IPRATROPIUM = SALBUTAMOL | _ [III DUAVENT® 500 meg / 2.5 mg per 2.5 mL PULMONEB ® SOLUTION FOR NEBULIZATION Anticholinergic / Beta,-agonist FORMULATION Each 25 mL pulmoneb contains: Ipratropium bromide (anhyarous), 500 meg Salbutamol (as sulfate) 25mg PHARMACOLOGY Ipratropium bromide Ipratropium bromide isa quatemary ammonium compound with anticholinergic (oarasympatholytc) properties, Similar to atropine it is a nonselective Competitive antagonist of muscarinic receptors present in arways and other organs. Ipratropium bromide relaxes smooth muscles of bronchi and bronchioles by blocking acetycholne-induced stimulation of quan cyclase thus reducing formation of cyclic guanosine monophosphate (cGMP), @ ‘mediator of bronchaconstrction. Ipratropium generally exhiis greater animuscarinic actvty of bronchial smooth muscle than on secretory (2.9, salary, astic) lanes. Ipratropium bromide isa potent bronchodilator, particularly in large bronchial aways; however, some evidence suggests tha! the drug also has bronchodilator activity in small aways, Bronchodiation results ftom relaxation of smooth muscles of the bronchial wee. The een of bronchodiation produced by ipratropium appears tobe determined by the eval of cholinergic parasympathetic bronchomator tone ané by inhibition af bronchoconstiction resulting from neural reflex activation of cholinergic pathways, Salbutamot Salbutaml stimulates adenyl cyclase, the enzyme which catalyzes te formation of eycic-2', adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediate the calblar responses, such as bronchial smooth muscle relaxation. In viro and in vivo pharmacologic ‘ties have demonstrated that salbutamol has a preferential effect on beta adrenergc receptors tat are especialy found in respiratory tact compared ‘with isoproterenel. Salutamal has been shown in mast controled studies to have more effect onthe respiratory trac, nthe form of bronchial smooth ‘muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular eects RATIONALE OF COMBINATION Ipratropium bromide-saloutamol fhed-dose combination (FDC) maximizes the response to treatmentin patients with bronchial asthma and chronic obstructive pulmonary disease (COPD) by increasing bronchodiaton trough two distinctly diferent mechanisms, .., anticholinergic (parasympatholytic) and Bet, agonist (sympathomimetic) effets. Simukaneous administration ofboth an anticholinergic (pratropium bromide) anda beta sympathomimatic (salbutamol sla) produce @ greater bronchodilator effect than when eter drug is used alone PHARMACOKINETICS “wo three-month double-blind, randomized, paral, mulicenter clinical tals were done ina total ot 1,067 patients with stable COPD comparing ipratropium bromide - salbutamol combinaton with each individual component. Pulmonary function test (PFT) response rates were analyzed using 12% and 15% increases in FEV, compared wih baseline values and were measured in various treatment groups on days 1, 28,87, and 85 in these trials, Regardless of ‘iether a 12% ora 15% increase in FEV, was used to define a postive response, the ipratropium bromide-saloutamol combination was superior tothe individual agents (9-<0.05; all comparisons within 30 minutes). A 15% or mare increase in FEV, was Seen > 80% of patients win receved te ipratropium and salbutamol ulate combination administered as a single inaltion aerosol. ‘Studies demonstrate that each component ofthe FDC contributed to the improvement pulmonary function produced by the combination especially during the first 45 hours after the dasing, and tha the ipratropium bromide-salbutamol inhalation was significantly more effective than ipratropium bromide or salbutamol administered alone, In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pater of absorption and exertion of two inhalatons ofthe ipratropium bromide-salutamol FDC to the two active components incviualy, the co-acmiistration of ipratropium bromide ftom a single inhalation preparation cid not significantly atthe systemic absorption of either component. Ipratropium bromide levels remained below detectable mits (<100 pg/mL). Pea salbutamol level obtained within 3 hours post-administraton was 492 4 132 pg/mL. Following this single acminstratin, 27.1 + 6.7% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine, From pharmacokinetic perspective, the synergistic efficacy of the FDC is lkaly tobe due to alocal effect onthe ‘muscarinic and beta adrenergic receptrs inte lung Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and a. acid glycoprotein, Wis partially metabolized to inactive ester hydrolysis products. Salbutamal is extensively metabolizes inthe ver, mainly to salbutamol 4-0- sulfate which has ile oF no beta-adrenergic stimulating etfect and no beta- adrenergic blocking effect. Unlike isoproterenol, salbutam is not metabolized by the enzyme catechol-O-mettytransterase and isnot a substrate for catecholamine cellar uptake processes. InbicaTions ‘+ Management of reversible bronchospasm associated with obstructive airway diseases (2.9. bronchial asthma) + For use in patients with chronic obstructive pulmonary disease (COPD) ona regular inhaled bronchodilator who continue o have evidence of bronchaspasm and who require a second bronchodilator DOSAGE AND ADMINISTRATION Dosage Each pulmoneb of Ipratropium Bromide-Salbutamol contains 2500 meg of salbutamol base (with each drop containing 50 mcg). (hildron 2 to 12 yoars: 3 drops /kg / dose, maximum dose 2500 mcg (2:5 mg) of salbutamol every 6 to 8 hours x ‘Adults (including elderly patients) and adolescents over 12 years of ag z Treatment of acute attacks: * 1 pulmoneb (2.5 mL) is sufficient for prompt symptom rte in many cases. + 2)pulmonebs (6 mL) may be required in severe