BETAFRINE

• Therapeutic Category
  • ANTIALLERGICS
• Pharmaceutical Form : Syrup
• Composition : Betamethasone 0.25 mg +Dexchlorpheniramine Maleate 2mg / 5 ml
• Active Substance : Betamethasone+Dexchlorpheniramine Maleate

MECHANISM OF ACTION:

Betafrine combines the anti-inflammatory and anti-allergic effects of the corticosteroid betamethasone (a derivative of prednisolone) with the antihistaminic activity of dexchlorphenamine maleate.

PHARMACOKINETICS:

Betamethasone:

It is absorbed from the gastrointestinal tract after oral administration.

The binding betamethasone to proteins is about 60 %.

It is metabolized in the liver and excreted in the urine.

The plasma half-life is about 5 hours.

The biological half-life is about 36 -54 hours.

Dexchlorpheniramine:

Bioavailability of dexchlorpheniramine is approximately 25 – 50%, 1^st pass via liver.

Distribution: it takes 2 -6 hours to reach its maximal plasma concentration

Peak plasma concentrations of dexchlorpheniramine were observed after 6 hours post dose application. The duration of effectiveness is: 4 – 8 hours

Plasma protein binding is about 72%.

It is metabolized in the liver where it turns into its inactive metabolites through demethylation process.

It is excreted in urine besides unchanged compound excreted in urine.

The elimination half-life of dexchlorpheniramine is approximately 14 – 25 hours.

INDICATIONS:

Treatment of difficult cases of respiratory, dermatologic and ocular allergies, as well as ocular inflammatory disorders where adjunctive systemic corticosteroid therapy is indicated.

Representative conditions include severe hay fever (pollenosis), severe bronchial asthma, perennial allergic rhinitis, atopic dermatitis (eczema), contact dermatitis, drug reactions, and serum sickness.

Inflammatory ocular disorders include allergic conjunctivitis, keratitis, non-granulomatous iritis, iridocyclitis, choroiditis, chorioretinitis and uveitis.

Betafrine controls the exudative and inflammatory aspects of ocular diseases, thus helping to preserve the functional integrity of the eye while allowing treatment of the specific infection or other cause with appropriate therapy.

CONTRA INDICATIONS:

Patients with systemic fungal infections, newborn and premature infants, patients receiving MAO inhibitor therapy and in those who have shown hypersensitivity or idiosyncrasy to any component of these products or drugs of similar chemical structures.

SIDE EFFECTS:

Betamethasone: Adverse reactions to this component are related to dose and duration of therapy. The small amount of corticosteroid in the combination makes the incidence of side effects less likely.

Adverse reactions reported for corticosteroids include:

-Fluid and Electrolyte Disturbances: Sodium retention, potassium loss, hypokalemic alkalosis; fluid retention; congestive heart failure in susceptible patients; hypertension.

-Muskoskeletal: Muscle weakness, corticosteroid myopathy, loss of muscle mass, aggravation of myasthenic symptoms in myasthenia gravis; osteoporosis; vertebral compression fractures; aseptic necrosis of femoral and humeral heads; pathologic fracture of long bones; tendon rapture.

-Gastrointestinal: Peptic ulcer with possible subsequent perforation and hemorrhage; pancreatitis, abdominal distention; ulcerative esophagitis.

-Dermatologic: skin atrophy, thin fragile skin; petechiae and ecchymoses; facial erythema; increased sweating; suppressed reactions to skin tests, allergic dermatitis, urticaria, angioneurotic edema.

-Neurologic: Convulsions; increased intracranial pressure with papilledema usually after treatment; vertigo; headache.

-Endocrine: Menstrual irregularities; development of cushingoid state; suppression of fetal intrauterine or childhood growth; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements of insulin or oral hypoglycemic agents in diabetics.

-Ophthalmic: Posterior subcapsular cataracts; increased intraocular pressure; glaucoma; exophthalmos.

-Metabolic: Negative nitrogen balance due to protein catabolism.

-Psychiatric: Euphoria, mood swings; severe depression to frank psychotic manifestations; personality changes; hyperirritability; insomnia.

-Others: Anaphylactoid or hypersensitivity and hypotensive or shock-like reactions.

