1. Nama of the medicinal product
Megaprazole 20 mg ,40 mg lyophilized powder in vial for reconstitution for IV Infusion
2. Qualitative and quantitative composition
Each viel contains: Esomeprazole sodium 21.3 mg aq. to Esomeprazole 20 mg ,Esomeprazole sodium 42.5 mg eq. to Esomeprazole 40 mg
Each vial contains <1 mmol sodium For full list of excipients see section 6 1.
3. Pharmaceutical form
lyophilized powder in viel for reconstitution for IV infusion.
off-white lyophilized powder giving clear coloriess solution after reconstitution
4. Clinical particulars
4.1 Therapeutic Indications
Megaprazole for infusion is indicated in adults for :
⦁ Gastric antisecretory treatment when the oral route is not possible, such as:
– gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe symptoms of reflux – healing of gastric ulcers associated with NSAlQ therapy.
– prevention of gastric and duodenal ulcers associated with NSAID therapy. in patients at risk.
– Prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers,
Megaprazole for infusion is indicated in children and adolescents aged 1-18 years for :
⦁ Gastric antisecretory treatment when the oral route is not possible, such as: gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe symptoms of reflux
4.2 Posology and method of administration
Gastric antisecrelory treatment when the oral route is not possible
Patients who cannot take oral medication may be treated parenterally with 20-40 mg once daily. Patients with reflux esophagitis should be treated with 40 mg once dally. Patients treated symptomatically for reflux disease should be treated with 20 mg once daily. For healing of gastric ulcers associated with NSAID therapy the usual dose is 20 mg once daily. For prevenlion of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be uaated With 20 mg once daily.
Usually the Intravenous treatment duration is short and transfer to oral treatment should be made as s00n as possible.
Prevention of rebl6edlOg of gastric and duodenal ulcers
Following merecectc endoscopy for acute bleeding gastric or duodenal ulcers 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous Intravenous Infusion of 8 mg/h givon over 3 days (12 hours).
The parenteral treatment period should be followed by oral acid· suppression therapy.
Method of administration
For instructions on reconstitution of the medicinal product before administration. see section 6.6.
40 mg dose The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
20 mg dose Half of the reconstituted solution should be given as an Intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.
80 mg bolus dose The reconstituted solution Should be given as a continuous intravenous infusion over 30 minutes.
8 mg bolus dose The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours
Renal impairment :Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section 5.2).
Hepatic impairment :GERD: Dose adjustment Is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg Megaprazoie IV. Should not be exceeded (see section 5.2).
Bleeding ulcers: Dose adjustment is not required in patlents with mild to moderate liver impairment for patients with severe liver Impairment, following an initial bolus dose of 80 mg Megaprazole for infusion, a continuous intraveooos infusion dose of 4 mgIh for 71.5 hours may be sufficient (see section 5.2).
Dose adjustment is not required in the elderly.
children and adolescents aged 1-18 years
Gastric 8ntiS6Cf9texy treatment when the oral route is not possible
Patients who cannot take 0ral medication may be treated parenterally once daily, as apart of a full treatment period for GERO (see doses in table below).
Usually the intravenous treatment duration should be short and transfer to oral treatment should be made as soon as possible.
Method of administration
For instructions on reconstitution of the medicinal product before administration, see section 8.6.
Infusion 40 mg The reconstituted solution should be given as an intravenous infusionover a period of 10 to 30 minutes.
20 mg Half of the reconstltuted solution should be given as an Intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.
10 mg Aquarter of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minotes. My unused solution should be discarded.
Hypersensitivity to the active substance, to substituted benzlmidazoles or to any of the excipients listed in section 6.1.
Esomeprazcle should not be used concomitantly with netfinavir (see section 4.5) .
4.4 Special warnings and precautions for use
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haemalemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be exduded, as treatment with Megaprazole may alteviate symptoms and delay diagnosis
Gastrointestinal infections Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).
Absorption of yitamin B12 Esomeprazole, as all add-blocklng medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores of risk factors for reduced vitamin 812 absorption on long term therapy.
Hypomagnesaemia :Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPls) like Esomeprazole for at least three months, and In most cases for a year. Serious manifestations of hypomagnesaomia such as fatigue. tetany, delirium, convulsions, dizzlness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most atrected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or whO take PPls with digoxin or
medicinal products that may cause hypomagnesaemia (e.g. diuretics), heanthcare professionals should consider measuring magnesium levels before starting ppl treatment and periodically during treatment
Combination with other medicines :
Co administration of Esomeprazole with atazanavir is not recommended (sae section 4 5). If the combination of atazanavir with a proton pump
inhibitor is judged unavoidable close clinical monitoring is recommended in combination with an Increase in the dote of atazanavir 10 400 mg with 100 mg of ritonavir Esomeprazole 20 mg should not be exceeded Esomeprazole Is a CYP2C19 inhibitor. When starting or ending treatment with Esomeprazole, the potential for interactions with medianal products metabolised through CVP2C 19 should be considered an interaction is observed between clopidogrel and Esomeprazole (see section 45). The clinical relevance of this interaction is uncetain As a precaution concomitant use of Esomeprazole and clopidogrel should be discouraged
Interference with laboratory tests:
Increased Chromogranln A (CgA) level may Interfere with investigations for neuroendocrine tumours. To avoid this interference , Esomeprazole treatment should be stopped for at least 5 deys before CgA measurements (see section 5.1). If CgA and gastrin leve!s have not returned to reference range after Initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.
