SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Omeprazol XXX 40 mg, powder for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial of powder for solution for infusion contains 42.6 mg Omeprazole Sodium equivalent to 40 mg Omeprazole. 1 ml of reconstituted solution for infusion contains mg Omeprazole sodium, equivalent to 0.40 mg omeprazole. Excipients: For a full list of excipients, see section PHARMACEUTICAL FORM Powder for solution for infusion. White or almost white dry powder 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Gastric antisecretory treatment in severely ill patients where oral therapy is inappropriate with: - Reflux oesophagitis, - Duodenal or benign gastric ulcer - Zollinger-Ellison-Syndrome 4.2 Posology and method of administration Dosage (adults only) Treatment in patients where oral therapy is inappropriate e.g. in severely ill patients with either reflux oesophagitis, duodenal ulcer or gastric ulcer: Omeprazol XXX 40 mg powder for solution for infusion given as an intravenous infusion once daily is recommended for up to 5 days. The i.v. infusion produces an immediate decrease in intragastric acidity and a mean decrease over 24 hours of approximately 90%. Zollinger-Ellison syndrome: Clinical experience in Zollinger Ellison syndrome is limited (see section 5.1) An initial dose of 60 mg of Omeprazol XXX 40 mg powder for solution for infusion in an intravenous infusion is recommended. A higher daily dose may be needed and must be determined individually. If this is more than 60 mg/day the daily dose must be distributed over two administrations. Administration Omeprazol XXX 40 mg powder for solution for infusion is for intravenous administration only and must not be given by any other route. Omeprazol XXX 40 mg powder for solution for infusion should only be dissolved in 100 ml 5% glucose solution for infusion. No other solutions for i.v. infusion should be used (see section 6.6). After reconstitution from a microbiological point of view, use immediately (i.e. within 6 hours) and any unused portion should be discarded. The duration of administration should be minutes. 1

2 For a 20 mg doses half of the reconstituted solution should be used and any unused solution should be discarded. Use in the Elderly: Dosage adjustment is not necessary. Use in Children: There is limited experience of use in children. Omeprazole should not be used in children under 1 year of age since no data are available. The dosage recommendations are as follows: Age Weight Dosage 1 year of age kg 10 mg once daily. The dosage can be increased to 20 mg once daily if needed. 2 years of age > 20 kg 20 mg once daily. The dosage can be increased to 40 mg once daily if needed. Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Impaired hepatic function: As half-life is increased in patients with impaired hepatic function, the dose requires adjustment and a daily dose of 10mg - 20mg may be sufficient. 4.3 Contraindications - Known hypersensitivity to omeprazole or to any of the other constituents of the formulation. - Omeprazole should not be administered with atazanavir due to an important reduction in atazanavir exposure (see section 4.5) 4.4 Special warnings and precautions for use In patients with peptic ulcer disease Helicobacter pylori-status should be determined if relevant. In patients who are shown to be Helicobacter pylori-positive, the elimination of the bacterium by eradication therapy should be aimed wherever possible. When gastric ulcer is suspected the possibility of malignancy should be excluded before treatment with Omeprazol XXX 40 mg powder for solution for infusion is instituted, as treatment may alleviate symptoms and delay diagnosis. The diagnosis of reflux oesophagitis should be confirmed endoscopically. Decreased gastric acidity due to any means including proton-pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. In patients with severe impaired hepatic function, liver enzyme values should be checked periodically during treatment with omeprazole. During combination treatment caution should be exercised in patients with renal or hepatic dysfunction (for dose restriction see section 4.2). Omeprazole should not be used in infants and children under the age of 1 year (see section 4.2). Blindness and deafness have been reported in the use of the injection form of omeprazole; therefore, in severely ill patients the monitoring of visual and auditory senses is recommended. 2