Dexchlorphenamine Maleate: Adverse reactions to this component have been the same as those reported with other conventional (sedating) antihistamines, and rarely cause toxicity. Slight to moderate drowsiness is the most frequent side effect of dexchlorphenamine maleate. Adverse effects of sedating antihistamines vary in incidence and severity. Among these are cardiovascular, hematologic (pancytopenia, thrombocytopenia, hemolytic anemia), neurologic (confusion, hallucinations, tremor), gastrointestinal (urinary retention), respiratory adverse reactions, and mood changes. The most common effects include sedation, sleepiness, dizziness, disturbed coordination, epigastric distress, rash, dry mouth and thickening of bronchial secretions

PRECAUTIONS:

• Betamethasone: Dosage adjustments may be required with remission or exacerbation of the disease process, the patient’s individual response to therapy and exposure of the patient to emotional or physical stress eg, serious infection, surgery or injury. Monitoring may be necessary for up to 1 year following cessation of long-term or high-dose corticosteroid therapy.

The lowest possible dose of corticosteroid should be used to control the condition under treatment. A gradual dosage reduction is recommended.

Corticosteroid effect is enhanced in patients with hypothyroidism or in those with cirrhosis.

Cautious use of corticosteroid is advised in patients with ocular herpes simplex because of possible corneal perforation.

Psychic derangements may appear with corticosteroid therapy. Existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Corticosteroids should be used with caution in: Nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyrogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis and myasthenia gravis.

Since complications of glucocorticoid treatment are dependent on dosage and duration of treatment, a risk/benefit decision must be made with each patient.

Corticosteroids may mask some signs of infection, and new infections may appear during use. When corticosteroids are used, decreased resistance and inability to localize infection may occur.

Prolonged corticosteroid use may produce posterior subcapsular cataracts (especially in children), glaucoma with possible damage to the optic nerves, and may enhance secondary ocular infections due to fungi or viruses.

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be considered. All corticosteroids increase calcium excretion.

Corticosteroid therapy in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis, close observation is necessary since reactivation of the disease may occur. During prolonged corticosteroid therapy, patients should receive chemoprophylaxis.

Growth and development of children on prolonged corticosteroid therapy should be followed carefully, since corticosteroid administration can disturb growth rates and inhibit endogenous corticosteroid production in these patients.

• Dexchlorphenamine Maleate: Betafrine products should be used with caution in patients with narrow angle glaucoma, stenosing peptic ulcer, duodenal obstruction, prostatic hypertrophy or bladder neck obstruction, cardiovascular disease including hypertension, in those with increased intraocular pressure or hyperthyroidism.

Effects on the Ability to Drive or Operate Machinery: Patients should be warned about engaging in activities requiring mental alertness eg, driving a car or operating appliances, machinery, and others.

Impairment of Fertility: Corticosteroid therapy may alter the motility and number of spermatozoa.

Use in pregnancy & lactation: The use of Betafrine products during pregnancy, in nursing mothers or in women of childbearing age requires that the possible benefits of the drug be weighed against potential hazards to mother and fetus or infant. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism.

Use in children: Safety and effectiveness of Betafrine products have not been established in children <2 years.

Use in the elderly: Conventional antihistamines may cause dizziness, sedation and hypotension in patients >60 years.

WARNINGS:

While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients receiving corticosteroids, especially high doses, because of possible hazards of neurological complications and lack of antibody response.

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles, and if exposed, to obtain medical advice. This is of particular importance in children.

INTERACTIONS:

Betamethasone:

Concurrent use of Phenobarbital, phenytoin , rifampicin or ephedrine may enhance the metabolism of corticosteroids, reducing their therapeutic effects.

Patients receiving both a corticosteroid and an estrogen should be observed for excessive corticosteroid effects.

Concurrent use of corticosteroids with potassium-depleting diuretics may enhance hypokalemia. Concurrent use of corticosteroids with cardiac glycosides may enhance the possibility of arrhythmias or digitalis toxicity associated with hypokalemia. Corticosteroids may enhance the potassium depletion caused by amphotericin B. In all patients taking any of these drug therapy combinations, serum electrolyte determinations, particularly potassium levels, should be monitored closely.

