INFORMATION FOR HEALTH PROFESSIONALS
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OMEPRAZOLE 20 mg capsules: hard gelatine size 2 capsules with an opaque pink body, marked "20" and an opaque reddish-brown cap marked "A/OM". Each capsule contains omeprazole 20 mg as enteric coated pellets.
AMOXYCILLIN 500 mg capsules: Red and gold capsules, printed with "APO 500".
CLARITHROMYCIN 500 mg tablets: Pale yellow, oval, film coated tablets.
Clarithromycin and amoxycillin have been shown to have inhibitory activity against Helicobacter pylori (H. pylori) in vitro both with an MIC90 of 0,03 mcg/mL. Omeprazole also has some bacteriostatic properties on H. pylori in vitro but the clinical relevance is unclear. Treatment with clarithromycin, amoxycillin, or omeprazole alone has proven ineffective in eradicating H. pylori. However, combined treatment with omeprazole, clarithromycin and amoxycillin is effective in eradicating H. pylori.
Large clinical trials indicate that the combination in LOSEC Hp7 OAC, given for seven days, results in eradication of H. pylori, on a per protocol basis, in about 90% of infected patients.
Eradication of H. pylori with LOSEC Hp7 OAC is also associated with rapid symptom relief, high rates of healing of any mucosal lesions, and long-term remission of peptic ulcer disease thus reducing complications such as gastrointestinal bleeding as well as the need for prolonged anti-secretory treatment
Omeprazole is a specific inhibitor of the enzyme H+,K+-ATPase- the acid pump in the parietal cell. It is rapid acting and provides control through reversible inhibition of gastric acid secretion.
Amoxycillin exerts its antimicrobial effect through inhibition of cell wall biosynthesis of mucopeptides and is bactericidal against susceptible organisms during the stage of active multiplication. Amoxycillin is active against H. pylori and gram-positive cocci and rod-shaped bacteria, gram-negative cocci and a great number of gram-negative rod-shaped bacteria. Resistance to H. pylori has not been observed.
Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50S ribosomal sub-units of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The MICs of clarithromycin are generally two-fold lower than the MICs of erythromycin.
The combination treatment consisting of omeprazole 20 mg bd, clarithromycin 500 mg bd and amoxycillin 1 000 mg bd has been studied and resulted in a doubled AUC of omeprazole compared to that obtained during treatment with omeprazole alone. There was a slightly increased AUC of amoxycillin while the plasma levels of clarithromycin were similar irrespective of whether the medication was administered alone or in combination.
Omeprazole is acid labile and is therefore administered orally as enteric-coated pellets in capsules. Absorption takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole is about 60%. The apparent volume of distribution in healthy subjects is approximately 0.3 L/kg. Concomitant intake of food has no influence on the bioavailability. Concomitant intake of clarithromycin results in an almost 2-fold increase in the plasma levels of omeprazole as a result of increased absorption or inhibited metabolism or both.
The plasma protein binding of omeprazole is about 95%.
The plasma elimination half-life of omeprazole is usually shorter than one hour.
Omeprazole is completely metabolised by the cytochrome P450 system (CYP), mainly by a specific CYP enzyme (CYP2C19) in the liver. 80% of a given dose is excreted as metabolites in the urine, and the remainder is found in the faeces, primarily originating from bile secretion.
Amoxycillin is stable in the presence of gastric acid and is well absorbed after oral administration, even in the presence of food. Peak blood levels are reached within 1.5-2 hours (6-7 mcg/mL after a single 500 mg capsule). It diffuses readily into most body tissues and fluids with the exception of brain and spinal fluid, except when meninges are inflamed.
The serum half-life is approximately 1 hour and the plasma protein binding is about 17%. Approximately 60% of a given dose is excreted in a biologically active form in the urine within 6 to 8 hours. Concomitant treatment with probenecid will delay the renal excretion of amoxycillin.
The bioavailability of clarithromycin is approximately 50%. Concomitant intake of food has no clinically significant influence on bioavailability. Peak blood levels are reached within 2 hours. The pharmacokinetics are non-linear. Steady state is attained within 2 to 3 days.
