ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals NJ, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Adverse reactions which have been reported with the use of antihistamines are as follows:Central Nervous SystemSedation and sleepiness (often transient), dizziness, disturbed coordination, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, paresthesias, neuritis, convulsions, euphoria, hallucinations, hysteria, faintness. IntegumentaryAllergic manifestation of rash and edema, excessive perspiration, urticaria, photosensitivity. Special SensesAcute labyrinthitis, blurred vision, diplopia, vertigo, tinnitus. CardiovascularHypotension, 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. Genitourinary Urinary frequency, difficult urination, urinary retention, early menses. Respiratory Dryness of nose and throat, thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness. Miscellaneous Fatigue, chills, headache, increased appetite/weight gain.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenic studies have not been done with cyproheptadine.Cyproheptadine had no effect on fertility in two-litter study in rats or two generation study in mice at about 10 times the human dose.Cyproheptadine did not produce chromosome damage in human lymphocytes or fibroblasts invitro; high doses (10 -4M) were cytotoxic. Cyproheptadine did not have any mutagenic effect in the Ames microbial mutagen test; concentrations of above 500 mcg/ plate inhibited bacterial growth.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Cyproheptadine is serotonin and histamine antagonist with anticholinergic and sedative effects. Antiserotonin and antihistamine drugs appear to compete with serotonin and histamine, respectively, for receptor sites.. Pharmacokinetics and MetabolismAfter single mg oral dose of 14C-labelled cyproheptadine HCl in normal subjects, given as tablets, 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 quaternary ammonium glucuronide conjugate of cyproheptadine. Elimination is diminished in renal insufficiency.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS 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.. 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.

DESCRIPTION SECTION.

DESCRIPTION. Cyproheptadine HCl USP, is an antihistaminic and antiserotonergic agent.Cyproheptadine hydrochloride USP is white to slightly yellowish crystalline solid, with molecular weight of 350.89, which is soluble in water, freely soluble in methanol, sparingly soluble in ethanol, soluble in chloroform, and practically insoluble in ether. It is the sesquihydrate of 4-(5 H-dibenzo [a,d]cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride. The molecular formula of the anhydrous salt is 21H 21NoHCl and the structural formula of the anhydrous salt is: Cyproheptadine hydrochloride USP is available for oral administration in mg tablets. Inactive ingredients include: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE PATIENT. Each tablet contains mg of cyproheptadine hydrochloride.. Pediatric Patients. Age to yearsThe 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 mg per square meter of body surface (8 mg/m 2). The usual dose is mg 1/2 tablet) two or three times day, adjusted as necessary to the size and response of the patient. The dose is not to exceed 12 mg day.Age to 14 years The usual dose is mg (1 tablet) two or three times day adjusted as necessary to the size and response of the patient. The dose is not to exceed 16 mg day. Adults The total daily dose for adults should not exceed 0.5 mg/kg/day. The therapeutic range is mg to 20 mg day, with the majority of patients requiring 12 mg to 16 mg day. An occasional patient may require as much as 32 mg day for adequate relief. It is suggested that dosage be initiated with mg (1 tablet) three times day and adjusted according to the size and response of the patient.

GERIATRIC USE SECTION.

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).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Cyproheptadine Hydrochloride Tablets USP, mg are available as white to off- white, round, flat-faced, beveled-edged tablets, debossed 4 on left side, 9 on right side of the scoring on one side and plain on the other side, containing mg of cyproheptadine HCl packaged in bottles of 100 (NDC 51407-272-01) and 1000 (NDC 51407-272-10) tablets. Tablets have functional scoring.PHARMACIST: Dispense in well-closed container as defined in the USP with child-resistant closure (as required).Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].Manufactured For:Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Rx Only551701Rev. 08/2019Marketed/Packaged by: GSMS, Inc. Camarillo, CA USA 93012. logo. 5517.

OVERDOSAGE SECTION.

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, the patient should be induced to vomit with syrup of ipecac. If patient is unable to vomit, perform gastric lavage followed by activated charcoal. Isotonic or 1/2 isotonic saline is the lavage of choice. Precautions against aspiration must be taken especially in infants and children. 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, as milk of magnesia, by osmosis draw water into the bowel and, therefore, are valuable for their action in rapid dilution of bowel content. Stimulants should not be used. Vasopressors may be used to treat hypotension.The oral LD 50 of cyproheptadine is 123 mg/kg, and 295 mg/kg in the mouse and rat, respectively.

PHARMACOKINETICS SECTION.

Pharmacokinetics and MetabolismAfter single mg oral dose of 14C-labelled cyproheptadine HCl in normal subjects, given as tablets, 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 quaternary ammonium glucuronide conjugate of cyproheptadine. Elimination is diminished in renal insufficiency.

PRECAUTIONS SECTION.

PRECAUTIONS General. Cyproheptadine has an atropine-like action and, therefore, should be used with caution in patients with:History of bronchial asthma Increased intraocular pressure Hyperthyroidism Cardiovascular disease Hypertension Information for Patients. Antihistamines may diminish mental alertness; conversely, particularly, in the young child, they may occasionally produce excitation. Patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving car or operating machinery.. 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.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenic studies have not been done with cyproheptadine.Cyproheptadine had no effect on fertility in two-litter study in rats or two generation study in mice at about 10 times the human dose.Cyproheptadine did not produce chromosome damage in human lymphocytes or fibroblasts invitro; high doses (10 -4M) were cytotoxic. Cyproheptadine did not have any mutagenic effect in the Ames microbial mutagen test; concentrations of above 500 mcg/ plate inhibited bacterial growth. Pregnancy. Pregnancy Category B. 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, 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, and 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).

PREGNANCY SECTION.

Pregnancy. Pregnancy Category B. 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.

WARNINGS SECTION.

WARNINGS Pediatric Patients. Overdosage of antihistamines, particularly in infants and young children, may produce hallucinations, central nervous system depression, convulsions, respiratory and cardiac arrest, and death. Antihistamines may diminish mental alertness; conversely, particularly, in the young child, they may occasionally produce excitation.. CNS Depressants. Antihistamines may have additive effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, tranquilizers, antianxiety agents.. Activities Requiring Mental Alertness. Patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving car or operating machinery. Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients (see PRECAUTIONS, Geriatric Use).