cases where an atack has not been relieved by 1 pulmoneb. O, as as prescribed by a physician, Maintenance treatment * 1 pulmoneb (2.5 mL) every 6-8 hours daly, o, as preseibed by a physician, ‘Administration +The solution fs intended anly for inhalation with sutable nebulzing devices and should not be taken orally: 1. Prepare your nebulizer for use 2. Remove the pulmoneb from the labeled stp by twisting and puling 38. Hold the pulmoneb upright and twist ofthe cap, transfer the contents tothe reservoir of your nebulizer Note: In most studies, a volume fil of 4 mL in the nebulizer chamber (using sterile normal saline as diluent) is recommended to ensure high ‘aerosol output, small respirable particle size and acceptably short treatment time. 4, Use your nebular, as instructed by the manufacturer, 5. After use, discard any remaining solution and thoroughly clean your nebulizer Other information + Since the solution contains no preservatves tis Important to use the cantent soon after opening. A new pulmaneb shouldbe used fr each administration to avoid microbial contamination, Discard partly used, opened or damaged pulmoneb, + Donat mix the inhalation solution with other drugs inthe same nebulizer. ‘CONTRAINDICATION ‘+ Patents wih hypertrophic obstructive cardiomyopathy or tachyarrhythmia + Patents with known hypersensitwty to any component ofthe drug produc o to atropine and its derivatives. WARNINGS. * Ipratropium bromide - salbutamol combination can produce paradoxical bronchospasm that can be ife-threatening, It occurs, discontinue the preparation immediatly and institute alternative therapy. It should be recognized that paradoxical bronchospasm, when associated with intaled formulations, frequently occurs wit the fst use of anew pulmoneb. + The salotamol sulate contained inthe formulation, lke ther beta-adrenergic agonists, can produce a cincaly significant cariovasculrelfect in some patents as measured by pulse rte, blood pressure andor other symptoms, Such effects are uncommon ater administration of the combination at recommended doses. PRECAUTIONS * Use with caution in patients withthe following contions: * Narrow-ange glaucoma, prostatic hypertropty or bladder-neck obstruction. © Convulsve disorders, hyperthyroidism, or diabetes melitus and in paints who are unusually responsive to sympathomimetic amines. Beta- ‘adrenergic agents may also produce significant hypokalemia in some patents, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular atfcts. The decrease in serum potassium i usually transient, not requiting supplementation, © Hepatic or ena disease, since use ofthe drug in these patients has not been studied + Use in Pregnancy: Safety and efficacy ofthe product during pregnancy has not yet been established. The inhibitory effect ofthe combination product on uterine contraction shouldbe taken into account. + Use in Lactation: itis not known wietner the components (ratropium bromide and salbutamol sulfate) of the FDC are excreted in human milk ‘Although lipd-nsoluble quaternary bases pass into breast mik, itis unikely that ipratropium bromide would reach he infant to an important exten, ‘especially when taken asa nebulzed solution, Because of the potential for tumorigniciy shown for salbutamol sue in some animal, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug tothe mother. ADVERSE DRUG REACTIONS The following adverse events were reported by two percent or more patients with COPD in a 12-week cotralled clinical tal on ipratropium bromide salbutamol sulfate combination (N=358) Body as a Whole (General Disorders): Headache, pain, infuenza, chest pain Gastrointestinal: Nausea ‘Respiratory: Bronchits, dyspnea, coughing, pneumonia, bronchospasm, oharynats, sinus, hints ‘Additonal adverse reactions, reported in less than two percent of patients include edema, fatigue, hypertension, dizziness, nervousness, paresthesia, tromor, ‘ysphoni, insomnia, darthea, ary mouth, dyspepsia, vomiting, arrhythmia, palpation, tachycardia, arthralgia, angina, increased sputum, taste perversion and urinary tractinfection/dysuria Aleroic-ype reactions such as skin rash, angioedema of the tongue, lips and face, urticaria, aryngospasm and anaphylactic reaction have also been reported. DRUG INTERACTIONS Anticholinergic agents: Athough ipratropium bromide is minimaly absorbed int the systemic circulation, thre is some potential for an additive interaction with concomitantly used anticholinergic medications. Beta-adrenergic agents: Co-adcinstration with otner sympatnomimethic agents may increase risk of adverse cardiovascular events. Beta- receptor blocking agents: Saloutamol and a bela-eceptor blocking agent inhibit each other's effect. Diuretics: The ECS changes andor hypokalemia which may result rom the administration of non-potassium sparing durtics (e.g. loop or thiazide uretics) can be acutely worsened by beta-agonsts, especially when te recommended dose ofthe beta agonist is exceeded ‘Monoamine oxidase inhibitors (MAO)) or Tricyclic antidepressant (TCAs): Concomitant administration with these agents may potentiate salbutamor' effect on the cardiovascular system. AVAILABILITY: Pulmonebs in box of 20's x 2.5 mL. ‘CAUTION: Foods, rugs, Devices, and Cosmetics Act protibits dispensing without prescription. ‘STORE AT TEMPERATURES NOT EXCEEDING 30°C, PROTECT FROM LIGHT. DO NOT FREEZE. DO NOT USE IF THE SOLUTION IS DISCOLORED. Manufactured by Mecispray Laboratories Pvt.Ltd 198 to L-146 Verna Industrial Estate Verna-Goa, India Imported and Distributed by United Laboratories, ne 656 Unted Steet, Mandaluyong City, Phipps For UNTED AMERICAN PHARMACEUTICALS, NC. 132 Pioneer Stet, Mandaluyong City, Prilppines 200 Reg. IPOPHIL Date of Revision: 11/2013,