Translation from Latvian Approved by SAM on Summary of Product Characteristics

Transcription

1 Approved by SAM on NAME OF THE MEDICINAL PRODUCT Eifilīns 150 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Active substance: Aminophylline (Aminophyllinum) Each tablet contains 150 mg aminophylline (125 mg theophylline anhydrous and 25 mg ethylenediamine). For the full list of excipients, see section PHARMACEUTICAL FORM Tablets. Round flat white to light yellow tablets with beveled edge. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of obstructive pulmonary diseases such as asthma, chronic bronchitis, pulmonary emphysema. Treatment and prophylaxis of bronchospasm associated shortness of breath. 4.2 Posology and method of administration Posology Adults The recommended dose is mg 3-4 times per day. The usual initial dose is 150 mg three times daily for a week. Afterwards, if there is a need and the medicinal product is well tolerated, the dose may be increased to mg per day administered in 3-4 times divided doses. The maximum single dose of aminophylline is 500 mg and the maximum daily dose mg. There is a narrow margin between therapeutic and toxic doses. Duration of the treatment may last from a few days to several months. Special populations Elderly In the elderly patients, the dose should be decreased. These patients have significantly extended theophylline elimination half-life and clearance. During long - term treatment elderly patients should undergo periodic monitoring of theophylline plasma concentration. Children Eifilīns 150 mg tablets are not recommended for children under 4 years of age due to the dose amount. Children and adolescents over 4 year of age: the first week of treatment - 6 mg/kg body weight per day; the second week of treatment mg/kg body weight per day given daily n divided doses. In order to avoid theophylline toxicity, it is recommended to determine the theophylline plasma levels. Hepatic impairment Dose decrease is necessary in patients with hepatic impairment. Theophylline plasma concentration monitoring is essential. 1

2 Renal impairment Dose adjustment is not required in patients with impaired renal function. Method of administration Eifilīns 150 mg tablets are for oral administration after meals with a glass of water. To achieve a stable therapeutic effect the dose should be adjusted individually. Treatment should be initiated with the lowest therapeutic dose. The optimal response to the treatment is achieved, if theophylline plasma levels are mg/l. Theophylline plasma concentration should be determined 4-6 hours after the last orally administrated dose and no earlier than 5 days from the initiation of the treatment. 4.3 Contraindications - Hypersensitivity to theophylline, other xanthines (caffeine, theobromine, pentoxifylline), ethylenediamine or to any of the excipients listed in section Recent myocardial infarction - Porphyria - Pregnancy and lactation - Eifilīns 150 mg tablets should not be co-administered with other xanthine medicinal products, fluvoxamine, as well as herbal preparations containing St. John's Wort. - Eifilīns 150 mg tablets should not be administrated concomitantly with ephedrine in children. 4.4 Special warnings and precautions for use In order to achieve optimal response to the treatment with as little risk as possible, theophylline plasma levels should be monitored regularly, particularly if the therapy is insufficient or undesirable effects have been observed. Care should be exercised in patients with - heart failure, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity; -arrhythmia (tachycardia, extrasystoles, except bradyarrhythmias), due to the possible risk of current clinical situation worsening; - hypertension, because theophylline may cause exacerbations; - hyperthyroidism, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity; - gastric ulcer, due to the possible risk of current clinical situation worsening; - epilepsy, due to the possible risk of current clinical situation worsening; -fever, increased body temperature for a long time period, a viral infection, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity; - liver failure, liver cirrhosis, acute hepatitis, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity; - acute pulmonary oedema or cor pulmonale, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity; - severe hypoxemia, due to the decrease of theophylline clearance, leading to severe and potentially dangerous theophylline toxicity. Smoking cessation reduces theophylline clearance, leading to severe and potentially dangerous theophylline toxicity. Tobacco smokers have shorter theophylline elimination half-life, to be taken into consideration increasing the dose. Aminophylline should be used with caution in elderly patients, due to the reduced theophylline clearance, leading to severe and potentially dangerous theophylline toxicity. 2

