is diminished in renal insufficiency.
Pharmacokinetics and Metabolism
After a single 4 mg oral dose of 14C-labelled cyproheptadine HCl in normal subjects, given as tablets, 2 to 20% of the radioactivity was excreted in the stools. Only about 34% of the stool radioactivity was unchanged drug, corresponding to less than 5.7% of the dose. At least 40% of the administered radioactivity was excreted in the urine. No detectable amounts of unchanged drug were present in the urine of patients on chronic 12 to 20 mg daily doses. The principle metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine. Elimination is diminished in renal insufficiency.

INDICATIONS AND USAGE
Perennial and seasonal allergic rhinitis Vasomotor rhinitis Allergic conjunctivitis due to inhalant allergens and foods Mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Amelioration of allergic reactions to blood or plasma Cold urticaria Dermatographism As therapy for anaphylactic reactions adjunctive to epinephrine and other standard measures after the acute manifestations have been controlled.
Genitourinary
Urinary frequency, difficult urination, urinary retention, early menses.

DOSAGE AND ADMINISTRATION
DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE PATIENT. Each tablet contains 4 mg of cyproheptadine hydrochloride. The total daily dosage for pediatric patients may be calculated on the basis of body weight or body area using approximately 0. 25 mg/kg/day or 8 mg per square meter of body surface (8 mg/m2). The usual dose is 2 mg (½ tablet) two or three times a day, adjusted as necessary to the size and response of the patient. The dose is not to exceed 12 mg a day. The usual dose is 4 mg (1 tablet) two or three times a day adjusted as necessary to the size and response of the patient. The dose is not to exceed 16 mg a day. The total daily dose for adults should not exceed 0. 5 mg/kg/day. The therapeutic range is 4 to 20 mg a day, with the majority of patients requiring 12 to 16 mg a day. An occasional patient may require as much as 32 mg a day for adequate relief. It is suggested that dosage be initiated with 4 mg (1 tablet) three times a day and adjusted according to the size and response of the patient.
Adults
The total daily dose for adults should not exceed 0.5 mg/kg/day. The therapeutic range is 4 to 20 mg a day, with the majority of patients requiring 12 to 16 mg a day. An occasional patient may require as much as 32 mg a day for adequate relief. It is suggested that dosage be initiated with 4 mg (1 tablet) three times a day and adjusted according to the size and response of the patient.

ADVERSE REACTIONS
Adverse reactions which have been reported with the use of antihistamines are as follows: Sedation and sleepiness (often transient), dizziness, disturbed coordination, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, paresthesias, neuritis, convulsions, euphoria, hallucinations, hysteria, faintness. Allergic manifestation of rash and edema, excessive perspiration, urticaria, photosensitivity. Acute labyrinthitis, blurred vision, diplopia, vertigo, tinnitus. Hypotension, palpitation, tachycardia, extrasystoles, anaphylactic shock. Hemolytic anemia, leukopenia, agranulocytosis, thrombocytopenia. Cholestasis, hepatic failure, hepatitis, hepatic function abnormality, dryness of mouth, epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation, jaundice. Urinary frequency, difficult urination, urinary retention, early menses. Dryness of nose and throat, thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness. Fatigue, chills, headache, increased appetite/weight gain.
Central Nervous System
Sedation and sleepiness (often transient), dizziness, disturbed coordination, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, paresthesias, neuritis, convulsions, euphoria, hallucinations, hysteria, faintness.
Integumentary
Allergic manifestation of rash and edema, excessive perspiration, urticaria, photosensitivity.
Cardiovascular
Hypotension, palpitation, tachycardia, extrasystoles, anaphylactic shock.
Hematologic
Hemolytic anemia, leukopenia, agranulocytosis, thrombocytopenia.
Digestive System
Cholestasis, hepatic failure, hepatitis, hepatic function abnormality, dryness of mouth, epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation, jaundice.
Respiratory
Dryness of nose and throat, thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness.