3 This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium free 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed with adults. Effects of omeprazole on the pharmacokinetics of other drugs: Drugs with ph dependent absorption - Atazanavir: Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. Thus, PPIs including omeprazole should not be co-administered with atazanavir. Although not studied, other daily doses of omeprazole may produce similar results and, therefore, also coadministration of any other doses of omeprazole is contraindicated (see section 4.3). - Ketoconazole and itraconazole: The absorption of ketoconazole and itraconazole from the gastrointestinal tract is enhanced by the presence of gastric acid. Administration of omeprazole may result in sub therapeutic concentrations of ketoconazole and itraconozole and the combination should be avoided. - Digoxin: Simultaneous treatment with omeprazole and digoxin in healthy subjects lead to a 10 % increase in the bioavailability of digoxin. This increase is not supposed to have clinical consequences in most patients; however caution should exercised in the elderly. Drugs metabolised by CYP2C19 and CYP2C9 (including warfarin and phenytoin) As omeprazole is metabolised in the liver by the cytochrome P450 enzyme system, it can inhibit the isoenzymes CYP 2C19 and CYP2C9 which can cause increased plasma concentrations of other drugs metabolised by these enzymes. This has been observed for diazepam (and also of other benzodiazepines as triazolam or flurazepam), phenytoin and warfarin. Periodic monitoring of patients receiving warfarin or phenytoin is recommended when starting and discontinuating omeprazole treatment an adjustment of warfarin or phenytoin dose may be necessary. Other drugs that could be affected are hexabarbital, citalopram, imipramine, clomipramine etc. Disulfiram: Omeprazole may inhibit the hepatic metabolism of disulfiram. Some possibly related cases of muscular rigidity have been reported. Ciclosporin: There are contradictionary data on the interaction of omeprazole with cyclosporine ciclosporin. Therefore, the plasma levels of cyclosporine ciclosporin should be monitored in those patients treated with omeprazole, because an increase in cyclosporine ciclosporin levels is possible. Tacrolimus: Although conflicting data have been reported, concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus, therefore this combination should be used cautiously. Clarithromycin: Plasma concentrations of omeprazole and clarithromycin are increased during concomitant administration. Vitamin B12: Omeprazole may reduce the oral absorption of vitamin B12. This should be taken into account in those patients with low basal levels who undergo a long-term treatment with omeprazole. St.John s wort: Because of a potentially clinically significant interaction St. John s wort should not be used concomitantly with omeprazole. 3

4 Other medicines and alcohol: There is no evidence of an interaction of omeprazole with caffeine, propranolol, theophylline, metoprolol, lidocaine, quinidine, phenacetin, oestradiol, amoxycilln, budesonide, diclofenac, metronidazole, naproxen, piroxicam, or antacids. The absorption of omeprazole is not affected by alcohol. Voriconazole: Voriconazole increased omeprazole Cmax and AUCτ by 116 % and 280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors which are CYP2C19 substrates may also be inhibited by voriconazole 4.6 Pregnancy and lactation There is limited experience on the use of Omeprazole in pregnant women. Experience to date indicates no increased risk of congenital malformations or other adverse effects of Omeprazole on pregnancy or the unborn child. Animal studies do not indicate direct or indirect harmful effects with respect to reproduction. Omeprazol XXX 40 mg powder for solution for infusion should only be prescribed during pregnancy when strictly indicated. Omeprazole is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Omeprazol XXX 40 mg powder for solution for infusion should be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman. 4.7 Effects on ability to drive and use machines No studies on the ability to drive and use machines have been performed. However, apart from side effects affecting the CNS or visual abilities (see 4.8.), no effects on the ability to drive are expected with omeprazole. 4.8 Undesirable effects Omeprazole is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use but in many cases a relationship to treatment with omeprazole has not been established. The following definitions of frequencies are used: Very common ( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1000 to< 1/100) Rare ( 1/10000 to< 1/1000) Very rare (< 1/10000), not known (cannot be estimated from the available data) Gastrointestinal disorders: - Common: diarrhoea, constipation, abdominal pain, nausea/vomiting, flatulence. - Rare: dryness of the mouth, stomatitis and gastrointestinal candidiasis, brownish-black discolorartonof the tongue and pancreatitis Nervous system disorders: - Common: headaches, dizziness drowsiness, insomnia, vertigo - Uncommon: paraesthesia - Rare: reversible mental confusion, agitation, aggressiveness, depression and hallucinations, particularly in severely ill patients. Endocrine disorders: 4

