DUOLIN Rotacaps (Levosalbutamol sulphate + Ipratropium bromide)

Transcription

1 Published on: 19 Sep 2014 DUOLIN Rotacaps (Levosalbutamol sulphate + Ipratropium bromide) Composition DUOLIN Rotacaps Each capsule contains: Levosalbutamol sulphate 100 mcg Ipratropium bromide.. 40 mcg Dosage Form Dry powder for inhalation Description DUOLIN rotacaps are a combination of ipratropium bromide and levosalbutamol sulphate. Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which inhibits vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Levosalbutamol sulphate is a relatively selective beta 2 -adrenergic agonist, whose activation leads to an increase in intracellular adenyl cyclase, the enzyme which catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'- adenosine monophosphate (camp). Pharmacology Pharmacodynamics No pharmacodynamic studies have been carried out on levosalbutamol sulphate and ipratropium bromide combination. Hence pharmacodynamics of levosalbutamol sulphate and ipratropium bromide has been discussed individually. Levosalbutamol Activation of beta 2 -adrenergic receptors on airways smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of camp. The increase in camp is associated with the activation of protein kinase A, which in turn, inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased camp concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways. Levosalbutamol acts as a functional antagonist to relax the airways, irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10-50% of which are beta2-adrenergic receptors. The precise function of these receptors has not been established. However, all beta-adrenergic agonist drugs can produce significant cardiovascular effects in some patients, as measured

2 by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. Ipratropium Bromide Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent increases in the intracellular concentration of Ca ++, which are caused by the interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle. In clinical trials using metered-dose inhalers in patients with reversible bronchospasm associated with asthma or COPD, significant improvements in pulmonary function (FEV 1 increases of 15% or more) occurred within 15 minutes, reached a peak in 1 2 hours, and persisted for approximately 4 hours. Controlled clinical studies have demonstrated that does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. DUOLIN rotacaps are expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta 2 -sympathomimetic (levosalbutamol sulphate) is designed to benefit the patient by producing a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. Pharmacokinetics No pharmacokinetic studies have been carried out on levosalbutamol sulphate and ipratropium bromide combination. Hence pharmacokinetics of levosalbutamol sulphate and ipratropium bromide has been discussed individually. Levosalbutamol Information available in published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is SULT1A3 (sulphotransferase). When racemic salbutamol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration time curves between the (R) - and (S)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, without charcoal pre-treatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-salbutamol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3. The primary route of elimination of salbutamol enantiomers is through renal excretion (80-100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the faeces. Following intravenous administration of racemic salbutamol, between 25% and 46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine. Special Populations Renal Impairment The effect of renal impairment on the pharmacokinetics of racemic salbutamol was evaluated in 5 subjects with creatinine clearance of 7-53 ml/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic salbutamol clearance. Caution should be used when administering high doses of levosalbutamol Inhaler to patients with renal impairment. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of levosalbutamol inhaler has not been evaluated. Ipratropium Bromide Absorption The therapeutic effect of Ipratropium is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel. Following inhalation, 10 to 30% of a dose is generally deposited in the lungs, depending on the formulation, device and

3 inhalation technique. The major part of the dose is swallowed and passes through the gastro-intestinal tract. The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes). Cumulative renal excretion (0-24 hours) of parent compound is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 13% of an inhaled dose. Based on these data the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively. Taking this into account, swallowed dose portions of ipratropium bromide do not contribute significantly to systemic exposure. Distribution The drug is minimally (less than 20%) bound to plasma proteins. The quaternary amine of the ipratropium ion does not cross the blood-brain barrier. Biotransformation Ipratropium has a mean total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), whereas after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%). Elimination After inhalation of ipratropium bromide either with HFA or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively. In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.2 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective. Special Populations Geriatric Patients In the pharmacokinetic study with 29 COPD patients, a subset of 14 patients was >65 years of age. Mean peak plasma ipratropium concentrations of 56±24 pg/ml were obtained following a single administration of 4 inhalations (21 mcg/puff) of ipratropium bromide HFA Inhaler (84 mcg). When these 14 patients were administered 4 inhalations q.i.d. (16 inhalations/day) for 1 week, the mean peak plasma ipratropium concentration only increased to 84±50 pg/ml, indicating that the pharmacokinetic behaviour of ipratropium bromide in the geriatric population is consistent with younger patients. Indications DUOLIN rotacaps are indicated for use in patients with COPD, who are on a regular bronchodilator, or who continue to have evidence of bronchospasm and require a second bronchodilator. Dosage And Administration The dosage of DUOLIN rotacaps is 1 rotacap, four times a day. Patients may take additional inhalations as required; however, the total number of rotacaps should not exceed 6 in 24 hours. DUOLIN rotacaps should be used only with the Cipla Rotahaler/ Revolizer. DUOLIN rotacaps must not be swallowed.