With a 500 mg dose every 12 hours, the principal metabolite, 14-hydroxyclarithromycin, attains a peak steady-state concentration of up to 1 mcg/mL.
Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin also penetrates the gastic mucosa. Levels of clarithromycin in gastric mucus and gastric tissue are higher when clarithromycin is co-administered with omeprazole than when clarithromycin is administered alone.
Clarithromycin is metabolised in the liver, mainly by CYP3A4 but CYP2C19 also seems to be involved. Clarithromycin is 1 to 2 fold more active than its principal metabolite, 14-OH-clarithromycin, except in the case of H. influenzae where the metabolite is twice as active as the parent compound.
The elimination half-lives are 4 to 5 hours and approximately 7 hours for the parent compound and the metabolite respectively.
Plasma protein binding is approximately 70%.
With 500 mg twice daily dosing, approximately 35% of unchanged medication is excreted in the urine. The 14-hydroxyclarithromycin is the major urinary metabolite and accounts for 10 to 15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5 to 10% of the parent compound is recovered from the faeces. Clearance is non-linear.
Impaired renal function will cause increased plasma levels of clarithromycin. Severe hepatic impairment will cause lower levels of the hydroxymetabolite.
Helicobacter pylori eradication in peptic ulcer disease
LOSEC Hp7 OAC is a combination package containing a bottle each of OMEPRAZOLE 20 mg capsules, AMOXYCILLIN 500 mg capsules, and CLARITHROMYCIN 500 mg tablets sufficient for 7 days of therapy. The package includes a detailed dosing description to facilitate patient compliance.
Morning and evening:
1 x Omeprazole 20 mg capsule, 2 x Amoxycillin 500 mg capsules, 1 x Clarithromycin 500 mg tablet
To ensure healing in patients with active peptic ulcer disease, see further dosage recommendations for Duodenal and Gastric ulcer in the LOSEC data sheet. If the patient is still H.pylori positive, other eradication therapy according to current recommendations should be used.
LOSEC Hp7 OAC should not be given to patients with severely impaired renal function because of the amoxycillin component. In addition, to avoid clarithromycin accumulation, the dose should be adjusted to 250 mg twice daily if renal clearance is less than 30 mL/minute. Combination therapy should then be prescribed as separate components
Dosage adjustment of the individual components is generally not needed in patients with impaired hepatic function but with normal renal function.
Dosage adjustment of the individual components is generally not needed in elderly patients with renal clearance greater than 30 mL/min.
There is no experience with this combination regimen in children.
Known hypersensitivity to omeprazole, penicillins, cephalosporins, macrolide antibiotics or any other excipients.
LOSEC Hp7 OAC should not be given concomitantly with cisapride, pimozide or terfenadine.
The dosage in this combination package is not suitable for patients with renal dysfunction (i.e. renal clearance less than 30 mL/minute).
When gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.
Serious and occasionally fatal hypersensitivity reactions have been reported in patients on penicillin or macrolide antibiotic therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before commencing therapy with LOSEC Hp7 OAC, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, macrolides or other allergens. If an allergic reaction occurs, appropriate therapy should be instituted and therapy with LOSEC Hp7 OAC discontinued.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxycillin and macrolides, and may range in severity from mild to life-threatening. Therefore it is important to consider this diagnosis in patients who present with severe diarrhoea subsequent to the administration of LOSEC Hp7 OAC.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy with LOSEC Hp7 OAC. If superinfections occur (usually involving Enterobacter, Pseudomonas or Candida ) treatment should be discontinued and appropriate therapy initiated.
The components of LOSEC Hp7 OAC i.e. omeprazole, clarithromycin and amoxycillin are not likely to affect the ability to drive or use machines.
LOSEC Hp7 OAC should not be given during pregnancy and lactation unless its use is considered essential.
Adverse events reported during clinical trials with this medication combination have reflected the adverse event profile of the three ingredients.
Most commonly reported have been headache, taste perversion and GI symptoms with diarrhoea, nausea and flatulence.