3 Caution is required when administering aminophylline with other medicinal products, due to the potential interactions (see section 4.5). Xanthines including theophylline, when used concomitantly with beta-2 adrenergic agonists, acetazolamide, corticosteroids or diuretics, increase risk of hypokalaemia. Therefore, it is recommended to monitor serum potassium levels (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Specific data on the interactions of aminophylline is not available. Aminophylline contains theophylline with known following interactions. Theophylline and - acetazolamide. Co-administration increases the risk of hypokalaemia. - adenosine. The anti-arrhythmic effect of adenosine is antagonised by theophylline. - allopurinol. Allopurinol may increase the theophylline plasma concentration. - azithromycin. Azithromycin may elevate plasma concentration of theophylline. - barbiturates. Barbiturates accelerate the metabolism of theophylline, reducing theophylline efficacy. - benzodiazepines. Theophylline may reduce the effects of benzodiazepines. - calcium channel blockers. Calcium channel blockers - dihydropyridine derivatives, including felodipine, amlodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine and nisoldipine, may increase the plasma levels of theophylline (increasing the effect). Diltiazem increases theophylline plasma concentration. Verapamil elevate plasma theophylline concentration increasing the effect of theophylline. - carbamazepine. Carbamazepine accelerates the metabolism of theophylline, reducing theophylline efficacy. - cimetidine. Cimetidine inhibits the metabolism and increases plasma concentration of theophylline. - ciprofloxacin. Ciprofloxacin increases plasma concentration of theophylline - clarithromycin. Clarithromycin inhibits the metabolism and increases plasma concentration of theophylline. - corticosteroids. Co-administration increases the risk of hypokalaemia (interaction usually does not apply to topical and inhaled corticosteroids). - disulfiram. Disulfiram inhibits the metabolism of theophylline (increased risk of toxicity). - diuretics. Increased risk of hypokalaemia, when theophylline co-administered with loop, thiazide or other diuretics. - doxapram. Doxapram increases CNS stimulation when used concomitantly with theophylline. - ephedrine. Ephedrine is not recommended for use together with theophylline in children. - erythromycin. erythromycin inhibits the metabolism of theophylline and increases theophylline plasma concentration; if erythromycin is administered orally, erythromycin plasma concentration is also reduced (interaction does not apply to topical erythromycin in small doses). - fluconazole. Fluconazole may increase plasma levels of theophylline (this usually involves repeated doses of fluconazole). - fluvoxamine. Fluvoxamine increases plasma concentration of theophylline (usually concomitant use is contraindicated, but if necessary reduce theophylline dose by half and monitor theophylline plasma levels). - halothane. Co-administration increases the risk of arrhythmia. - influenza vaccine. Co-administration may result in increased plasma theophylline concentrations. - interferon alpha. Interferon alpha inhibits the metabolism and increases theophylline plasma concentration. - isoniazid. Isoniazid may increase the plasma concentrations of theophylline. - ketamine. Co-administration increases the risk of convulsions. - ketoconazole. Ketoconazole may increase plasma theophylline concentration. 3

