SEROBID Rotacaps (Salmeterol xinafoate)

Table of Content

Composition

Each capsule contains:

Salmeterol (as Salmeterol Xinafoate IP) ……….50 mcg

Excipient……………………………………………q.s.

Dosage Form

Dry powder for inhalation

Pharmacology

Pharmacodynamics

Salmeterol is a selective, long-acting (12-hour) beta2-adrenoceptor agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta2-adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta1- and beta2-adrenoceptors. In vitro studies show salmeterol to be at least fifty times more selective for beta2-adrenoceptors than salbutamol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart, comprising 10–50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to 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 inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Salmeterol contains a long side chain, which binds to the exo-site of the receptor. These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta2 agonists. In humans, salmeterol inhibits the early and late phase response to inhaled allergen, with the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids which should not be stopped or reduced when salmeterol is prescribed.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lungs. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness. Salmeterol has been studied in the treatment of conditions associated with COPD and has been shown to improve symptoms, pulmonary function and quality of life.

Pharmacokinetics

Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.

Absorption

Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable. Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 patients with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.

Distribution

The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Metabolism

Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base has been detected in either urine or feces.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to (alpha)-hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of (alpha)-hydroxysalmeterol in vitro.

Elimination

In 2 healthy subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.

Indications

SEROBID ROTACAPS are indicated for the treatment of asthma (including patients with nocturnal asthma and exercise‑induced asthma) only as concomitant therapy with inhaled corticosteroid.

SEROBID ROTACAPS are also indicated for the long-term, maintenance treatment of bronchospasm associated with COPD (including emphysema and chronic bronchitis).

Dosage and Administration

Adults

Asthma: 1 Rotacap twice daily. This may be increased to 2 Rotacaps twice daily in severe cases.

COPD: 1 Rotacap twice daily.

Children

Children (over 4 years): 1 Rotacap twice daily.

Children (under 4 years): Not recommended

SEROBID Rotacaps should only be inhaled with the Cipla Rotahaler/Revolizer device.

Contraindications

SEROBID ROTACAPS are contraindicated in patients with hypersensitivity to salmeterol xinafoate or to the excipients.

Warnings and Precautions

Long-acting beta2-adrenergic agonists, such as salmeterol, the active ingredient in SEROBID ROTACAPS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SEROBID ROTACAPS should only be used as additional therapy for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including SEROBID ROTACAPS.

Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy. The lowest effective dose of SEROBID ROTACAPS should be used.

Do not use SEROBID ROTACAPS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

SEROBID ROTACAPS should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be a life-threatening condition.

The SNS and SMART studies enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.

SEROBID ROTACAPS should not be used as a treatment for acutely deteriorating asthma.

SEROBID ROTACAPS should not be used to treat acute asthma symptoms for which a fast and short-acting inhaled bronchodilator is required. Patients should be advised to have their medicinal product to be used for the relief of acute asthma symptoms available at all times.

Salmeterol should be administered with caution in patients with thyrotoxicosis.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma or COPD.

SEROBID ROTACAPS should not be used in conjunction with an inhaled, long-acting beta2-agonist.

The management of asthma should normally follow a stepwise program.  Salmeterol should not be used (and is not sufficient) as the first treatment for asthma. SEROBID ROTACAPS is not a substitute for oral or inhaled corticosteroids. Corticosteroids should not be stopped or reduced when SEROBID ROTACAPS is initiated.

The recommended dosage should not be exceeded. 

Serious asthma-related adverse events and exacerbations may occur during treatment with SEROBID ROTACAPS. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on SEROBID ROTACAPS.

There have been very rare reports of increases in blood glucose levels and this should be considered when prescribing to patients with a history of diabetes mellitus.

Potentially serious hypokalaemia may result from β2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

Paradoxical bronchospasm.

As with other inhaled asthma and COPD medications, SEROBID ROTACAPS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEROBID ROTACAPS, it should be treated immediately with a short-acting, inhaled bronchodilator; SEROBID ROTACAPS should be discontinued immediately; and alternative therapy should be instituted.

Immediate hypersensitivity reactions.

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

Upper airway symptoms.

Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEROBID ROTACAPS.

Cardiovascular Effects

SEROBID ROTACAPS like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. SEROBID ROTACAPS, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of SEROBID ROTACAPS at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown.

Metabolic Effects

Doses of the related beta2-adrenoceptor agonist salbutamol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of SEROBID ROTACAPS at recommended doses.

Drug Interactions

Inhibitors of Cytochrome P450 3A4

Due to the potential increased risk of cardiovascular adverse events, the concomitant use of salmeterol with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.

Corticosteroids and Cromoglycate

In clinical trials, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently.

Methylxanthines

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving salmeterol has not been completely evaluated. Based on the available data, the concomitant administration of methylxanthines with SEROBID ROTACAPS did not alter the observed adverse event profile.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEROBID ROTACAPS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma or COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics.

Pregnancy

Pregnancy category C. There are insufficient data on the use of salmeterol during pregnancy in women to assess the possible harmful effects. In animal studies, foetal abnormalities occur after administration of beta2-adrenoreceptor agonists.

Use of SEROBID ROTACAPS during pregnancy should only be considered if the expected benefit to the expectant mother is greater than any possible risk to the foetus.

Lactation

It is unknown whether salmeterol is excreted in human breast milk. Animal studies in rats have shown excretion of salmeterol in breast milk. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with SEROBID ROTACAPS should be made taking into account the benefit of breastfeeding to the infant and the benefit of SEROBID ROTACAPS therapy to the, lactating woman.

Undesirable Effects

Tremor, muscle cramps, headache, palpitations, incidences of hypokalaemia, dizziness, anxiety, nausea, migraine, nasal/sinus congestion, rhinitis, pallor, influenza, bronchitis and insomnia have been reported.

Hypersensitivity reactions, rash (itching and redness), anaphylactic reactions including oedema and angioedema, bronchospasm and anaphylactic shock may occur.

Paradoxical bronchospasm, arthralgia, non-specific chest pain, anaphylactic reactions, including oedema and angio-oedema, bronchospasm and anaphylactic shock, hyperglycaemia, cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extra systoles), contact dermatitis, eczema, oral mucosal abnormalities, joint pain, oropharyngeal irritation, nervousness have been reported.

The pharmacological side effects of beta2-agonist treatment, such as tremor, headache and palpitations have been reported, but tend to be transient and to reduce with regular therapy. Tremor and tachycardia occur more commonly when administered at doses higher than 50 mcg twice daily.

As with other inhalational therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and fall in peak expiratory flow rate (PEFR) after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. SEROBID ROTACAPS should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

Overdosage

The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under UNDESIRABLE EFFECTS eg tremor, headache, tachycardia, dizziness, increase in systolic blood pressure etc. The preferred antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm.

Additionally, hypokalaemia can occur and, therefore, serum potassium levels should be monitored. Potassium replacement should be considered.

Packaging Information

SEROBID Rotacaps: Each sales pack contains 30 rotacaps

Last Updated:  September 2013
Last Reviewed: June 2015