Concurrent use of corticosteroids with coumarin-type anticoagulants may increase or decrease the anticoagulant effects, possibly requiring adjustment in dosage.

Combined effects of non-corticosteroid anti-inflammatory drugs or alcohol with glucorticosteroids may result in an increased occurrence or increased severity of gastrointestinal ulceration.

Corticosteroids may decrease blood salicylate concentrations. Acetylsalicylic acid should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Dosage adjustments of an antidiabetic drug may be necessary when corticosteroids are given to diabetics.

Concomitant glucocorticoid therapy may inhibit the response to somatotropin.

Dexchlorphenamine Maleate:

 Monoamine oxidase (MAO) inhibitors prolong and intensify the effects of antihistamines; severe hypotension may occur. Concomitant use of dexchlorphenamine maleate with alcohol, tricyclic antidepressants, barbiturates or other central nervous system depressants may potentiate the sedative effect of dexchlorphenamine. The action of oral anticoagulants may be inhibited by antihistamines.

DOSAGE AND ADMINISTRATION:

Betafrine should be taken with food.

Dosage should be individualized and adjusted according to the specific disease being treated, its severity, and the response of the patient. As improvement occurs, the dosage should be reduced gradually to the minimum maintenance level and discontinued where possible. When symptoms of respiratory allergies are adequately controlled, slow withdrawal of the combination product and treatment with an antihistamine alone should be considered.

Adults and Children >12 years: Recommended Initial Dose: 1-2 tabs (or 1-2 teaspoonfuls) 4 times daily, after meals and at bedtime. The dose is not to exceed 8 tabs (or 8 teaspoonfuls) per day. In younger children dosage should be adjusted according to the severity of the condition, and the response of the patient, rather than by age or body weight.

Children 6-12 years: Recommended Dosage: ½ tab (or ½ teaspoonful) 3 times a day. If an additional daily dose is required, it should be taken preferably at bedtime. The dose is not to exceed 4 tabs (or 4 teaspoonfuls) a day.

Children 2-6 years: Initial Dose: ¼-½ teaspoonful 3 times a day with adjustment of dosage according to patient response. Daily dose is not to exceed 2 teaspoonfuls.

OVERDOSAGE:

Betafrine is a combination product and, therefore, the potential toxicity of each of its components must be considered. Toxicity from a single excessive dose of Betafrine results primarily from the dexchlorphenamine component. The estimated lethal dose of the antihistamine dexchlorphenamine maleate is 2.5-5 mg/kg.

Symptoms:

 Overdosage reactions with conventional (sedating) antihistamines may vary from central nervous system depression (sedation, apnea, diminished mental alertness, and cardiovascular collapse) to stimulation (insomnia, hallucinations, tremors, convulsions) to death. Other signs and symptoms may include dizziness, tinnitus, ataxia, blurred vision and hypotension. In children, stimulation is dominant, as are atropine-like signs and symptoms (dry mouth, fixed, dilated pupils, flushing, fever and gastrointestinal symptoms). Hallucinations, incoordination and convulsions of the tonic-clonic type may occur. In adults, a cycle consisting of depression with drowsiness and coma, and an excitement phase leading to convulsions followed by depression may occur.

A single excessive dose of betamethasone is not expected to produce acute symptoms. Except at the most extreme dosages, a few days of excessive glucorticosteroid dosing is unlikely to produce harmful results except in patients at particular risk due to underlying conditions or on concomitant medications likely to interact adversely with betamethasone

Treatment of Acute Overdosage:

 Immediately induce emesis (in a conscious patient) or administer gastric lavage. Dialysis has not been found helpful.

Treatment of the signs and symptoms of overdosage is symptomatic and supportive. Stimulants should not be used. Vasopressors may be used to treat hypotension. Convulsions are best treated with a short-acting depressant eg, thiopental. Maintain adequate fluid intake and monitor electrolytes in serum and urine, with particular attention to sodium and potassium balance. Treat electrolyte imbalance if necessary.

STORAGE CONDITIONS:

BETAFRIN tablets: Store below 25˚c. Protect from light.

BETAFRIN syrup: Store below 30˚c. Protect from light.

PACKAGING:

BETAFRIN tablets: Box of 20 Tablets.

BETAFRIN syrup: Glass bottle 60 mL, 100mL