FULLFORM Rotacaps (Beclomethasone dipropionate + Formoterol fumarate)

Table of Content

Composition

FULLFORM 200 Rotacaps

Each capsule contains:

Beclomethasone dipropionate ...... 200 mcg

Formoterol fumarate ....... 6 mcg

FULLFORM 400 Rotacaps

Each capsule contains:

Beclomethasone dipropionate ....... 400 mcg

Formoterol fumarate ....... 6 mcg

Dosage Form

Dry powder for inhalation

Description

FULLFORM Rotacaps is a combination of beclomethasone dipropionate, a synthetic glucocorticoid with a potent anti-inflammatory activity and formoterol fumarate, a selective long-acting beta2-agonist. Beclomethasone dipropionate given by inhalation has a potent anti-inflammatory action within the lungs but does not cause adverse systemic glucocorticoid effects at therapeutic doses. Formoterol is a very potent long-acting beta2-agonist with a high intrinsic activity and a rapid onset of action.

Pharmacology

Pharmacodynamics

FULLFORM Rotacaps contains beclomethasone dipropionate and formoterol fumarate, which have different modes of action and show additive effects.

Formoterol

Formoterol fumarate is a long-acting, selective beta2-adrenergic agonist with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lungs as a bronchodilator. In vitro studies have shown that formoterol has over 200-fold greater agonist activity at beta2-receptors than at beta1-receptors.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including formoterol, are, at least in part, attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from the cells, especially from mast cells.

Formoterol is a potent selective beta2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction.The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation, and lasts for duration of 12 hours after a single dose.

Beclomethasone Dipropionate

Beclomethasone dipropionate is a prodrug with weak glucocorticoid receptor binding affinity. It is hydrolyzed via esterase enzymes to the active metabolite beclomethasone 17 monopropionate (B17MP), which has high topical anti-inflammatory activity.

Pharmacokinetics

Formoterol

Absorption

Following inhalation of a single 120 mcg dose of formoterol fumarate by 12 healthy subjects, formoterol reached a maximum plasma drug concentration of 92 pg/mL within 5 minutes of dosing.

Following inhalation of 12 to 96 mcg of formoterol fumarate by 10 healthy males, urinary excretion of both (R,R)- and (S,S)-enantiomers of formoterol increased proportionally to the dose. Thus, absorption of formoterol following inhalation appeared linear over the dose range studied.

As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.

Distribution

The binding of formoterol to human plasma proteins in vitro was 61%-64% (34% primarily to albumin) at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31%-38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose.

Metabolism

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored

Excretion

Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59%-62% of the radioactivity was eliminated in the urine and 32%-34% in the faeces over a period of 104 hours. Renal clearance of formoterol from blood in these subjects was about 150 mL/min. Following inhalation of a 12 mcg or 24 mcg doses by 16 patients with asthma, about 10% and 15%-18% of the total dose was excreted in the urine as unchanged formoterol and direct conjugates of formoterol, respectively. Following inhalation of 12 mcg or 24 mcg dose by 18 patients with COPD the corresponding values were 7% and 6-9% of the dose, respectively.

Based on plasma concentrations measured following inhalation of a single 120 mcg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. From urinary excretion rates measured in these subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13.9 and 12.3 hours, respectively. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively, following single inhaled doses between 12 and 120 mcg in healthy volunteers and single and repeated doses of 12 and 24 mcg in patients with asthma. Thus, the relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.

Special Populations

Gender: After correction for body weight, formoterol pharmacokinetics did not differ significantly between males and females.

Geriatric and Pediatric: The pharmacokinetics of formoterol have not been studied in the elderly population, and limited data are available in pediatric patients.

In a study of children with asthma who were 5 to 12 years of age, when formoterol fumarate 12 or 24 mcg was given twice daily by oral inhalation for 12 weeks, the accumulation index ranged from 1.18 to 1.84 based on urinary excretion of unchanged formoterol. Hence, the accumulation in children did not exceed that in adults, where the accumulation index ranged from 1.63 to 2.08 (see above). Approximately 6% and 6.5% to 9% of the dose was recovered in the urine of the children as unchanged and conjugated formoterol, respectively.