4 - lithium preparations. Theophylline accelerates the excretion of lithium, therefore, decreasing lithium plasma concentration. - methotrexate. Methotrexate may increase theophylline plasma levels. - mexiletine. Mexiletine increases theophylline plasma levels. - norfloxacin. Norfloxacin increases theophylline plasma levels. - estrogens. Estrogens reduce the excretion of theophylline and increase plasma concentrations. Interaction with combined oral contraceptives may also apply to combined contraceptive transdermal patches. It is unlikely that low-dose hormone replacement therapy may interact with theophylline. - pentoxifylline. Pentoxifylline increases plasma theophylline concentration. - phenytoin. Co-administration decreases plasma concentrations of both medicines. - primidone. Primidone accelerates metabolism of theophylline reducing its efficacy. - propafenone. Propafenone increases plasma concentration of theophylline. - quinolones. Concomitant use of theophylline and quinolones may increase the risk of convulsions. - rifampicin. Rifampicin accelerates the metabolism of theophylline reducing its plasma concentration. - ritonavir. Ritonavir accelerates the metabolism of theophylline reducing its plasma concentration. - St. John's Wort (Hypericum perforatum). St. John's wort reduces theophylline plasma levels (concomitant administration is not recommended). - sucralfate. Sucralfate may reduce the absorption of theophylline (medicinal products should be used with a 2 hour interval between the medicines). - sulfinpyrazone. Sulfinpyrazone reduces plasma theophylline concentration. - beta-2 adrenergic agonists. Concomitant use of theophylline and high doses of beta-2 adrenergic agonists (salbutamol, terbutaline, formoterol, salmeterol, bambuterols and fenoterol) increase risk of hypokalaemia. - tobacco. Tobacco smoking accelerates the metabolism of theophylline, therefore, reducing plasma theophylline concentration. - zafirlukast. Co-administration may increase theophylline plasma levels and decrease zafirlukast plasma concentration. Alcoholic beverages should be avoided during the therapy. Effects on laboratory tests. When using a spectrophotometric method for theophylline plasma level determination, the results can be increased, if the patient drink coffee, tea, cola, chocolate or take paracetamol. 4.6 Fertility, pregnancy and lactation Theophylline crosses the placenta and may reach possibly dangerous levels in foetal blood, which may lead to increased neonatal agitation and apnoea. Aminophylline should only be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Theophylline is secreted in breast milk and may be associated with irritability in the infant and other undesirable effects, such as restlessness, agitation, insomnia, tachycardia and tremor. Theophylline concentration in the milk of breast-feeding mothers is about 70% of the concentration in the plasma of breast-feeding mothers. An infant per day can receive about 10% of maternal theophylline dose, therefore Eifilīns 150 mg tablets should not be used during lactation. Especially dangerous if the mother consumes products containing methylxanthines: coffee, chocolate, cocoa, cola or strong tea. 4.7 Effects on ability to drive and use machines It is unknown whether theophylline affects the ability to drive and use machinery. Patients should be advised not to drive or operate machinery if affected by dizziness or headache. CNS disorders induced by high doses may occur without prior symptoms. 4

5 4.8 Undesirable effects Like all medicines aminophylline can cause side effects, although not everybody gets them. Their frequency is defined using the following conventions: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000), including case reports. Cardiac disorders: rare tachycardia, palpitations, extrasystoles, arrhythmia. Nervous system disorders: common headache, dizziness, insomnia, tremor, restlessness, irritability. Gastrointestinal disorders: common nausea, abdominal pain, diarrhoea, vomiting. Metabolism and nutrition disorders: common appetite lost. Renal and urinary disorders: common diuresis. Skin and subcutaneous tissue disorders: rare hypersensitivity reactions caused by ethylenediamine such as urticarial, erythema, exfoliative dermatitis. If theophylline plasma concentration is greater than 20 mg/l, the undesirable effects are more apparent, frequent and severe. Patients with heart failure, tendency to tachycardia, hepatic impairment and elderly patients are more likely to experience adverse effects (see section 4.4). 4.9 Overdose Theophylline has a narrow therapeutic index, therefore, acute or chronic overdose is possible. If patient experience overdose symptoms, hospitalization is required due to possible rapid development of life - threatening symptoms. Symptom severity depends on the theophylline plasma concentrations. Theophylline toxicity is most likely to occur when plasma concentrations exceed mg/l, and always occurs, if it is above 30 mg/l. Symptoms of acute overdose: prolonged vomiting (may be bloody), nausea, abdominal pain, agitation, dizziness, anxiety, insomnia, headache, metabolic acidosis, hyperglycaemia, hypokalaemia, tachycardia. Most serious symptoms are cramps and arterial hypotension. Symptoms of chronic overdose may appear suddenly with moderate gastrointestinal symptomatology, but metabolic acidosis, hyperglycaemia, hypokalaemia usually are absent. May also occur cardiac rhythm disorders. Treatment Acute overdose: gastric lavage may be of value to delay absorption of medicinal product, if undertaken within 2 hours of ingestion. Repeated oral administration of activated charcoal enhances the elimination of theophylline from the organism. In general, theophylline is metabolised rapidly and haemodialysis is not warranted. Seizures may be treated with diazepam intravenously (i/v). Hypokalaemia should be corrected by intravenous infusion of potassium chloride. Propranolol or esmolol may be administered intravenously to reverse extreme tachycardia, arterial hypotension and ventricular arrhythmia. Treatment of overdose is supportive - maintaining blood pressure, providing adequate hydration. If theophylline plasma levels are above 50 mg /l, haemodialysis is used. Chronic overdose: in most cases dose reduction or temporary Eifilīns 150 mg tablets discontinuation is sufficient. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other systemic drugs for obstructive airways diseases. Xanthines. ATC code: R03DA05 5

6 Aminophylline is a mixture of theophylline and ethylenediamine. During digestion aminophylline releases theophylline, therefore, aminophylline has the same effects and indications as theophylline, but aminophylline is more soluble in water. Theophylline, xanthine derivative, is a bronchodilator that relaxes not only smooth muscle of the bronchial airways, but also pulmonary blood vessels. Ethylenediamine exert a mild spasmolytic action as well. It also increases the solubility of theophylline. Aminophylline mechanism of action is complex and not completely known. Theophylline effect is based on selective inhibition of enzyme phosphodiesterase activity, therefore, increasing intracellular 3 ', 5'- adenosine monophosphate (camp) concentration. Theophylline increases the excretion of endogenous catecholamines, inhibits calcium ions from entering cells, inhibits certain prostaglandins and releases of inflammatory mediators from mast cells. Theophylline competitively binds to adenosine receptors in the heart, central nervous system (CNS), bronchial tubes and other organs, inhibiting adenosine activity and effects. Thus aminophylline affects a variety of organism functions: improves alveolar ventilation; slightly dilates pulmonary, renal and coronary blood vessels; stimulates myocardial Contractility; increases cardiac stroke and minute volume; moderately stimulates the CNS, including respiratory centres, promotes gastric acid secretion; improves renal blood flow and glomerular filtration, therefore, increasing diuresis. Theophylline research over the past decade has shown its anti-inflammatory and immunomodulating activity. Theophylline increases the myocardial oxygen consumption. 5.2 Pharmacokinetic properties Absorption. Aminophylline is well absorbed from the gastrointestinal tract. Bioavailability is approximately 90%. Concomitant intake of food prolongs absorption of aminophylline. Stable therapeutic effect is achieved at theophylline concentrations of mg/l ( µm / L). Theophylline is approximately 40-50% bound to plasma proteins. Theophylline has a narrow therapeutic index. Plasma theophylline concentrations over 20 mg/l increase risk of side effects and toxicity. Biotransformation and elimination. About 90% of theophylline is metabolised in the liver mainly by cytochrome P450 isozymes, particularly CYP1A2. The biotransformation results in 1,3-dimethyluric acid, 1-methyluric acid and methylxanthine metabolites, which are excreted in the urine. In adults 10% of theophylline is excreted unchanged. Hepatic clearance is affected by such factors as age, smoking, food and concomitant administration of other medicinal products. In cases of heart failure, liver impairment, chronic alcoholism and pulmonary oedema theophylline clearance is decreased. The elimination half-life of theophylline in non-smoking patients with asthma and almost no pathological changes in the other organs and organ systems is 6 to12 hours; in smokers 4 to 5 hours; newborn and premature children 10 to 45 hours. The elimination half-life is decreased in children and smokers comparing to non-smoking adults, therefore, they require relatively higher doses, according to body weight. Theophylline crosses the placenta and passes into breast milk. Ethylenediamine does not affect the pharmacokinetics of theophylline. 5.3 Preclinical safety data Studies in animals have shown a correlation between theophylline concentrations in plasma and severity of toxic effects. Teratogenicity. A study in rats, mice and rabbits that received theophylline during organogenesis period have shown theophylline - induced teratogenic effects. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 6

7 Potato starch, calcium stearate. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25 ºC. Protect from light and moisture. 6.5 Nature and contents of container 10 tablets in opaque polyvinyl chloride film and aluminum foil blister 3 blisters (30 tablets) and the package leaflet in a carton pack. 6.6 Special precautions for disposal and other handling No special requirements. 7. MARKETING AUTHORISATION HOLDER JSC Olainfarm. Address: 5, Rupnicu St., Olaine, LV-2114, Latvia. Phone Fax olainfarm@olainfarm.lv 8. MARKETING AUTHORISATION NUMBER(S) DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION / / DATE OF REVISION OF THE TEXT