4.5 Interaction with other medicinal products and other forms of interaction :
Effects of Esomeprazole on the pharmacokinetics of other medicinal products Protease inhibitors
Omeprazole has been reported to Interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibrtors other possible interaction mechanisms are via inhibition of CVP 2C 19 For atazanavir and nelfinavir decreased S8Nm levels have been reported when given together with omeprazole and concomitant administration is not recommended. co administration of omeprazole (40 mg once deily) with atazanavir 300 mg ritonavir 100 mg 10 healthy
volunteers resulted in a substantial redection in atazanavir exposure (approxemately 75% decrease in AUG, C- and C-,). Increasing the
atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure The co-adminrstration of omeprazole (20 mg qd) with atazanavir 400 mg /ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg , 100 mg qc without omoprazole 20 mg qd Co-administration of omeprazolt (40 mg qd) reduced mean nelfimvir AUC. c max and C min by 36-39″ and mean AUC, c man and C min – for the pharmacologically active metabolite m8 was reduced by 75-92’%. Due to the simiral pharmacodynamic effects and pharmacokinetic properties of omeprazole and Esomeprazo, concomitant administration with Esomeprazole and atazanavir is not recommended (see section 4.4) and concomitant
administration with Esomeprazole and neiflnavir is contraindicated (see section 4.3). For saquinavir (with concomitant ritonavir), Increased serum levels (80- 1130%) have been reported during concomitant omeprazole treatment (40 mg qd). Treaement with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir with concomitant ritonavir). Treatment with ESOI”I”IepI’8Z 20 mg qd had no eft’act on tne exposure of amprenavir (with and without concomiant
nitonavir). Treatment with omeprazo6a 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir).
When given together with PPls. methotrexate levels have been reported to increase in some patients. in high dose methotrexate administration temporary with drawal of Esomeprazole may need to be considered
Concomitant administration of Esomeprazole has been reported to Increase the serum levels of tacrolimus. A reinforced monitoring of
tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted If needed.
Medicinal products with pH dependent absorption :
Gastric acid suppression during treatment with esomeprazole and other PPis might decrease or Increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorpition of medicinal products such as ketoconazole, itraoonazole and erlotinib can decrease and the absorption of digoxin can incerease during treatment with Esomeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy supjects increased the bioavailability of digoxin by 10% (up 10 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However. caution should be exercised when Esomeprazole is given at high doses in elderly patients. Therapeutic medicinal product monitoring 0f digoxin should then be reinforced Diazepam Concomitant oral administration of 30 mg Esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam
Concomrtant oral administration of 40 mg Esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epiteptic patients it is recomended to monitor the plasma concentrations of phenytoin when treatment with Esomeprazole is introduced orwithdrawn
Omaprazole (40 mg once daity) increased voriconazole (a CY?2CI9 substrate) C max and AUC by 15% and 41% respectively.
Omeprazole as well as Esomeprazola act 8S inhibitors of CYP2C19 Omeprazoie, given in doses of 40 mg to healthy subjects in a coss-overstudy, Increased Cmax and AUC for cilostazol by 18% and 26% respectively and one of its active metabolites by 29% and 69%
respectively. Therefore a dose reduction of Cilostazol from 100mg b.i.d 10 50mg bid. should be consiaered.
In healthy volunteers, concomitant oral administration of 40 mg Esomeprazole and asapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life but no signlficant increace in peak plasma levels of cisopride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with Esomeprazole
interraction studies have only been performed in adults
4.6 Fertility pregnancy and lactation :
Clinical data on exposed pregnancies with Megaprazole are insufficient. with the racemic mixture, omeprazole data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Caution should be exercised when prescribing Megaprazole to pregnant women.
A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no matformative or foeto/neonatal toxicity of Esomeprazole
It Is not known whether Esomeprazole is excreted in human breast milk, there Is insufficient information on the effects of Esomeprazote in newborns infants Esomeprazole should not be used during breast-feeding
4.7 Effects on ability to drive and use machines
Esomeprazole has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section 4.8). If affected patients should not drive or use machines.