Omeprazole is well tolerated and adverse reactions have generally been mild and reversible. The following events 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.
Rarely rash and/or pruritus.
In isolated cases photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), alopecia.
In isolated cases arthralgia, muscular weakness and myalgia.
Headache.
Rarely dizziness, paraesthesia, somnolence, insomnia, vertigo and aggression.
In isolated cases reversible mental confusion, agitation, depression and hallucinations, predominantly in severely ill patients.
Diarrhoea, constipation, abdominal pain, nausea/vomiting and flatulence.
In isolated cases dry mouth, stomatitis and gastrointestinal candidiasis.
Rarely increased liver enzymes.
In isolated cases encephalopathy in patients with pre-existing severe liver disease; hepatitis with or without jaundice, hepatic failure.
In isolated cases gynaecomastia.
In isolated cases leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.
Rarely malaise.
Hypersensitivity reactions e.g. urticaria (rarely) and in isolated cases angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock.
In isolated cases increased sweating, peripheral oedema, blurred vision, taste disturbance, hyponatraemia.
As with other penicillins, untoward reactions will be essentially limited to sensitivity phenomena, particularly in individuals who have previously demonstrated hypersensitivity to penicillins.
Exanthema.
Rarely urticaria.
In isolated cases erythema multiforme, exfoliative dermatitis.
Loose stools, nausea, vomiting.
In isolated cases Clostridium difficile - caused diarrhoea, pseudomembranous colitis.
Rarely eosinophilia.
In isolated cases moderate thrombocytosis.
Such reactions as anaemia, neutropenia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leucopenia and agranulocytosis have been reported during therapy with other penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomenon.
Moderate rise in SGOT has been noted, but the significance of this finding is unknown.
In isolated cases anaphylactic reactions, angioedema and interstitial nephritis.
As with other macrolides, QT prolongation, ventricular tachycardia and torsade de pointes have rarely been reported with clarithromycin.
Headache.
Transient side-effects such as anxiety, dizziness, vertigo, insomnia, hallucinations, bad dreams, tinnitus, confusion, disorientation, psychosis, and depersonalization have been reported. However, a cause and effect relationship has not been established.
Nausea, vomiting, abdominal pain, diarrhoea, dyspepsia.
In isolated cases Clostridium difficile-caused diarrhoea, pseudomembranous colitis, glossitis, stomatitis, oral monilia and tongue discolouration.
Rarely hypoglycaemia
In isolated cases thrombocytopenia and leukopenia.
Rarely increased liver enzymes.
In isolated cases hepatocellular and/or cholestatic hepatitis, with or without jaundice.
In vary rare instances, hepatic failure and fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
In isolated cases increased serum creatinine, but an association has not been established.
Taste perversion.
Allergic reactions have been reported ranging from urticaria and mild skin eruptions to anaphylaxis and Stevens-Johnson syndrome/toxic epidermal necrolysis. Reversible hearing impairment, alteration of the sense of smell and tooth discolouration have been reported.
Based on the experience with each individual component, LOSEC Hp7 OAC may interact with the following drugs; astemizole, carbamazepine, cisapride, cyclosporin, diazepam, digoxin, disopyramide, ergotamine, ketoconazole, itraconazole, lovastatin, methotrexate, midazolam, oral contraceptives, phenytoin, pimozide, rifabutin, ritonavir, simvastatin, tacrolimus, terfenadine, theophylline, triazolam, warfarin and zidovudine. Further information is provided below.
Elevated plasma levels of these four medicines have been reported in patients receiving concomitant clarithromycin, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level. In exceptional cases this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsade de pointes.
Clarithromycin may potentiate the effect of carbamazepine due to a reduction in the rate of excretion.
Clarithromycin has been reported to produce elevation of the serum level of cyclosporin, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level.
Omeprazole decreases the metabolic clearance of diazepam as a result of metabolic inhibition by omeprazole at the CYP2C19 level.
The effects of digoxin may be potentiated and elevated digoxin serum concentration has been reported with concomitant administration of clarithromycin.
Clarithromycin has been reported to produce elevation of the serum level of disopyramide, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level.
