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MIMS Full Prescribing Information
Periactin
Company Aspen
Primary Section: Cardiovascular System - Antimigraine preparations
MIMS revision date: 01 Dec 2010
Composition Cyproheptadine hydrochloride.
Excipients Maize starch, calcium hydrogen phosphate, lactose, magnesium stearate.

Description Chemical name: the sesquihydrate of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine
hydrochloride. Molecular formula (of the anhydrous salt): C H N.HCl. MW: 350.89. Cyproheptadine hydrochloride
is a white to slightly yellowish crystalline solid which is soluble in water to the extent of about 4 mg/mL, freely
soluble in methanol, sparingly soluble in ethanol, soluble in chloroform and practically insoluble in ether.
Actions Pharmacology. Periactin (cyproheptadine hydrochloride) is a serotonin and histamine antagonist with
anticholinergic and sedative effects. It is also recommended for the symptomatic treatment of allergic disorders and
pruritic dermatoses, as well as certain types of vascular headaches. Antiserotonin and antihistamine drugs appear
to compete with serotonin and histamine, respectively, for receptor sites.
Animal studies have shown cyproheptadine hydrochloride to be an effective serotonin and histamine antagonist,
comparable, in general, to that of the most active known substances.
Cyproheptadine hydrochloride antagonises the following effects of serotonin in laboratory animals:
bronchoconstrictor (guinea pig); vasodepressor (dog); spasmogenic (isolated rat uterus); oedema (rat); lethal
(Haemophilus pertussis treated mouse).
In all these effects, cyproheptadine hydrochloride approaches, equals or surpasses the activity of specific serotonin
antagonists, such as l-benzyl-2-methyl-5-methoxytryptamine (BAS) and l-benzyl-2-methyl-5-hydroxytryptamine
(BMS). In contrast, specific antihistamines, even the most potent, show little or no serotonin antagonism. Thus,
cyproheptadine hydrochloride must be considered a serotonin antagonist as well as a histamine antagonist.
Cyproheptadine hydrochloride antagonises or blocks the following effects of histamine in laboratory animals:
bronchoconstrictor (guinea pig); vasodepressor (dog); spasmogenic (isolated guinea pig ileum); anaphylactic shock,
active and passive (guinea pig, mouse); increased gastric secretion (Heidenhain pouch dog).
That cyproheptadine hydrochloride protects both guinea pigs and mice against anaphylactic shock is unusual. In
guinea pigs, the pulmonary aspects of anaphylactic shock are attributable to the release of endogenous histamine
and can be controlled by substances with specific antihistaminic activity. In mice, however, where histamine release
seems to be less important and serotonin release may be involved, specific antihistamines are of little value in
protecting against anaphylaxis. Thus, the protective effect of cyproheptadine hydrochloride in mice may be an
antiserotonin effect.
The inhibitory effect of cyproheptadine hydrochloride in histamine induced gastric secretion is also unusual because
specific antihistamines do not influence this effect of histamine.
Because of its marked activity as an antagonist of serotonin and histamine in laboratory animals, cyproheptadine
hydrochloride was evaluated in humans in situations where standard antihistamines are not effective.
In one evaluation, skin reactions were induced in test subjects by the intradermal injection of histamine, serotonin,
and histamine releasing substances, such as Compound 48-80. The weals and flares resulting from the injections
were observed, as well as the degree of blueness of the weals produced by intravenous injection of a protein dye,
coomassie blue. Coomassie blue was used as an indicator of capillary leakage of plasma proteins because of its
propensity for plasma binding and its safety for use in humans. Cyproheptadine hydrochloride and two standard
antihistamines were administered orally in moderate therapeutic doses. Only cyproheptadine hydrochloride led to a suppression of the wealing responses and the capillary damage demonstrated by the bluing reaction. Acute and chronic toxicity studies in various laboratory animals indicate that cyproheptadine hydrochloride has an adequate margin of safety. In doses far greater than those in the therapeutic range, ataxia, sedation and tachycardia can be produced, but other objective signs of toxicity are not evident. The oral LD of cyproheptadine is 123 mg/kg, and 295 mg/kg in the mouse and rat, respectively. There was no evidence of histomorphological changes in the various organs when doses approximating subacute
lethal doses were administered to dogs, monkeys, rabbits and mice. Twelve months of oral toxicity studies in dogs
did not reveal functional or anatomical changes. In chronic toxicity studies in rats, only at dosages of 10 to 12
mg/kg/day, far in excess (approximately 200 times) of those required for pharmacodynamic effects, was reversible
vacuolisation of the beta cells of the pancreatic islets noted. This was not observed in the other four species of
animals used in the toxicity studies. After six months of continuous drug administration, there was no evidence of
derangement of carbohydrate metabolism in humans, as measured by serial blood sugar determinations and
glucose tolerance tests.