4 Contraindications Hypersensitivity to any component of the formulation, or to atropine and its derivatives. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. It is also contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soya bean and peanut. Warnings And Precautions Since DUOLIN rotacaps contains a combination of ipratropium bromide and levosalbutamol sulphate, the warnings and precautions for both drugs should be observed. Paradoxical Bronchospasm: DUOLIN rotacaps can produce paradoxical bronchospasm that can be life-threatening. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted. Cardiovascular Effects Like other beta-adrenergic agonists, the levosalbutamol sulphate contained in DUOLIN rotacaps can produce clinically significant cardiovascular effects in some patients, as measured by pulse rate, blood pressure and/or symptoms. Although such effects are uncommon after administration of DUOLIN rotacaps at recommended doses, if they occur, discontinuation of the drug may be indicated. In addition, beta-adrenergic agents have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. Large doses of intravenous racemic salbutamol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Therefore, DUOLIN rotacaps should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension, in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Do Not Exceed Recommended Dose Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of ipratropium bromide or levosalbutamol sulphate, as demonstrated by rare cases of urticaria (including giant urticaria), angio-oedema, skin rash, bronchospasm, anaphylaxis, oropharyngeal oedema, pruritus and laryngospasm. If such a reaction occurs, therapy with DUOLIN Rotacaps should be stopped at once and alternative treatment should be considered. Effects Seen with Anticholinergic Drugs DUOLIN rotacaps contain ipratropium bromide and may cause urinary obstruction and, therefore, should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction. There have been isolated reports of ocular complications (i.e. mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes. Thus patients must be instructed in the correct administration of DUOLIN rotacaps and warned against the accidental release of the contents into the eye. Antiglaucoma therapy is effective in the prevention of acute

5 narrow-angle glaucoma in susceptible individuals and patients who may be susceptible to glaucoma should be warned specifically on the need for ocular protection. Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately. Effects Seen with Sympathomimetic Drugs Preparations containing sympathomimetic amines such as levosalbutamol sulphate should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous racemic salbutamol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Additionally, beta-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Drug Interactions No formal drug interaction studies have been performed with DUOLIN rotacaps and these or other medications commonly used in the treatment of COPD. Anticholinergic Agents Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is therefore advised in the co-administration of DUOLIN rotacaps with other anticholinergic-containing drugs. Beta-Adrenergic Agents Caution is advised in the co-administration of DUOLIN rotacaps and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects. Beta-Receptor Blocking Agents These agents and levosalbutamol inhibit the effects of each other. Beta-receptor blocking agents should be used with caution in patients with hyper-reactive airways. Diuretics The ECG changes and/or hypokalaemia 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-agonist-containing drugs, such as DUOLIN rotacaps, with non-potassium-sparing diuretics. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants DUOLIN rotacaps 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 levosalbutamol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants. Digoxin Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic salbutamol to normal volunteers who had receieved digoxin for 10 days; hence, it is advisable to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and levosalbutamol. Renal Impairment DUOLIN rotacaps have not been studied in patients with renal impairment. It should be used with caution in these patient