Clarithromycin has been reported to produce elevation of the serum level of ergotamine, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level.
The absorption of ketoconazole and itraconazole may decrease during treatment with omeprazole, as it does during treatment with other acid secretion inhibitors and antacids.
Clarithromycin has been reported to produce elevation of the serum level of lovastatin, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level.
Rhabdomyolysis coincident with the co-administration of clarithromycin and the HMG-CoA reductase inhibitor lovastatin has rarely been reported.
One case of toxic reaction to methotrexate has been reported in a patient on concomitant therapy with amoxycillin.
Clarithromycin has been reported to produce elevation of the serum level of midazolam, probably as a result of the metabolic inhibition by clarithromycin at the CYP3A4 level.
Amoxycillin may in rare cases decrease the effect of oral contraceptives.
Omeprazole may slightly decrease the metabolic clearance of phenytoin as a result of metabolic inhibition by omeprazole at the CYP2C19 level.
Clarithromycin has been reported to produce elevation of the serum level of phenytoin.
Rifabutin will induce the metabolism of clarithromycin resulting in a 60% decrease of the plasma concentration. Clarithromycin has been reported to produce elevation of the serum level of rifabutin.
Ritonavir may inhibit the metabolism of clarithromycin, probably as a result of metabolic inhibition by ritonavir at the CYP3A4 level. Doses of clarithromycin greater than 1 g/day should not be co-administered with ritonavir.
Rhabdomyolysis coincident with the co-administration of clarithromycin and the HMG-CoA reductase inhibitor simvastatin has rarely been reported.
The administration of clarithromycin to patients who are receiving theophylline has been associated with increased serum theophylline levels and potential theophylline toxicity.
Clarithromycin has been reported to produce elevation of the serum level of triazolam, probably as a result of metabolic inhibition by clarithromycin at the CYP3A4 level.
Clarithromycin has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in prolongation of prothrombin time. Omeprazole may slightly decrease the metabolic clearance of the less potent warfarin enantiomer, R-warfarin, as a result of metabolic inhibition by omeprazole at the CYP2C19 level. It is recommended that coagulation tests be monitored closely when initiating or ceasing treatment with LOSEC Hp7 OAC in patients co-prescribed warfarin.
Simultaneous oral administration of clarithromycin and zidovudine to HIV-positive adults may result in decreased steady state zidovudine concentrations. This can be largely avoided by staggering the doses of clarithromycin and zidovudine by 1 to 2 hours.
The amoxycillin component of LOSEC Hp7 OAC will result in high urine concentrations of amoxycillin which may result in false positive reactions when tested for the presence of glucose in urine.
Concomitant intake of food has no effect on the bioavailability of omeprazole, amoxycillin, or clarithromycin.
Rare reports have been received of overdosage with omeprazole. In the literature doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole. Also apathy, depression and confusion have been described in single cases.
The symptoms described in connection to omeprazole overdosage have been transient, and no serious outcome due to omperazole has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses and no specific treatment has been needed.
High doses are generally well tolerated.
Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. Allergic reactions accompanying overdosage should be treated by gastric lavage and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.
3 years when stored below 25°C and protected from light and moisture.
3 years when stored tightly closed in the original container below 25°C.
Shelf-life of three months when stored in non-original container.
3 years when stored below 25°C and protected from light and moisture.
5 years when stored below 25°C and protected from light.
Prescription Medicine.
LOSEC Hp7 OAC contains the following:
OMEPRAZOLE 20 mg: HDPE bottles of 14 capsules.
AMOXYCILLIN 500 mg: HDPE bottles of 28 capsules
CLARITHROMYCIN 500 mg: HDPE bottles of 14 tablets
AMOXYCILLIN 500 mg is used under license from Apotex NZ Ltd
CLARITHROMYCIN 500 mg is used under license from Abbott Laboratories NZ Ltd.
AstraZeneca Limited
303 Manukau Road, Epsom
PO Box 1301
Auckland
Telephone: (09) 623-6300
21 December 2005
(IDS 090699, V24)