Cyproheptadine hydrochloride has CNS effects in laboratory animals, including anticonvulsant and antitremor activity
and behavioural effects. It has weak peripheral anticholinergic activity and moderate local anaesthetic action. It
exerts highly effective protection against burn shock in mice. Most of these properties are evident only with doses
much larger than those used in therapy. In the rat, for instance, behavioural effects are produced only by doses 50
to 100 times greater than those required to produce antiserotonin activity.
Cyproheptadine is not a hormone, but has effects on certain endocrine systems in humans, possibly as a result of
its antiserotonin activity. It acts centrally to reduce adrenocorticotrophic hormone (ACTH) secretion and, thus, tends
to cause modest reductions in adrenal corticosteroid output and plasma cortisol levels. This effect has been studied
with variable results in the treatment of Cushing's disease and Nelson's syndrome. Cyproheptadine may reduce
plasma growth hormone levels during the early phase of sleep and in response to exogenous arginine or insulin, but
does not reduce linear growth. Neither has an increase in linear growth in undersized children been demonstrated
beyond that which would normally be expected as a result of improved nutrition. These endocrine effects of
cyproheptadine have not been shown to have adverse clinical significance.
Pharmacokinetics and metabolism. After a single 4 mg oral dose of 14C-labelled cyproheptadine
hydrochloride in normal subjects, given as tablets or syrup, 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 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 to 20 mg daily doses of a Periactin syrup formulation. 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 As an antiallergic and antipruritic. Periactin has a wide range of antiallergic and antipruritic activity
and can be used successfully in the treatment of acute and chronic allergies and pruritus, e.g. dermatitis (including
neurodermatitis and neurodermatitis circumscripta), eczema, eczematoid dermatitis, dermatographism, mild local
allergic reactions to insect bites, hay fever and other seasonal rhinitis, perennial allergic and vasomotor rhinitis,
allergic conjunctivitis due to inhalant allergens and foods, urticaria, angioneurotic oedema, drug and serum
reactions, anogenital pruritus and pruritus of chickenpox.
As therapy for anaphylactic reactions, adjunctive to adrenaline and other standard measures after the acute
manifestations have been controlled.
Migraine and vascular types of headache. Periactin has been reported to have beneficial effects in a significant
number of patients diagnosed as having vascular types of headache, such as migraine and histamine cephalalgia.
Many patients who have not been able to obtain adequate relief from any other agent have reported amelioration of
symptoms with Periactin. The characteristic headache and feeling of malaise may disappear within an hour or two
after the first dose.
Contraindications Cyproheptadine should not be used for therapy of an acute asthmatic attack.
Newborn or premature infants. This drug should not be used in newborn or premature infants. Use in infants has
been associated with apnoea, cyanosis and respiratory difficulty.
Other conditions. Hypersensitivity to cyproheptadine and other drugs of similar chemical structure; monoamine
oxidase inhibitor (MAOI) therapy (see Interactions); angle closure glaucoma; stenosing peptic ulcer; symptomatic
prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; elderly, debilitated patients.
Use in lactation. Because of the higher risk of antihistamines for infants generally, and for newborn and
premature infants in particular, antihistamine therapy is contraindicated in breastfeeding mothers.
Precautions Antihistamines should not be used to treat lower respiratory tract symptoms, including those of
acute asthma.
Paediatric use. Safety and effectiveness in children below the age of 2 years have not been established.
Overdosage of antihistamines, particularly in infants and children, may produce hallucinations, CNS depression,
convulsions, respiratory and cardiac arrest, and death.
Antihistamines may diminish mental alertness; conversely, particularly in the young child, they may occasionally
produce excitation.
Newborn and premature infants: see Contraindications.
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.
Other. Rarely, prolonged therapy with antihistamines may cause blood dyscrasias.
Cyproheptadine has an atropine-like action and, therefore, should be used with caution in patients with a history of
bronchial asthma; increased intraocular pressure; hyperthyroidism; cardiovascular disease; or hypertension.
Carcinogenicity/ mutagenicity and impairment of fertility. Cyproheptadine has not been evaluated in
long-term carcinogenicity studies.
Cyproheptadine at about ten times the human dose had no effect on fertility in a two litter study in rats or a two
generation study in mice.
Cyproheptadine did not produce chromosome damage in human lymphocytes or fibroblasts in vitro; high doses (10-
4M) were cytotoxic. Cyproheptadine did not have any mutagenic effect in the Ames microbial mutagen test;
concentrations above 500 microgram/plate inhibited bacterial growth.