5 - Rare: gynaecomastia. Blood and lymphatic system disorders: - Rare: leucopenia, thrombocytopenia, agranulocytosis, pancytopenia and haemolytic anaemia. Hepatobiliary disorders: - Uncommon: increase in hepatic enzymes. - Rare: encephalopathy in patients with pre-existing severe hepatic insufficiency, hepatitis with or without jaundice, hepatic failure. Musculoskeletal and connective tissue disorders: - Rare: arthralgia, muscular weakness and myalgia. Skin and subcutaneous tissue disorders: - Uncommon: rash and/or pruritus, urticaria. - Rare: photosensitivity, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis); TEN), alopecia. Other: - Uncommon: malaise. - Rare: hypersensitivity reactions such as angio-oedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock; increased sweating, peripheral oedema, visual disorders, taste disturbances and hyponatraemia. Isolated cases of irreversible visual impairment have been reported in critically ill patients who have received Omeprazole, particularly at high doses, however no causal relationship has been established. The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 yrs with acidrelated disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive oesophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of omeprazole treatment on puberty and growth. 4.9 Overdose Intravenous doses of up to 270 mg on a single day and up to 650 mg over a three-day period have been given in clinical trials without any dose related adverse effects. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: ATC code: proton pump inhibitors, A02BC01 Omeprazole reduces gastric acid secretion through a unique mechanism of action. It is a specific inhibitor of the gastric proton pump in the parietal cell. It is rapidly acting and produces reversible control of gastric acid secretion with once daily dosing. Intravenous administration of omeprazole results in an immediate reduction of intragastric acidity and a mean decrease over 24 hours of approximately 90% in patients with duodenal ulcer disease. A single 40mg i.v. dose has similar effect on intragastric acidity over a 24 hour period as repeated oral dosing with 20mg once daily. A higher dose of 60mg i.v. twice daily has been used in a clinical study in patients with Zollinger - Ellison syndrome. Site and mechanism of action 5

6 Omeprazole is a weak base and is concentrated and converted to the active form in the acid environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H +, K +,-ATPase - the proton pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for effective inhibition of both basal acid secretion and stimulated acid secretion irrespective of the stimulus. All pharmacodynamic effects observed are explained by the effect of omeprazole on acid secretion. No tachyphylaxis has been observed during treatment with omeprazole. Paediatric data In a non-controlled study in children (1 to 16 yrs of age) with severe reflux oesophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved oesophagitis level in 90 % of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed GERD were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50 % after 8 weeks of treatment irrespective of the dose. 5.2 Pharmacokinetic properties Distribution The distribution volume of omeprazole in the body is relatively small (0.3 L/kg of body weight) and corresponds to that of the extracellular fluid. Approximately 95 % is protein bound. Metabolism and elimination Omeprazole is entirely metabolised, mainly in the liver by CYP 2C19. After intravenous administration of 40 mg omeprazole for 5 days, the absolute measured bioavailability increased by about 50 %; this can be explained by decreased hepatic clearance due to saturation of the CYP2C19 enzyme. The sulphone, sulphide and hydroxy-omeprazole are found in plasma. These metabolites have no significant effect on acid secretion. About 20 % of administered dose is excreted in faeces and the remaining 80 % is excreted in urine as metabolites. The two major urinary metabolites are hydroxy-omeprazole and the corresponding carboxylic acid. The plasma half-life is about 40 minutes, and the total plasma clearance is 0.3 to 0.6 L/min. Relationship between plasma concentration and effect Omeprazole accumulates as a weak base in the acid environment of the intracellular channel system of the parietal cells. In this acid environment omeprazole is protonised and converted into the active substance, omeprazole sulphenamide. The active substance binds covalently to the gastric proton pump (H +,K + -ATPase) on the secretory surface of the gastric parietal cell and inhibits its activity. The duration of the inhibition of acid secretion is therefore substantially longer than the period in which omeprazole-base is present in plasma. The degree of inhibition of acid secretion is directly correlated to the area under the plasma concentration-time curve (AUC) but not to the plasma concentration at any given time. Special populations Elderly: The bioavailability of omeprazole is slightly elevated in the elderly, and the elimination rate is slightly diminished. But the individual values are nearly equal to that of young healthy subjects, and there is no indication that the tolerance in elderly patients treated with normal doses of omeprazole is reduced. Children: When treating paediatric patients from the age of 2 years with the recommended doses, the resulting plasma concentrations are similar to those in adults. During treatment with the recommended doses to children from the age of 1 year similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole. Impaired renal function: 6