CONTRAINDICATIONS
This drug should not be used in newborn or premature infants. Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers. Hypersensitivity to cyproheptadine and other drugs of similar chemical structure. Monoamine oxidase inhibitor therapy (See DRUG INTERACTIONS Angle-closure glaucoma Stenosing peptic ulcer Symptomatic prostatic hypertrophy Bladder neck obstruction Pyloroduodenal obstruction Elderly, debilitated patients.
Other Conditions
Hypersensitivity to cyproheptadine and other drugs of similar chemical structure. Monoamine oxidase inhibitor therapy (See DRUG INTERACTIONS Angle-closure glaucoma Stenosing peptic ulcer Symptomatic prostatic hypertrophy Bladder neck obstruction Pyloroduodenal obstruction Elderly, debilitated patients

Newborn or Premature Infants
This drug should not be used in newborn or premature infants.
Nursing Mothers
Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.
Pediatric Patients
Overdosage Antihistamines may diminish mental alertness; conversely, particularly, in the young child, they may occasionally produce excitation.
Pregnancy
Reproduction studies have been performed in rabbits, mice, and rats at oral or subcutaneous doses up to 32 times the maximum recommended human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to cyproheptadine. Cyproheptadine has been shown to be fetotoxic in rats when given by intraperitoneal injection in doses four times the maximum recommended human oral dose. Two studies in pregnant women, however, have not shown that cyproheptadine increases the risk of abnormalities when administered during the first, second and third trimesters of pregnancy. No teratogenic effects were observed in any of the newborns. Nevertheless, because the studies in humans cannot rule out the possibility of harm, cyproheptadine should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from cyproheptadine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see CONTRAINDICATIONS
Pediatric Use
Safety and effectiveness in pediatric patients below the age of two have not been established (see CONTRAINDICATIONS, Newborn or Premature Infants WARNINGS, Pediatric Patients
Geriatric Use
Clinical studies of cyproheptadine HCl tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS, Activities Requiring Mental Alertness
Special Senses
Acute labyrinthitis, blurred vision, diplopia, vertigo, tinnitus.
Pediatric Patients
The total daily dosage for pediatric patients may be calculated on the basis of body weight or body area using approximately 0. 25 mg/kg/day or 8 mg per square meter of body surface (8 mg/m2). The usual dose is 2 mg (½ tablet) two or three times a day, adjusted as necessary to the size and response of the patient. The dose is not to exceed 12 mg a day. The usual dose is 4 mg (1 tablet) two or three times a day adjusted as necessary to the size and response of the patient. The dose is not to exceed 16 mg a day.

CNS Depressants
Antihistamines may have additive effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, tranquilizers, antianxiety agents.
Drug Interactions
MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines. Antihistamines may have additive effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, tranquilizers, antianxiety agents.

WARNINGS
Overdosage Antihistamines may diminish mental alertness; conversely, particularly, in the young child, they may occasionally produce excitation. Antihistamines may have additive effects with alcohol and other CNS depressants, e. , hypnotics, sedatives, tranquilizers, antianxiety agents. Patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving a car or operating machinery. Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients (see PRECAUTIONS, Geriatric Use.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Long-term carcinogenic studies have not been done with cyproheptadine. Cyproheptadine had no effect on fertility in a two-litter study in rats or a two generation study in mice at about 10 times the human dose. Cyproheptadine did not produce chromosome damage in human lymphocytes or fibroblasts in vitro
Miscellaneous
Fatigue, chills, headache, increased appetite/weight gain.
OVERDOSAGE
Antihistamine overdosage reactions may vary from central nervous system depression to stimulation especially in pediatric patients. Also, atropine-like signs and symptoms (dry mouth; fixed, dilated pupils; flushing, etc.) as well as gastrointestinal symptoms may occur. If vomiting has not occurred spontaneously If patient is unable to vomit When life threatening CNS signs and symptoms are present, intravenous physostigmine salicylate may be considered. Dosage and frequency of administration are dependent on age, clinical response, and recurrence after response. (See package circulars for physostigmine products.) Saline cathartics Stimulants should not be used. Vasopressors may be used to treat hypotension. The oral LD 50

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