Prednisolone Chlorphenamine Maleate Histacort® 2mg/2mg Tablet Corticosteroid / Antihistamine FORMULATION Each tabiet contains: Prednisolone. 2mg Chiorphenaming maleate amg PRODUCT DESCRIPTION Prednisoione + Chlorphenamine maleate (Histacort®), is a round, two-layered tablet 5/16 inch in diameter. It is bisected on the orange layer ‘and fat plain on the yellow layer. PHARMACOLOGY Prednisolone Prednisolone is a synthetic glucocorticoid. Its the biologically active form of prednisone. The therapeutic use of prednisolone is based on the ant-nfammatory and immunosuppressve activites of ghcocorteois, The suppression of infanmatory response is independent of the initiating stimulus, ‘The antvintammalory activity of prednisolone is based on the following mechanisms: (1) inhibition of the adherence of neutrophils and manocyiemacrophages 1 he eapiaygndothelal cl fhe named aoa, (2) blocking of te fet of macrophage Marae bony factor 3) decreased activaton of plasminogen fo plasmin, and (4) inhibin of phospholipase AZ acy thereby lowering the formation of prostaglandins, leukobienes and elated compounds Chlorphenamine maleate Chiaphenamine maleate s an alkyamine derivative, sedating antihistamine that works by competltvely antagonizing te elects of histamine fon Hi receptors. Chiorphenamine biocks various physiological and pathophysiological effects of histamine, including increased capillary Bermeabilly and dation, formation of edema, the flare and eh response, and the constriction of gastrointestinal and respiratory smooth Clinically, chlorphenamine's most important effect ison the smooth muscle of the vascular tree where it blocks histamine-induced increased capillary permeabilty and incompletely prevents histamine-induced fal in blood pressure. Chiorphenamine counteracts both edema and wheal formation aring Seconda i jury, antiga of Nstamine-elesing pharmacologic agers. Chorphenamne'senhistamine efet (Getermined by suppression of wheal and flare induced by intradermal administration of histamine) is apparent within 6 hours after a singla ‘ral dose and may persist for up to at least 24 hours. Chiorpnenamine also has weak antimuscarinic and moderate antiserotonin and local anesthetic actions. PHARMACOKINETICS Prednisolone Predrisolone is rapidly absorbed from the gastrointestinal rac, producing peak plasma concentrations approximately 1 to 2 hours after an bral dose. The bisavallabity of prednisolone when taken orally usually 70-60). Sproxmately Predrisolone is mostly bound to abbumin and corcosterid-binding globulin; the volume of distribution and clearance are dose dependent ‘The plasma hal-fe of prednisolone falls between 2.1 10 3.5 hours. Reduction in prednisolone metabolism by impalement of hepatic or renal function or by orgs (@'2. yelosporine, oral contraceptives), prolongs the elimination haf whe acceleration of metabosm in hyperthyroid and by snayme-inducing drags (e'g. aniconwuloants, rramplen) wil shorten the plasma elimination hale markedly. The ehfninaton of prednisolone fonds to be more fap ih chiléren than n adults. elmination Ws slower in older, postmencpausal women Prednisolone is excreted in breast mik to a small extent. It can cross the placenta ang achieve significant concentrations inthe fetus. Prednisolone is extensively metabolized mainly in the liver. Over 80% ofthe administered dose is excroted inthe urine. Chlorphenamine Maleate Chiorphenamine maleate appears to be well absorbed after oral administration but i undergoes substantial metabolism in the asirdintestiial mucosa dng absorption andin te ver on fret pass. Only about 25-#5% oa sgl oal dose of chorphenamine maleate Frmedlate release tablet reaches the systemic creulaion unchanged CChlorphenamine appears inthe plasma within 30-60 minutes with peak plasma concentrations occurring within 2-6 hours after oral ‘dministration as chorphenamire maleate conventional tabiel or solution ° Chlorphenamine’s distribution into human body tissues and Nuids has not been fully characterized, undergoes rapid and extensive Gitruionincucing te salva. Te drug andlor ts melaboltes appear to be denbuted n smal amounts nto ie, Chlorphenamne is about 9:72% bound to plasma proteins In vivo. CChlorphenamine is rapidly and extensively metabolized. Aside from substantial metabolism in the gastrointestinal mucosa during absorption {nd fist pase matabolism inthe Iver, i undorgoos N-aoalkylation to form monodesmothylchlorpheniramine and Sanson aidesmethyichlorpheniramine. tis also principally melabelized fo other unidentified metabolites Chlorphenamine's terminal eiinaton hatte in adults with normal renal ane hepatic urctin ranges from 12-43 hours. Elimination haf In plants wih roi ra fare undergaing henadalyas anges rom 240-340 hours Chonlonamio and te mutabolts are excreted aihost completly nthe une; unary excretion of chorphenamine ana fs N-deakyated metaboltes decreases as urnary pH increases and INDICATIONS. For the symptomatic relief of allergy such as hay fever, urticaria, emergency treatment of anaphylactic reactions and other allergic Andinflammatory conaitons. ” sen py ° DOSAGE AND ADMINISTRATION DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND PATIENT RESPONSE, Recommended Initial Dose in Adults and children over 12 years old 1 to 2 tablets four times a day (after meals and at beatime) + After improvement i noted, gradual aduco dose unt the lowast dose which wil maintain an adoquatedlnical response fs reached * Consider slow withdrawal ofthe combination product and substituting with an antihistamine alone when allergy symptoms are adequately controlled, ‘CONTRAINDICATIONS. + Hypersensitivity to prednisolone, chlorphenamine maleate, or to any ingredient ofthe product + systemic fungal infections + Newborn and premature infants + Patients receiving monoamine oxidase (MAO) inhibitors WARNINGS AND PRECAUTIONS. Prednisolone In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated, Corticosteroids can produce reversible hypothalamic-ptutary adrenal (HPA) suppression with the potential for glucocorticoid insufficiency after withdrawal of treatment. Metabolic clearance of conticasteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in patient's thyroid status may necessitate dosage adjustment Corticosteroids may mask some signs of infection and new infections may appear during ther use, There may be decreased resistance and Inability to localize infection when caricostoroide are Used. ‘appear cerns ¥ Restrict prednisolone use in active tuberculosis to cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management ofthe disease in conjunction with an appropriate antituberculosis regimen If corticosteroids are indicated in patients wit latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. These patients should recelve chemoprophylaxis during prolonged corticosteroid therapy. Persons who are on drugs which suppress the immune system are more suscepti to infection than healthy ingividuals. Chickenpox and measles, for example, can have a more serious or even fatal course in nar-immune patients on corticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis wit pooled intravenous immunoglobulin (IG) may be indicated. If Chickenpox develops, treatment with antiviral agents may be considered, Do not undertake other immunization procedures in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response. Corticosteroids may activate latent amoebiasis. Therefore, itis recommended that latent or active amoebiasis be ruled out before initiating Corticosteroid therapy in any patient who has spent ime inthe tropics or in any palient with unexplained dlarrmea Use corticosteroids with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid: Induced immunosuppression may lead fo Strongyloides hyperinfection and dissemination witn widespread larval migration, ‘often accompanied by severe enterocoltis and potentially fatal gram-negative septicemia, In corebral malaria, use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding ‘Average and large doses of hydrocortisone or cortisone can cause elavation of blood pressure, salt and water retention and increased excretion of potassium. These effects are less likely to occur with prednisolone and ather synthetic corticosteroids except when used in large ‘doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to ung! or viruses. Use the lowest possible dose of corticosteroid to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual Drug-induced secondary adrenocortical insufficiency may be minimized by gradual dose reduction. This type of relative insufficiently may persist for months after discontinuation of therapy: theretore, corticosteroid therapy should be roinsttuted !n any situation of strass occurring uring that period. Since mineralocoricoid secretion may be impaired, a mineralocoricoid should be administered concurrently. ‘There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Use corticosteroids cautiously in patients with ocular herpes simplex because of possible corneal perforation Psychic derangements may appear when corticosteroids ate used, ranging trom euphoria, insomnia, mood swings, personality changes, and severe depression fo frank psychotic manfestaions. Exsting emetional stably or psychotic tendencies may be aggravated by conicasterods. Use aspirin cautiously in conjunction with corticosteroids in hypoprothrombinemia. Use corticosteroids with caution in nonspecific