CYCLOHEPTADINE HCL
DESCRIPTION:
PERIACTIN* (Cyproheptadine HCl) is an antihistaminic and antiserotonergic agent.
Cyproheptadine hydrochloride is a white to slightly yellowish, crystalline
solid, with a 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-(5H-
dibenzo(a,d)cyclohepten- 5-ylidene)-1-methylpiperidine hydrochloride. The
empirical formula of the anhydrous salt is C21H21N.HCl.
PERIACTIN is available in tablets, containing 4 mg of cyproheptadine
hydrochloride, and as a syrup in which 5 mL contains 2 mg of cyproheptadine
hydrochloride, with a pH range of 3.5 to 4.5.
The tablets also contain the following inactive ingredients: calcium phosphate,
lactose, magnesium stearate, and starch. The syrup contains the following
inactive ingredients: alcohol 5%, D & C Yellow 10, artificial flavors, glycerin,
purified water, sodium saccharin, and sucrose, with sorbic acid 0.1% added as
preservative.
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ACTIONS/CLINICAL PHARMACOLOGY:
PERIACTIN 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.
Pharmacokinetics And Metabolism
After a single 4 mg oral dose of 14C-labelled cyproheptadine HCl in normal
subjects, given as tablets or syrup, 2-20% 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 significant difference in the mean
urinary excretion exists between the tablet and syrup formulations. No
detectable amounts of unchanged drug were present in the urine of patients on
chronic 12-20 mg daily doses of PERIACTIN Syrup. The principal 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.
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
WARNINGS:
Pediatric Patients
Overdosage of antihistamines, particularly in infants and young children, may
produce hallucinations, central nervous system depression, convulsions, 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 a car or operating machinery.
Antihistamines are more likely to cause dizziness, sedation, and hypotension in
elderly patients.
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 a 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 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; high doses (10-4 M) were cytotoxic. Cyproheptadine did not
have any mutagenic effect in the Ames microbial mutagen test; concentrations of
above 500 mcgm/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 PERIACTIN, 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, and
WARNINGS, Children.
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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Adverse reactions which have been reported with the use of antihistamines are as
follows:
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.
Special Senses: Acute labyrinthitis, blurred vision, diplopia, vertigo,
tinnitus.
Cardiovascular: Hypotension, palpitation, tachycardia, extrasystoles,
anaphylactic shock.
Hematologic: Hemolytic anemia, leukopenia, agranulocytosis, thrombocytopenia.
Digestive System: 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.
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 The 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 LD50 of cyproheptadine is 123 mg/kg, and 295 mg/kg in the mouse and
rat, respectively.
DOSAGE AND ADMINISTRATION:
DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE
PATIENT.
Each PERIACTIN tablet contains 4 mg of cyproheptadine hydrochloride. Each 5 mL
of PERIACTIN syrup contains 2 mg of cyproheptadine hydrochloride.
intended primarily for administration to pediatric patients, the syrup is also
useful for administration to adults who cannot swallow tablets.
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 (0.11 mg/lb/day) or
8 mg per square meter of body surface (8 mg/m(squared)). In small children for
whom the calculation of dosage based upon body size is most important, it may be
necessary to use PERIACTIN syrup to permit accurate dosage.
Age 2 To 6 Years
The usual dose is 2 mg (1/2 tablet or 1 teaspoon) 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.
Age 7 To 14 Years
The usual dose is 4 mg (1 tablet or 2 teaspoons) 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.
Adults
The total daily dose for adults should not exceed 0.5 mg/kg/day (0.23
mg/lb/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 or 2 teaspoons) three times a day and adjusted according to the size and
response of the patient.
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