6 populations. Racemic salbutamol is known to be substantially excreted by the kidney, and risk of toxic reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hepatic Impairment DUOLIN rotacaps have not been studied in patients with hepatic impairment. It should be used with caution in these patient populations. Pregnancy There are no adequate and well-controlled studies of ipratropium bromide or levosalbutamol sulphate in pregnant women. Because animal reproduction studies are not always predictive of human response, DUOLIN rotacaps should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Lactation It is not known whether the components of DUOLIN rotacaps are excreted in human milk. DUOLIN rotacaps should not be used by breastfeeding mothers, unless the expected benefit is thought to outweigh the risks. The benefit: risk ratio when levosalbutamol is administered for tocolysis has not been established. Certain adverse reactions, such as maternal pulmonary edema, have been reported during or following treatment of premature labour with beta- 2- agonists, including racemic salbutamol. Undesirable Effects Since DUOLIN rotacaps contains both ipratropium and levosalbutamol, the side effects of both the components should be expected. Levosalbutamol side effects seen in adults and adolescents include tremor, pain, pharyngitis, rhinitis, nervousness, tachycardia, dizziness, headache, hypokalaemia, dry mouth, throat irritation, urinary retention, nausea, vomiting, sweating, weakness, myalgia/muscle cramps arrhythmia, anaphylactic reactions, cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. In very rare instances, paradoxical bronchoconstriction has been observed. If, because of inappropriate handling, the DUOLIN rotacap powder enters the eyes in patients with narrowangle glaucoma, a rise in intraocular pressure may occur. In these cases, eye drops should be administered to induce miosis. Potentially serious hypokalaemia may result from beta 2 -agonist therapy. This effect may be potentiated by hypoxia. Particular caution is advised in severe asthma, along with monitoring of serum potassium levels. Other side effects such as palpitation, fine tremors of the skeletal muscle (particularly the hand) and muscle cramps may occur. In a few cases, nervousness, headache, dizziness, fatigue, and sleeplessness have also been reported. In addition to the adverse events reported in clinical trials, the following adverse events have been observed in post approval use of levosalbutamol. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extra systoles), asthma, chest pain, cough increased, dyspnea, nausea, nervousness, rash, tachycardia, tremor, and urticaria. Because these events have been reported spontaneously from a population of unknown size, estimates of frequency cannot be made. In addition, levosalbutamol, like other sympathomimetic agents, can cause adverse reactions such as hypertension,

7 angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx. Ipratropium Bromide The following side effects have been reported during treatment with ipratropium bromide. The frequencies given below are based on clinical trials involving patients who have been treated with ipratropium. Frequencies Very common 1/10 1/100 < 1/10 1/1,000< 1/100 Rare 1/10,000 < 1/1,000 Very rare < 1/10,000 Immune system disorders Hypersensitivity Anaphylactic reaction Angio-oedema of tongue, lips, face Nervous system disorders Headache Dizziness Eye disorders Blurred vision Glaucoma (1) Intraocular pressure increased (1) Eye pain (1) Mydriasis (1) Halo vision Conjunctival hyperaemia Corneal oedema Accommodation disorder Rare Cardiac Disorders Increased heart rate Palpitations Rare

8 Supraventricular tachycardia Atrial fibrillation Rare Respiratory, Thoracic and Mediastinal Disorders Cough Pharyngeal oedema Dry throat Bronchospasm Throat irritation Paradoxical bronchospasm (2) Laryngospasm Gastro-intestinal Disorders Dryness of mouth Vomiting Gastro-intestinal motility disorder e.g. Diarrhoea Constipation Nausea Stomatitis Skin and Subcutaneous Disorders Skin rash Pruritus Urticaria Rare Renal and Urinary Disorders Urinary retention (3) (1) ocular complications have been reported when aerolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes during nebuliser therapy (2) as with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. DUOLIN inhaler should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted. (3) the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction. Other side-effects include urticaria including giant urticaria, hypotension back pain, headache, influenza-like symptoms, dizziness, dyspepsia, bronchitis, COPD exacerbations, dyspnea, sinusitis and urinary tract infection.

9 Other side-effects that have been reported include urticaria including giant urticaria, hypotension back pain, headache, influenza-like symptoms, dizziness, dyspepsia, bronchitis, COPD exacerbations, dyspnea, sinusitis and urinary tract infection. In a 5-year placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients receiving ipratropium CFC. Additionally, urinary retention, mydriasis, gastrointestinal distress (diarrhoea, nausea, vomiting), cough and bronchospasm, including paradoxical bronchospasm, hypersensitivity reactions, intraocular pressure increased, accommodation disorder, heart rate increased, pharyngeal edema, and gastrointestinal motility disorders have been reported during the post-marketing period with use of ipratropium. Overdosage Levosalbutamol The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under adverse reactions, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalaemia may also occur. As with all sympathomimetic medications, cardiac arrest and, even, death may be associated with the abuse of levosalbutamol. Treatment consists of discontinuation of levosalbutamol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial in treating overdosage of levosalbutamol. Ipratropium Bromide Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration. Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angio-oedema, rash, bronchospasm, anaphylaxis, and oropharyngeal oedema. Packaging Information DUOLIN Rotacaps Each sales pack contains 30 rotacaps Last Updated: Jul 2015 Last Reviewed: Jul 2015 DUOLIN Rotacaps Source URL: