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Oxantil Injection

1.  NAME OF THE MEDICINAL PRODUCT 

                                                        OXANTIL

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Active substance: Etophylline 160 mg, Theophylline monohydrate 40 mg in 2 ml. 

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Solution for injection 

Clear, colorless solution


4. CLINICAL PARTICULARS

4. 1 Therapeutic indications 

Brain perfusion disorders (cerebral malatia, thrombosis and embolism, atherosclerosis of cerebral arteries), chronic ischemic heart disease and chronic obstructive pulmonary disease (it is a part of treatment for some patients), pulmonary emphysema. 

4.2 Posology and method of administration 

 Adult dosage 

 The solution for injection is administered intramuscularly or very slowly intravenously. 2-3 vials might be administered in intravenous infusion of 5% glucose solution or isotonic sodium chloride solution as well.  The daily dose should not exceed 6 ampoules (960 mg of etophylline and 240 mg of theophylline). 

4.3 Contraindications 

 Theophylline derivatives intoxication, hypersensitivity to methylxantine derivatives, acute myocardial infarction, arrhythmias, severe hepatic insufficiency. 

4.4 Special warnings and precautions for use 

During  intravenous administration, the injection should be administered slowly.  If the application lasts less than 2 minutes, it may cause uncomfortable heat.  Subcutaneous application causes pressure pain at the injection site, which takes about half an hour, and therefore this method is less suitable route of application. 

4.5 Interactions with other medicinal products and other forms of interaction

 Most of interactions are interactions of theophylline.  Cimetidine increases the plasma levels of theophylline and etophylline.  Smoking, barbiturates, phenylbutazone and hydantoin AEDs increase the plasma clearance of theophylline, on the contrary allopurinol decreases its clearance.  A reduction in the clearance of theophylline should be counted in the administration of macrolide antibiotics (erythromycin, oleandomycin).  Oral contraceptives, diuretics, corticosteroids, immunosuppressants and quinolones potentiate the effects of theophylline.  After  propanolol administration the theophylline serum levels may be almost double, due to the reduction of N-demethylation of theophylline due to binding to cytochrome P 450 . In combination with ephedrine, theophylline may lead to increased incidence of nausea, insomnia and nervousness.  Increased risk of ventricular arrhythmia due to the interaction of halothane and  theophylline is caused by increased sensitivity to endogenous catecholamines. 

4.6 Pregnancy and lactation 

The application of theofylline preparations during pregnancy should be approached with regard to weight gain.  Theophylline clearance in pregnant women has not changed, but the volume of distribution and elimination half-life is increased.  In the third trimester, the reduction in clearance of 20-53% was observed. Even if theophylline crosses the placental membrane, the data on teratogenicity have not been published.  Plasma concentrations in infants may be similar to maternal plasma concentrations.  In newborns of mothers who have taken theophylline transient tachycardia, irritability and vomiting were observed. These effects occur primarily when maternal plasma levels reach the upper therapeutic concentration.  Data concerning etophyllin concentration in breast milk are not available in literature. Less than 1% of theophylline concentration in the blood of mothers is eliminated in breast milk.  The ratio of theophylline concentration in milk to concentration in serum is 0.67. 

4.7 Effects on ability to drive and use machines 

Active ingredients in therapeutic doses don´t have a negative impact on the attention of drivers and machine operators.  With reference to the risk of side effects described below is recommended that the patient ability to drive shall be decided by the physician according to the current state of health.

4.8 Undesirable effects 

 Etophylline is very well tolerated derivative of theophylline. In some vegetatively labile individuals after etophylline administration vasomotor disorders - dizziness, scotoms, circles in front of eyes, etc.may occur. Headache, collapse with chills, worsening of tinnitus have been also described. A case of worsening of exanthem disease appeared.

 Among side effects of theophylline, nausea, strong heartbeat, stimulation of CNS, including irritability, insomnia and tremors should be noted.  More severe side effects are muscle cramps and cardiac arrhythmia (sinus tachycardia, ventricular extrasystoles and atrial).  Seizures occur in higher incidence if the plasma concentration of theophylline exceeds levels of 40 micrograms / ml.  The danger is that symptoms appear without warning.  After administration of normal doses, there are not such high plasma levels and therefore according to the proper therapeutic regime incidence of adverse events does not come into consideration. 

4.9. Overdose 

 In toxicological study in mice that have received a product containing 22 mg of theophylline and 88 mg of etophylline to determine LD 50 values (mg / kg) were after intraperitoneal administration 469.9, 465.2 after intramuscular administration and 1207.0 after oral administration.  Etophylline´s acute toxicity is lower than theophylline. In plasma concentrations 50-100 µg/ml  of theophylline and 100-300 µg/ml  of etophylline maintained during the two-hour infusion administration apparent toxic effects of combinations of these substances were found.  LD 50 values of etophylline found in four-subchronic toxicological tests in mice, were 404 mg / kg after intraperitoneal administration and 600 mg / kg after oral administration. 

 In overdose, toxic symptoms characteristic for theophylline and other methylxanthine derivatives intoxication, may occur. Theophyllin toxicity is manifested in the gastrointestinal tract as vomitus of persistent nature. In children are usually accompanied by hematemesis. Symptoms of gastrointestinal toxicity are probably caused by central effects of theophylline, rather than its direct effect on the stomach. Stimulating effect of methylxanthines on the CNS acts at various levels, medullary - increased respiratory rate and increased sensitivity to CO 2, nausea and vomiting, bradycardia.  Stimulation of the cortex leads to restlessness, agitation, tremors, increased excitability, headaches, convulsions, difficulty in concentration and to behavioral disorders.  At hypothalamic level stimulating effect of methylxanthines leads to hyperthermia. 

 The cardiovascular toxicity is often manifested by sinus tachycardia.  During theophylline intoxication hyperglycemia is often present. In theophylline poisoning hypokalaemia occurs, which is manifested by muscle weakness, paralytic ileus, and polyuria. 

 Treatment: 

 In high plasma concentrations of theophylline and etophylline or cramps, hypotension, or arrhythmias any method of elimination should be used.  Hemodialysis is effective, peritoneal dialysis does not have any effect.  Further treatment is symptomatic: hypokalemia treatment, in convulsions diazepam or phenobarbital is administered ,in hypotension fluids should be supplied. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: Vasodilator

ATC code: C04AD

Mechanism of action 

Etophylline was developed during the search of soluble theophylline derivatives and therefore its pharmacological effects are close to theophylline and other xanthine compounds.  Etophylline causes relaxation of smooth muscles of different types, such as muscle blood vessels, bladder, seminal vesicles and uterus. In animal experiments causes a slight drop in blood pressure associated with increased cardiac output and reduced peripheral resistance, after which starts the secondary rise in peripheral resistance. This biphasic effect is less effective than can be observed after theophylline.  Increase of the coronary flow observed in experiments and clinical trials is due to direct vasodilatory effect of etophylline and also indirectly by increasing of perfusion volume.  Direct vasodilatory effect on pulmonary artery of etophylline leads to an increase of blood flow from the lungs and increase of performance of left ventricule.  Low doses of etophylline increase cardiac output due to the increase of ejection fraction.  Positive inotropic effect of etophylline is evident in the experiments on isolated heart as well.  In the cerebral bloodstream its therapeutic effect is not likely in vasodilation, but rather in the redistribution of the cerebral circulation from healthy areas to sites affected by ischemia.  There may assert its blocking effect on adenosine receptors, which was found in other methylxantines, eg theophylline. Antiedematous effect is probably related to the blockade of adenosine receptors also. Etophylline stimulatory effects on the respiratory center, connected with an increase of respiratory volume, also participates in the mechanism of its effect on the treatment of cerebral circulation disorders.  Bronchospasmolytic effects of theophylline are shown in experiments on guinea pigs, where it was inhibited bronchoconstriction induced by different mediators. 

 Compared with theophylline, bronchospasmolytic effect of etophylline is less pronounced.  Among other pharmacological effects, diuretic effect of etophylline should be mentioned, which is more intense than the diuretic effects of theophylline at the same concentrations. 

 5.2 Pharmacokinetic properties 

A pharmacokinetic study in humans who received theophylline in combination with etophylline intravenously (340 mg etophylline + 100 mg of theophylline) and orally in the form of tablets (680 mg etophylline + 200 mg theophylline) and drops of the same doses, demonstrated that maximum serum concentrations reached in theophylline and in etophylline about the same time. Plasma elimination half-life was from 5.0 to 7.2 hours for theophylline and 5.5 to 6.9 hours for etophylline. 

Table kinetic constants after intravenous etophyllineu and theophylline in combination: 

Parametr Parameter

etofylinEtophylline

t he ofylin Theofylin

 

x x

s with

x x

s with

r r

0,99 0.99

0,004 0.004

0,98 0.98

0,03 0.03

RV   (%) RV (%)

2,7 2.7

1,03 1.03

4,80 4.80

6,0 6.0

t 1 (h) t 1 (h)

5,45 5.45

0,93 0.93

5,04 5.04

1,13 1.13

V cc (l) V cc (l)

32,90 32.90

8,3 8.3

28,20 28.20

5,4 5.4

CL tot (l/h) CL tot (l / h)

5,0 5.0

1,2 1.2

4,07 4.07

1,5 1.5

AUC  (µg.h/ml) AUC (μg.h / ml)

72,4 72.4

18,3 18.3

26,80 26.80

9,4 9.4

T cc (h) T cc (h)

7,8 7.8

1,2 1.2

7,30 7.30

1,6 1.6

 x - average value 

 s - standard deviation 

 r - correlation coefficient of one-compartment model 

 RV - residual variations 

 t 1 - biological half-life 

 V cc - central volume of distribution 

 CL tot - total clearance 

 AUC - area under the curve 

 T cc - central transit time 

 Theophylline and etophylline are bound to two different binding sites of human plasma albumin.  In assessing of the pharmacokinetics of theophylline and its derivatives,it should be taken into account the great interindividual variability, because the degradation of theophylline in the liver is not constant. Plasma clearance is different mainly in adults and in children. The lowest is in premature infants, and gradually increases up to 6-17 years, when its value is stabilised. There are no age differences in adulthood.

 Those values are influenced by smoking, which accelerates the biotransformation of theophylline, which is explained by the stimulation of liver enzymes by polycyclic acids contained in tobacco.  Plasma clearance is affected by various drugs such as clonidine and macrolide antibiotics, which reduce it.  Changes in theophylline clearance also occur due to various diseases, such as heart, liver diseases and infections, which indicates the reduction in clearance.  On the contrary,in patients with cystic fibrosis an increase in theophylline clearance has been described. 


6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients 

Water for injection. 

6.2 Incompatibilities 

 Not applicable.

6.3 Shelf life 

4 years

6.4 Special precautions for storage 

Store at 10-25 ° C.  

6.5 Nature and contents of container 

Clear glass with a label, insert PVC box   

Package size:  5 ampoules of 2 ml.

6.6 Special precautions for disposal

 Any unused product or waste material should be disposed in accordance with local requirements. 

7. MARKETING AUTHORISATION HOLDER 

BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic

8. MARKETING AUTHORISATION NUMBER(S) 

 83 / 769 / 92-S / C 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

September 14th, 1992 / April 8th  2009

10. DATE OF REVISION OF THE TEXT

April 8th,  2009