SUMMARY OF PRODUCT CHARACTERISTICS 1. Name of the medicinal product SYNTOPHYLLIN 2. Qualitative and quantitative composition Active substance: 240 mg Aminophylline (ie theophylline monohydrate 205.7 mg and 34.3 mg edamine) in 10 ml. For a full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection Clear, colorless or very slightly yellowish solution. 4. Clinical particulars 4. 1 Therapeutic indications Bronchial asthma, chronic obstructive bronchitis, obstructive pulmonary emphysema, respiratory insufficiency with hypoventilation, idiopathic apnea in newborns. This medicine is used to treat adults and children 4.2 Posology and method of administration a) Dosage for children: Stimulation of respiration in neonatal apnea: Intravenous initial dose of 6 mg / kg of body weight in 20 minutes, a maintenance infusion of 1 to 1.5 mg / kg /per hour. Intravenous initial dose of 6 mg / kg body weight from in 20 minutes, maintenance dose in children aged 6-52 weeks, using the formula: dose (mg / kg / h) = (0.008 x age in weeks) + 0.21 At higher ages, the recommended dosage is listed in the table:
Maintenance dose is usually divided into 4 doses in 24 hours or applied as a continuous infusion. b) Dosage for adults: The starting dose for adults is 10 ml (240 mg) of solution for injection, slowly, intravenously for 5 minutes, or 5 mg / kg of body weight as an infusion of isotonic sodium chloride solution, lasting 30-60 minutes. To maintain a therapeutic concentration of theophylline it might be continued with the maintenance dose according to the following table:
The maximum single dose is 500 mg, the maximum daily dose is 1500 mg of aminophylline. 4.3 Contraindications Intoxication by preparations containing theophylline, hypersensitivity to theophylline and edamin, thyrotoxicosis, severe liver insufficiency, tachydysrhythmia, acute myocardial infarction, epilepsy. 4.4 Special warnings and precautions for use While taking oral preparation containing theophylline the dose should be reduced by the amount that has been already applied by a different application route (for a narrow therapeutic range). Syntophyllin can not be applied intramuscularly. During the asthma attack use of Syntophyllin is the next next step of a comprehensive treatment which includes administration of oxygen, inhaled short-acting beta-agonists, corticosteroids, subcutaneous administration of beta-agonists. If insufficient effect of initial dose of Synthophyllin , the betamimetic is applied in the infusion. If patient was already treated with xanthic derivatives, the dose must be determined from examined concentrations of theophylline in plasma. Individual dosing is necessary due to influence on pharmacokinetic of theophylline by various factors (age, weight, diet, smoking, liver function, drug interactions). When calculating the dose, the conversion to ideal body weight is used (lean body mass). During the transition to oral dosage forms , when infusion is ended to use the preparation with prolonged effect with controlled release. The rapidly acting preparations are needed 4-6 hour interval between the end of infusion and administration of. 4.5 Interactions with other medicinal products and other forms of interaction Glukonan vápenatý může potencovat vznik srdečních arytmií při léčbě kardioglykozidy. Thiazidová diuretika snižují exkreci vápníku (potenciální riziko vzniku hyperkalciémie). Aminophyllin administered simultaneously with procaine, hypotensive and vasodilator drugs potentiates the drop of blood pressure. Simultaneously administered beta-agonists, inhaled anesthetics and glucocorticoids may increase the incidence of side effects. . Barbiturates, phenylbutazone, carbamazepine, phenytoin, primidone, nifedipine, rifampicin reduces concentrations of free theophylline in plasma. Its plasma concentrations are increased by cimetidine, ranitidine, erythromycin, troleandomycin, clindamycin, lincomycin, quinolones, oral contraceptives, anabolic steroids, disulfiram, caffeine, azatioprim , cyclophosphamide, diltiazem, verapamil, isoniazid, mexiletin, methyldopa, methotrexate, and beta-blockers. The rise of the concentration of theophylline after starting treatment with acyclovir was described. Aminophyllin administered with flumanezil together extends the half-life of midazolam. Repeated administration of lanzoprazol reduces levels of theophylline due to microsomal enzyme induction. . Fluexetín inhibits the metabolism of theophylline by inhibiting CYP1A2. Co-administration of clinofloxacin increases the concentration of theophylline. 4.6 Pregnancy and lactation When using Syntophyllin during pregnancy and lactation, the potential benefits for the mother and the potential risk to the fetus must be considered. Theophylline crosses the placenta and reaches therapeutic levels in fetus. In newborns of mothers who have taken theophylline, transient tachycardia, irritability and vomiting were observed. These effects appear more likely when the mother's plasma levels reach the upper therapeutic limit. During pregnancy, the pharmacokinetics of theophylline changes. In the third trimester reduced clearance of theophylline, in some cases by 20-53% was observed. Cases of toxicity, requiring a dose reduction were observed. Due to poromild tocolytic effect theophylline may delay delivery. Theophylline passes into breast milk. 4.7 Effects on ability to drive and use machines Some side effects occurring during treatment with xanthin products may decrease the ability to drive or operate machinery. 4.8 Undesirable effects The incidence of adverse effects is closely linked to the correct treatment, to respect for contraindications, the correct dosage and to the correct application speed. Due to the narrow therapeutic width of theophylline in some patients symptoms of overdose even in therapeutic plasma concentrations may occur. Theophylline may cause nausea, vomiting, epigastric pain, diarrhea and bleeding in gastrointestinal tract. It also increases the secretion of gastric juices and reduces the tone of the lower oesophageal sphincter, which can lead to gastroesophageal reflux. Theophylline can cause sinus tachycardia or supraventricular or ventricular extrasystoles already at therapeutic plasma concentrations. Polytopic atrial extrasystoles may also occur. After rapid intravenous injection, hypotension may occur. Deaths likely due to cardiovascular toxicity of theophylline have been observed. Theophylline stimulates the central nervous system, which is manifested by insomnia, increased excitability, headaches, or tremor. Higher plasma concentrations may provoke epileptic seizures. Adverse reactions to skin are often characterized by rashes of various types, by pruritus, by erythroderma and by exfoliative dermatitis. They are usually of moderate level. It is usually a hypersensitivity to edamin that can be confirmed by skin tests. In these cases it is recommended to prescribe theophyllin preparation instead of aminophyllin preparation. 4.9. Overdose Předávkování přípravku vyvolá hyperkalciémii. Theophylline has a low therapeutic index. Symptoms of overdose are usually observed at plasma concentrations above 20 mg / l, but they can occur at therapeutic plasma levels of 10-15 mg / l. Lethal concentration is above 50 mg / l. In chronic intoxication the symptoms of poisoning appear in lower plasma levels than in acute poisoning. Persons over 60 years and children in the first years of life are more sensitive to intoxication. Clinical signs of poisoning are manifested by gastrointestinal (nausea, vomiting and diarrhea) symptoms, cardiovascular symptoms (tachycardia, supraventricular and ventricular arrhythmias, hypotension) and by symptoms of overirritation of central nervous system (vomiting, hyperventilation, agitation, tremor, muscle cramps). Metabolic disorders: hypokalemia, hyperglycemia, hypophosphatemia, hypocalcemia, metabolic acidosis or respiratory alkalosis may be present. In rare cases, intoxication might be complicated by psychosis, dementia, acute pancreatitis, rhabdomyolysis and by acute renal failure. Treatment: At high plasma concentrations of theophylline or in cramps, in hypotension or cardiac arrhythmias any method of elimination should be used. The most effective elimination is achieved by haemoperfusion through charcoal or through resin. Hemodialysis is also effective, peritoneal dialysis is ineffective. Other treatment is symptomatic: treatment of hypokalemia, in convulsions diazepam or phenobarbital is administered, in hypotension is necessary to supplement the volume of the circulating fluid, in supraventricular tachycardia verapamil may be used, in ventricular tachycardia beta-blocker or procainamide might be administered. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Bronchodilator ATC code: R03DA05 Mechanism of effect Syntophyllin injection contains aminophylline, the molecular complex of methylxanthine derivative of theophylline with edamin. Own effect is caused by theophylline. It has a bronchodilator effect, acts stimulatory on breathing center, increases the frequency and strength of heart contractions, has a weak diuretic effect, stimulates the CNS and increases gastric secretion. 5.2 Pharmacokinetic properties Approximately 60% of theophylline is bound to plasma proteins, especially to albumin. Plasma protein binding is higher in asthmatics and newborns compared to healthy individuals. In diseases that lead to a decrease in plasma albumin levels (for example, nephrotic syndrome and cirrhosis of the liver) and in neonates the amount of bound substance is reduced. After intravenous administration, the effect is achieved in a few minutes. Volume of distribution of theophylline is 0.45 liters / kg in average. In adults approximately 10% of the substance is excreted unchanged in urine. In newborns quantities of unchanged substance may reach up to 50% of the applied dose. There are large interindividual differences in biotransformation in the liver among the subjects, leading to large differences in clearance, plasma concentrations and half-life of theophylline. Liver metabolism is influenced by other factors: age, smoking, diet, liver function, heart failure and simultaneously administered drugs. The pharmacokinetics of theophylline is not influenced by kidney function failure. Theophylline crosses the placenta and crosses into breast milk. Pharmacological effect of theophylline correlates with plasma levels well. In therapeutic concentrations (with bronchodilatory effect) are considered levels of theophylline 10-20 mg / l, which represents the 55-110 micromol / l. Levels above 20 mg / l may be potentially toxic. 5.3 Preclinical safety data Results of toxicology studies have not shown arguments against the administration in the listed indications and doses. 6. Pharmaceutical particulars 6.1 List of excipients Water for injection 6.2 Incompatibilities For the infusion preparation isotonic sodium chloride solution is the best. Product has an alkaline pH and must not be mixed with injecting solutions with acidic pH, particularly the B-group vitamins, vitamin C, promethazine, chlorpromazine, insulin, tetracycline, erythromycin, amiodarone, hydrocortisone, dobutamine, verapamil chloride, mazipredonium chloride, potassium salts of benzylpenicillin. When mixing the solution it leads to interaction and to clot formation or not. 6.3 Shelf life 5 years 6.4 Special precautions for storage Keep the ampoules in a box at a temperature of +10 ° C to +25 ° C. 6.5 Nature and contents of container Clear glass with a label, insert a PVC box Package size: 5 ampoules of 10 ml 6.6 Special precautions for disposal No special requirements. 7. marketing authorisation holder BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic 8. marketing authorisation number(s) 39/774/92-S/14/770/92-S/C 9. date of first authorisation/renewal of the authorisation December 12th, 1992 10. date of LAST REVISION OF THE TEXT November 30th, 2005 |
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