7 In patients with renal impairment the kinetics of omeprazole was very similar to that in healthy subjects. But, because the renal elimination is the most important excretory pathway for metabolised omeprazole, the elimination rate is reduced to a degree corresponding to the reduction in renal function. If omeprazole is given once daily, accumulation can be avoided. Impaired hepatic function: In patients with chronic hepatic disease the clearance of omeprazole is reduced, and the plasma halflife can increase up to approximately 3 hours. The bioavailability can then be greater than 90 %. Omeprazole given in a dosage regime of 20 mg once daily for 4 weeks was tolerated well, and no accumulation of omeprazole or its metabolites was observed. CYP2C19 poor metabolisers: In a small percentage of the patients (CYP 2 C19 poor metabolisers)with genes coding for a nonfunctional CYP2C19 enzyme, a reduced elimination of omeprazole has been observed. In these cases, the terminal elimination half-life can be approximately 3 times as long as the normal value, and the area under the plasma concentration-time curve (AUC) can increase by up to 10 times. 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole or subjected to partial fundectomy. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. In mutagenicity studies (in-vitro and in-vivo), there were no findings of clinical relevance. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium hydroxide (for ph adjustment) Disodium edetate 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years Chemical and physical in-use stability has been demonstrated for 6 hours at 25ºC after reconstitution with 5% glucose solution. From a microbiological point of view, the product should be used immediately following reconstitution, unless reconstitution has taken place under controlled aseptic conditions. 7

8 6.4 Special precautions for storage Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Do not store above 25ºC.. Reconstituted product: For storage conditions of the reconstituted medicinal product, see section Nature and contents of the container Omeprazol XXX 40 mg powder for solution for infusion: 1 and 5 injection vial(s) per container. The packaging is a colourless, type I glass injection vial with a 15 ml capacity and a protective cap consisting of 2 components: an aluminium frame and a chlorobutyl rubber stopper. 6.6 Instructions for use and handling The entire contents of each vial should be dissolved in approximately 5ml and then immediately diluted to 100 ml. Normal saline for infusion or 5 % dextrose for infusion should be used. No other solutions for i.v. infusion should be used. Use on one patient during one treatment only. The reconstituted solution should be clear and free from visible particles. DO NOT USE if any particles are present in the reconstituted solution. Preparation: 1. With a syringe draw approximately 5 ml of infusion solution from the infusion bottle or bag. 2. Add the infusion solution to the vial with the freeze dried omeprazole, mix thoroughly making sure all omeprazole is dissolved. 3. Draw the omeprazole solution back into the syringe. 4. Transfer the solution in the infusion bottle or bag. 5. Repeat 1-4 to make sure all omeprazole is transferred from the vial into the infusion bottle or bag. Alternative preparation for infusions in flexible containers: 1. Use a double ended transfer needle and attach to the injection membrane of the infusion bag. Connect the other needle-end from the vial with freeze-dried omeprazole. 2. Dissolve the omeprazole substance by pumping the infusion solution back and forward between the infusion bag and the vial. 3. Make sure all omeprazole is dissolved. 7. MARKETING AUTHORISATION HOLDER To be completed nationally 8. MARKETING AUTHORISATION NUMBER(S) 8

9 To be completed nationally 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION To be completed nationally 10. DATE OF REVISION OF THE TEXT To be completed nationally 9