Use in pregnancy (Category A)
The use of any drug in pregnancy or in women of childbearing potential requires that the anticipated benefit be
weighed against possible hazards to the embryo or fetus.
Reproduction studies have been performed in rabbits, mice and rats at doses up to 32 times the human dose and
have revealed no evidence of impaired fertility or harm to the fetus due to cyproheptadine. There are, however, no
adequate or well controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Use in lactation 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 breastfed infants from Periactin, a
decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the
importance of the drug to the mother (see Contraindications).
Interactions MAOIs prolong and intensify the anticholinergic effects of antihistamines.
Antihistamines may have additive effects with alcohol and other CNS depressants, e.g. hypnotics, sedatives,
tranquillizers, antianxiety agents.
Drugs with antiserotonin activity, such as cyproheptadine, may interfere with serotonin enhancing antidepressant
drugs.
Effect on laboratory tests Cyproheptadine may cause a false positive test result for tricyclic antidepressant
drugs when evaluating a drug screen (e.g. urine, serum).
Adverse Reactions The side effects that appear frequently are drowsiness and somnolence. Many patients
who complain initially of drowsiness may no longer do so after the first three or four days of continuous
administration.
Adverse reactions which have been reported with the use of antihistamines include the following.
Central nervous system. Sedation, sleepiness (often transient), dizziness, disturbed coordination, confusion,
restlessness, excitation, nervousness, tremor, irritability, aggressive behaviour, insomnia, paraesthesia, neuritis,
convulsions, euphoria, hallucinations, hysteria, faintness.
Integumentary. Allergic manifestations of rash and oedema, excessive perspiration, urticaria, photosensitivity.
Special senses. Acute labyrinthitis, blurred vision, diplopia, vertigo, tinnitus.
Cardiovascular. Hypotension, palpitation, tachycardia, extrasystoles, anaphylactic shock.
Haematological. Haemolytic anaemia, leucopenia, agranulocytosis, thrombocytopenia.
Digestive system. Cholestasis, hepatic failure, hepatitis, hepatic function abnormality, dryness of mouth, epigastric
distress, anorexia, nausea, vomiting, diarrhoea, constipation, jaundice.
Genitourinary. Frequency of micturition, difficult micturition, urinary retention, early menses.
Respiratory. Dryness of nose and throat, thickening of bronchial secretions, tightness of chest and wheezing, nasal
stuffiness, epistaxis.
Miscellaneous. Fatigue, chills, headache, increased appetite/ weight gain.
Dosage and Administration Allergies and pruritus. Dosage must be individualised. Since the
antiallergic effect of a single dose usually lasts four to six hours, the daily requirement should be given in divided
doses three times a day or as often as necessary to provide continuous relief.
Adults. The therapeutic range is from 4 to 20 mg a day, 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 three times a day and adjusted according to the size and response of the patient. The dosage is not to
exceed 32 mg a day.
Children.7 to 14 years. The usual dosage is 4 mg three times a day. This dosage may be adjusted as necessary
according to the size and response of the patient. If an additional dose is required, it should be taken preferably at
bedtime. The dosage is not to exceed 16 mg a day.
2 to 6 years. It is suggested that the dosage be initiated with 2 mg two or three times a day and adjusted as
necessary according to the size and response of the patient. If an additional dose is required, it should be taken at
bedtime. The total dosage is not to exceed 12 mg a day.
Under 2 years. There is no recommended dosage schedule for children under 2 years of age.
Migraine and vascular types of headache. For prophylaxis or treatment, the recommended dosage is 4 mg
initially, repeated in 30 minutes if necessary; not to exceed 8 mg in a four to six hour period. Relief is usually
obtained in responsive patients with two doses (total 8 mg) and maintained with 4 mg every four to six hours.
Overdosage Signs and symptoms. Antihistamine overdosage reactions may vary from CNS depression or
stimulation to convulsions, respiratory and cardiac arrest, and death, especially in infants and children. Also,
atropine-like signs and symptoms (e.g. dry mouth, fixed dilated pupils, flushing) as well as gastrointestinal
symptoms may occur.
Treatment. If vomiting has not occurred spontaneously the patient should be induced to vomit, if conscious, 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 product information for physostigmine.)
Saline cathartics, e.g. milk of magnesia, draw water into the bowel by osmosis and, therefore, are valuable for their
action in rapid dilution of bowel content.
Stimulants should not be used.
Vasopressors may be used for hypotension.
Presentation Tablets, 4 mg (white, flat, circular, bevel edged, scored on one side, marked P4 on reverse): 100's.
Product Image: Periactin 4 mg
Product Image: Periactin 4 mg
Poisons Schedule S3.
Date of TGA approval or last amendment 12/03/2010

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