Hepatic/Renal Impairment

The pharmacokinetics of formoterol have not been studied in subjects with hepatic or renal impairment.

Beclomethasone Dipropionate

Absorption

When administered via inhalation, systemic absorption of unchanged beclomethasone dipropionate occurs through the lungs with negligible oral absorption of the swallowed dose. There is extensive conversion of beclomethasone dipropionate to the active metabolite, B-17-MP, within the lungs prior to absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. The absolute bioavailability following inhalation is approximately 60% of the nominal dose for -B17-MP. Beclomethasone dipropionate is absorbed rapidly with peak plasma concentrations first being observed (tmax) at 0.3 hours. B-17-MP appears more slowly with a tmax of 1 hour. There is an approximately linear increase in systemic exposure with increasing inhaled dose.

Distribution

The tissue distribution at steady state for beclomethasone dipropionate is moderate (20L) but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%).

Metabolism

Beclomethasone is cleared very rapidly from the systemic circulation, by metabolism mediated via esterase enzymes that are found in most tissues. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclomethasone-21-monopropionate (B-21-MP) and beclomethasone (BOH) are also formed but these contribute little to systemic exposure.

Excretion

The elimination of beclomethasone dipropionate and B-17-MP is characterized by high plasma clearance (150 and 120L/h) with corresponding terminal elimination half-lives of 0.5 hours and 2.7 hours. Following oral administration of titrated beclomethasone dipropionate, approximately 60% of the dose was excreted in the faeces within 96 hours, mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine. The renal clearance of BDP and its metabolites is negligible.

Indications

FULLFORM Rotacaps is indicated in the regular treatment of asthma, where use of a combination (long acting beta2-agonist and inhaled corticosteroid) has been found to be appropriate.

Dosage and Administration

FULLFORM Rotacaps are for inhalation use, only through the Cipla Rotahaler/Revolizer.

Asthma

Adults and adolescents (12 years and above): 

FULLFORM 200/400 Rotacaps

1-2 Rotacaps twice daily

Contraindications

FULLFORM Rotacaps is contraindicated in patients with a history of hypersensitivity to any of the components of the drug product.

Warnings and Precautions

Formoterol

Asthma-related Death

Formoterol fumarate dihydrate belongs to the class of long-acting beta2-adrenergic agonists (LABAs). In a study with salmeterol, a different long-acting beta2-agonist, a higher rate of death due to asthma was observed in the patients treated with salmeterol (13/13,176) than in the placebo group (3/13,179). No study adequate to determine whether the rate of asthma-related death is increased with formoterol has been conducted.

In the Treatment of Asthma

Formoterol should not be used (and is not sufficient) as the first treatment for asthma.

When treating patients with asthma long-acting beta2-adrenergic agonists should only be used as additional therapy for patients not adequately controlled on an inhaled corticosteroid alone or whose disease severity clearly warrants initiation of treatment with two maintenance therapies.

Formoterol should not be used in conjunction with another LABA.

Whenever formoterol is prescribed, patients should be evaluated for the adequacy of the anti-inflammatory therapy they receive. Patients must be advised to continue taking anti-inflammatory therapy unchanged after the introduction of formoterol, even when their symptoms improve.

The daily dose of formoterol should not be increased beyond the maximum recommended dose.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of formoterol. Regular review of patients as treatment is stepped down is important. The lowest effective dose of formoterol should be used.

Serious asthma-related adverse events and exacerbations may occur during treatment with Formoterol. Patients should be advised that if, after initiation of formoterol, their symptoms persist, or if the number of doses of formoterol required to control their symptoms increases, this usually indicates a worsening of the underlying condition. In these circumstances, they should be advised to continue treatment but to seek medical advice as soon as possible.

Patients should not be initiated on formoterol or the dose increased during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Formoterol must not be used to relieve acute asthma symptoms. In the event of an acute attack, a short-acting beta2-agonist should be used. Patients must be informed of the need to seek medical treatment immediately if their asthma deteriorates suddenly.

Concomitant Conditions

Special care and supervision, with particular emphasis on dosage limits, is required in patients receiving formoterol when the following conditions may exist:

Ischemic heart disease, cardiac arrhythmias, especially third degree atrioventricular block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, or other severe cardiovascular disorders, such as tachyarrhythmias or severe heart failure.

Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval and in patients treated with drugs affecting the QTc-interval.

Caution should be used when co-administering theophylline and formoterol in patients with pre-existing cardiac conditions.

Due to the hyperglycemic effect of beta2-stimulants, including formoterol, additional blood glucose controls are recommended in diabetic patients.

Hypokalemia

Potentially serious hypokalemia may result from beta 2-agonist therapy, including formoterol. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia and concomitant treatment. It is recommended that serum potassium levels be monitored in such situations.

Paradoxical Bronchospasm

As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy substituted.

Immediate hypersensitivity reactions may occur after administration of formoterol, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm.

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that formoterol is not administered for at least 12 hours before the start of anaesthesia as there is a risk of cardiac arrhythmias.

Beclomethasone Dipropionate

Inhaled steroid treatment should not be stopped abruptly.

Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored.

Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.

Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled beclomethasone dipropionate therapy should be treated with special care, and adrenocortical function regularly monitored.

Following introduction of inhaled beclomethasone dipropionate, withdrawal of systemic therapy should be gradual and patients encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.

Similarly replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

Treatment with beclomethasone dipropionate should not be stopped abruptly.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast acting inhaled bronchodilator. Beclomethasone should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

Visual Disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy which have been reported after use of systemic and topical corticosteroids.

Drug Interactions

Formoterol

Beta-blockers may weaken or antagonize the effect of formoterol. Therefore formoterol should not be given together with beta-blockers (including eye drops) unless there are compelling reasons.

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol may be potentiated.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.

Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of formoterol and may require titration of the dose.

Concomitant treatment with monoamine oxidase inhibitors macrolides or tricyclic antidepressants may potentiate the beta2-adrenergic stimulant effect of formoterol on cardiovascular system including agents with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions. There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

Concomitant treatment with xanthine derivatives, systemic corticosteroids, or diuretics may potentiate a possible hypokalemic effect of beta2-agonists. Hypokalemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

The bronchodilating effects of formoterol can be enhanced by anticholinergic drugs.

Beclomethasone Dipropionate

Beclomethasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such agents.

Patients with Renal and Hepatic Impairment

There is no need to adjust the dose in elderly patients or in those with hepatic or renal impairment.

Pregnancy 

Formoterol

There were no teratogenic effects revealed in animal tests. In animal studies formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight. The effects appeared at considerably higher systemic exposures than those reached during clinical use of formoterol. However, until further experience is gained, formoterol is not recommended for use during pregnancy (particularly at the end of pregnancy or during labor) unless there is no more established alternative. As with any medicine, use during pregnancy should only be considered if the expected benefit to the mother is greater than any risk to the fetus.

Beclomethasone Dipropionate

There is inadequate evidence of the safety of beclomethasone dipropionate in human pregnancy. In animal reproduction studies with beclomethasone dipropionate, adverse effects typical of potent corticosteroids were only seen at high systemic exposure levels. Direct inhaled application ensures minimal systemic exposure. Administration of drugs during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

Lactation

Formoterol

Formoterol has been detected in the milk of lactating rats, but it is not known whether formoterol passes into human breast milk, therefore mothers using formoterol should refrain from breast feeding their infants.

Beclomethasone Dipropionate

The excretion of beclomethasone dipropionate in milk has not been studied in animals. It is reasonable to assume that beclomethasone dipropionate is secreted in milk but at the dosage used for direct inhalation, there is low potential for significant levels in breast milk. Beclomethasone dipropionate should only be used in a nursing mother if the expected benefit justifies the risk to the newborn/infant.

Effects on Ability to Drive and Use Machines

Formoterol

Patients experiencing dizziness or other similar side effects should be advised to refrain from driving or using machines.

Beclomethasone Dipropionate

Beclomethasone dipropionate has no or negligible influence on the ability to drive and use machines.