ulcerative colts, especially i there is a probabilly of impending perforation, abscess or other pyogenic infections, dvericultis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, ‘and myasthenia gravis. Corticosteroids may increase or decrease moilty and number of spermatozoa in some patients. Chlorphenamine maleate Chiorphenamine maleate, ike other sedating antihistamines, may cause drowsiness. Observe caution while driving or performing other {asks requiring alertness Use chlorphenamine maleate with caution in pationts with narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, Prostate hypertrophy or bladder neck obstruckon, cardiovascular disease Including hypertonsion, n those wth ineroasoa Intraocular Bressure, oF nypernyroicim ‘There have been occasional reports of convulsions in patients taking anthistamines. Use chlorphenamine maleate and other antihistamines with eauton in patients with eplepsy pa * " ‘Since many anthistamines, including chlorphenamine maleate, are excreted inthe urine in its active form, dasage reduction may be evessary n patents wih fenal impairment. “ ¥ Chlorphenamine maleate should not be given to neonates because these patients are more susceptible to its antimuscarinic effects ‘Avoid inappropriate use, particulary for postural giddiness in elderty patients, since they are more susceptible to many adverse effects of INTERACTION WITH OTHER MEDICAMENTS. Prednisolone Anticgnvulsants, lampicin and other drugs that stimulate hepatic metabolism: Lessen the elec of prednisolone due to enhancement of prednisolone ciéarance Cyclosporin: Decreases metabolism of prednisolone in the early phase of combination therapy; this increases plasma half-life and reduces idsrarce of precnsolono. Pradnisolone dosage in such cases may require adjustmant. " Corticosteroids: Previous long-term treatment with other corticosteroids may reduce plasma prednisolone hatf-ife. ral contraceptives and estrogen: Cause alterations in plasma protein binding and metabolism of prednisolone which can result in exposure Of women to increased levels of unbound prednisolone for long periods of time. P * Aspirin and other Nonstoroidalantintammatory drugs (NSAIDs): Concomitant administration of prednisolone an aspirin causes changes in {Sfeyaieplauma protern binang and fs rate of metabolem which may lower plasma saleylate loves ° “ Aspirin and other NSAIDs may increase the risk of gastrointestinal ulceration in patients receiving corticosteroids. ‘Antacids: Large doses of antacids may impair prednisolone absorption Insulin and other antidiabetic agents: Since glucocortcosteroids, including prednisolone, may increase blood glucose concentrations, dosage aagjstment of insulin anor oral hypogiycertc agents may be required in fates with dlabetes melltuS “ Carbimazole or Methimazole: Patients with Grave's disease receiving carbimazole or methimazole may sill have enhanced metabolism: thus, there may be significant increases in the clearance and decreases the plasma halt of prednisolone Ketoconazole: Causes impairment of metabolic and renal clearance of prednisolone Vaccines & Toxoids: Corticosteroids inhibit antibody response and may cause a diminished response to toxoids and lve or inactivated Vaccines, Defer routine administration of vacches or toxoids unti corticosteroid therapy is discontinued Potassium-depleting Drugs: Drugs that deplete potassium (e.9., ampothericn 8), including potassium-depleting siurtics (eg. hiazies, rovemide, shen ate), may emane tee petsssumuesling ehet of qucscoricads, Closely monkor sotum potaesui of patents Feceiving polasstundepleing drugs and cortcosterods Chlorphenamine maleate CNS Depressants: Chlorphenamine maleate and other sedating antihistamine may enhance the sedative effects of CNS depressants Including alcohol, baroturates, hypnotics, opioid analgesics, anxiolvtic sedatives, and antipsychotics. Antimuscarinic Drugs: Chlorphenamine maleate may have addtive antimuscarinic action with other antimuscarinic drugs, such as atropine dangerous hyperonsive reactions voed with sked combinatons oF anthistamines and drecly acing sympatnomimetcs, YP" O° STATEMENT OF USAGE FOR HIGH-RISK GROUPS Podiatric Precaution Prednisolone and other corticasteroid-containing medications should be avoided in babies under 1 year. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Pregnancy and Lactation malaleoraing malas Inger shod abe Sed lrg the rd tmestr of pregnaney because of he risk of savers Pragnisolone and chlophenamine maleate are excreted in small amounts in breast mik and should therefore be avoided by breastfeeding Geriatric Patients Elderly patients are more likely to suffer confusional states and neurological effects of chlorphenamine maleate's anticholinergic effects Use the lowest possible dose that elicits the desired therapeutic response in elderly patients. ADVERSE EVENTS/UNDESIRABLE EFFECTS Prednisolone Fluid and Eloctrolyte Disturbances: Sodium retention, fui retention, congestive heart failure in susceptible patients, potassium loss, Fypokalemic skalosis, hypertension “ pane pater Musculoskeletal: Muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosts bt femoral and humeral heads, pathologie fracture of long bones Gastrointestinal: Peptic ulcer with possible perforation and hemorrhage, pancreatts, abdominal distention, elevation in serum iver enzyme fovels which are usually reversible upon dscontnuation of Westmont ulcerative esophag ts “mn Dermatologic: Impaired wound healing, thin fragile skin, petechiae and ecchymoses, facial erythema, increased sweating; may suppress reactions to skin test, urticaria, edema Nourological: Convulsions, increased intracranial pressure with papiledema or pseudo-tumor cerebri usually after treatment, psychiatric, disorders, vertigo, headache Endocrine: Menstrual iregularies, development of Cushingoid stat, suppression of growth in children; hirsutism, secondary adrenocortical ‘and pilutary unresponsiveness, particulary in times of stress, as in trauma, surgery, or ilness; decreased carbohyrate tolerance, manfestations of latent diabetes mellitus, increased raquiraments far insulin or oral hypoglycomic agonts in dabatos ‘Ophthalmic: Posterior subcapsular cataracts, increased inraocular pressure, glaucoma, exophthalmas Metabolic: Negative nitrogen balance due to protein catabolism ‘Others: increased susceptibiliy to infections, increased appetite, malaise, nausea, weight gain ‘Chiorphonamine maleate Chlorphenamine maleate may cause slight to moderate drowsiness, dry mouth, and blurred vision ‘Allergic sensitization to chlorphenamine maleate can also occur. ‘There have been some reports of bone marrow depression, exfoliative dermatitis and isolated reports of bload dyscrasias, including agranulocytosis, thrombocytopenia, pancytopenia, and aplastic anemia. Facial dyskinesias have also been reported. ‘Antihistamines like chlorphenamine maleate have also been reported to affect the senses of smell and taste. OVERDOSAGE AND MANAGEMENT Prednisolone ‘As the clinically effective dose of corticosteroids vary according to the indications and requirements of individual patients, itis hardly possible to define “excessive” dosage of corticosteroids and there have been no reports on the effects of accidental ingestion of large quantities of prednisolone over a short period of time. However, continued use of large doses of corticosteroids, which are often necessary to elicit a nical response, without proper dose reduction leads to exaggeration of usual corticosteroid-related problems such as mental symptoms, moon face, abnormal fat deposits, fluid retention, excessive appetite, weight gain, hypertichosis, acne, striae, ecchymosis, increased ‘sweating, pigmentation, dry scaly skin, thinning scalp har, increased blood pressure, tachycardia, thrombophlebitis, decreased resistance to infection, negative nitrogen balance with delayed bone and wound healing, headache, weakness, menstrual disorders, accentuated menopausal symotoms, neuropathy, fractures, osteoporosis, peptic ulcer, decreased glucose tolerance, hypokalemia, and adrenal insufficiency. Hepatomegaly and abdominal distention have also been seen in children Acute overdosage should be treated immediately by gastric lavage or emesis followed by supportive and symptomatic therapy. Chiorphenamine maleate CChlorphenamine maleate is potentially dangerous when taken in excessive dases. Intoxicated patients may be unconscious and show hypotension, coma, and occasionally, convulsions, which are difficult to treat. Ventricular arrhythmias have also been reported after, ‘excessive doses with other similar histaminet antihistamines, Initial excitation is often seen in children, Supportive treatment is adequate in most cases. Consider oral activated charcoal or gastric lavage in patients presenting early. Control Seizures with diazepam. Correct hypoxia, electrolyte abnormalities and acidosis in patients with arrhythmias while avoiding antiarrhythmic “rugs if possible. ‘CAUTION Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without a prescription. ‘STORAGE STORE AT TEMPERATURES NOT EXCEEDING 30°C, AVAILABILITY Box of 100's in Blstor Foil Manufactured by ASIAN ANTIBIOTICS, INC. No, 130 Pioneer Street Mandaluyong City, Philippines {or UNILAB, Inc. No. 68 United Street, Mandaluyong City Metro Manila, Philippines Revision Date: May 2010 ai Reg iPOPhil Pooodd012419 Trusted Quality Healtheare