Undesirable Effects

Formoterol

Following adverse reactions ranked in descending order of frequency, as follows: very common (≥ 1/10); common (≥1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, <1/1,000); very rare (< 1/10,000); unknown (frequency cannot be estimated from available data) have been observed with formoterol:

Immune system disorders

Very rare: Hypersensitivity (including hypotension, angioneurotic edema)

Rare: Hypersensitivity reactions e.g. bronchospasm, exanthema, urticaria, pruritus

Metabolism and nutrition disorders

Rare: Hypokalemia

Very rare; hyperglycemia

Psychiatric disorders

Uncommon: Agitation, anxiety, nervousness, restlessness, insomnia

Central Nervous system disorders

Common: Headache, tremor

Uncommon: Dizziness

Very rare: Dysgeusia

Cardiac disorders

Common: Palpitations

Uncommon: Tachycardia

Rare: Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles

Very rare: Peripheral edema. Angina pectoris, prolongation of QTc-interval

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchospasm, throat irritation, including paradoxical bronchospasm, acute asthma exacerbation*

Unknown: Cough**

Skin and subcutaneous tissue disorders

Unknown: Rash**

Gastrointestinal disorders

Uncommon: Dry mouth

Rare: Nausea

Musculoskeletal and connective tissue disorders

Uncommon Muscle cramps, myalgia

Investigations

Unknown Increased blood pressure (including hypertension)**

Vascular Disorders

Very rare Variations in blood pressure

*The percent of patients with serious asthma exacerbations in clinical studies was higher for formoterol than for placebo, and the biggest numerical imbalance was observed in children 5-12 years old.

** These adverse events were reported in patients treated with formoterol during the post-marketing experience.

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases. Treatment with beta2agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.

Beclomethasone Dipropionate

Very common (≥1/10), common (≥1/100 and <1/10) and uncommon (≥1/1000 and <1/100) events were generally determined from clinical trial data. The incidence in placebo and comparator groups has not been taken into account in estimation of these frequencies. Rare (≥1/10,000 and <1/1000), and very rare (<1/10,000) events were generally determined from spontaneous data.

Very common undesirable effects reported were candidiasis of the mouth and throat and hoarseness/throat irritation.

Infections and infestations

Very common: Candidiasis of the mouth and throat.

Immune system disorders

Hypersensitivity reactions with the following manifestations have been reported:

Uncommon: Rash, urticaria, pruritus, erythema.

Very rare: Angioedema, respiratory symptoms (dyspnea and/or bronchospasm) and anaphylactoid/anaphylactic reactions.

Endocrine disorders

Possible systemic effects include:

Very rare: Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma.

Psychiatric disorders

Very rare: Anxiety, sleep disorders and behavioral changes, including hyperactivity and irritability (predominantly in children)

Unknown: Depression, aggression (predominantly in children).

Respiratory, thoracic and mediastinal disorders

Common: Hoarseness, throat irritation.

Eye disorder

Not known: Vision, blurred

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Formoterol

There is no clinical experience to date on the management of overdose of formoterol; however, an overdosage of formoterol would be likely to lead to effects that are typical of beta2-adrenergic agonists: nausea, vomiting, headache, tremor, palpitations, tachycardia, palpitation, insomnia, ventricular arrhythmias, metabolic acidosis, hypokalemia, and hyperglycemia, angina, hypertension or hypotension, somnolence, prolongation of QTc interval, , dry mouth, dizziness, , may be associated with overdose of formoterol.

Supportive and symptomatic treatment is indicated. Serious cases should be hospitalized. Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.

Beclomethasone Dipropionate

There is no specific treatment for an overdose of beclomethasone dipropionate. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

Acute inhalation of beclomethasone dipropionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements.

However if higher than recommended dosage (1,500mcg) is continued over prolonged periods, some degree of adrenal suppression may result. Monitoring of adrenal reserve may be necessary. In cases of beclomethasone dipropionate overdose, therapy may still be continued at a suitable dosage (within the approved range) for symptom control.

Storage and Handling Instructions

Store below 25ºc.

Protect from heat and moisture.

Keep the container tightly closed.

Packaging Information

FULLFORM 200 Rotacaps ....... Pack containing 30 Rotacaps

FULLFORM 400 Rotacaps ....... Pack containing 30 Rotacaps

 

Last Updated: December 2018

Last Reviewed: December 2018