4.8 Undesirable effects
Summary of the safety profile
Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials and also from post marketing use in addition the safety profile is similar for different formulations. treatment indications, age groups and patient populations no dose related adverse reactions have been identified
Tabulated list of adverse reactions
The following adverse medicinal product reactions have been identified or suspectea in the clinical trials programme for Esomeprazole administered orally or intravenously and post-marketing when administered orally. The reactions are classified according to frequency very common >1/10 common >1/100 to <1/10 uncommon >1/1000 to <1 /100 rare >1/10,000 to <1/1,000 very rare <1/10,000 not known (cannot be estimated from the available data) Administration site reactions have mainly been Observed in a study with high-dose exposure over 3 days (72 hours) (see section 5.3) Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole (me racemate) intravenous injection, especially at high doses, but no causal relationship has been established.
Reportjng of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit risk balance of the medicinal product
The safety results are consistent with the known safety profile of Esomeprazole, and no new safety signats were identified.
There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280 mg were gastrointestinal symptoms and weakness. Single oral doses of 80 mg Esomeprazole and intravenous doses of 308 mg Esomeprazole over 24 hours were uneventful. No specific antidote is known. Esomeprazole Is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose. treatment should be symptomatic and general supportive measures should be utilised.
5. Pharmacological properties :
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitor Esomeprazole is the a-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and s-scmer of omeprazcle have similar pharmacodynamic activity.
Mechanism of action
Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic envIronment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.
After 5 days of oral dosing with 20 mg and 40 mg of Esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours respectively, over 24 hours in symptomatic GERD patients. The effect is similar irrespective of whether Esomeprazole is admlnisterad orally or intravenously.
Using AUC as a surrogate parameter for plasma concentration. a relationship between inhibition of acid secretion and exposure has been shown after oral administration of Esomeprazole.
During intravenous administration of 80 mg Esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h for 23.5 hours, Inlragastric pH above 4. and pH above 8 was maintained for a mean time of 21 hours and 11-13 hours, respectively. over 24 hours in healthy subjects.
Healing of reflux esophagitis with Esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks, and In 93% after 8 weeks of oral treatment. The occurrence of rebleeding within 3 days was 5.9% In the M&gaprazole treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleedlng in the Megaprazole treated versus the placebo treated group was 7.7% vs 13.8%. During treatment with antisecretory medicinal products. serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with Investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to snow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of ECl cens possibly related to the Increased serum gastrin levels. have been observed In both children and adults during long-term treatment with Esomeprazole. The findings are considered to be of no clinical Significance.
During long-term oral treatment with ennsecretcrv medicinal products, gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric aciditY due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and campylobacter and, in hospitalised patients. possibly also clostridium difficile
In a placebo-controlled study there was no significant difference between Esomeprazole and placebo for the primary endpoint time to discontinuation due to symptom worsening. There was no sign ficant difference between Esomeprazole and placebo in the primary endpoint. Change from baseline of number of occurrences of symptoms of GERD. Results from the paediatric studies further show that 0.5 mg/kg and 1.0 mg/kg Esomeprazole in < 1 month old end 1 to 11 month old infants, respectively. reduced the mean percentage of time with intra-oesophageal pH < 4.
The safety profile appeared to be similar to that seen in adults.
In a study in paediatric GERD patients «1 to 17 years of age) receiving long-term PP! treatment. 61 % of the chIldren developed minor degrees of ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumours
5.2 Pharmacokinetic properties
The apparent volume of distribution at steady state in healthy subjects Is approximately 0.22 l/kg body weight. Esomeprazoie is 97% plasma protein bound.
Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of Esomeprazole is
dependent on the polymorphic CYP2C19, responsible for the formation g(!he hydroxy- and desmettlyl metabofites of Esomeprazole. The remaining part is dependent on another specitic iaoforrn, CYP3A4, respon5ibIe for !he formation of EsorneprazoIe suIphone. the main metabolite in plasma
The parameters below reflect mainly the pharmaooIdnetics in individual. With a functional CYP2C19 enzyme. exteoaive metaboliseni. Total plasma dearance is about 17 l/h after a single dose and about 91th aftGl repeated administrabon The plasma elimination haIf-ife is about 1.3 houl’1 after repeated once daity dosing. Esomeprazole is completely eliminated from plasma bel’wgen doses with no tendency fof’ accumulation during once daily administration. The major metabolites of Esomeprazole have no effect on gastric add seaetion. Almost 80% of an oral dose of Esomepraz.oIe Is excreted as metabolites In the urine, the remalndor in the faeces. Lass than 1 % of tho parent medicinal prodUd is found in urine.
Total exposure (AUC) incnlases with repeated adminIstration of Escmeprazote. This Increase Is dose-dependent and results In 8 non-lioear dose-AUC relationship after repeated administration. This time- and dose-depeodency is due 10 a decrease of first pass metabolism and systemic clearance probably caused by inhibition of the CYP2C19 enzyme by Esomeprazoie and/or Its su1phone metabolite. Following repeated doses of 40 mg administered as Intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/l The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol. Asmaller increase (of apprt»l 30%) can be seen in total exposure after intravenous adlTW\istration compared to oral administration. There is a dose-linear inclease it! total exposure following Intravenous administration of Escmeprazote as a 30-minute infusion (40 mg, 80 mg or 120 mg) fohowed by a continuous infusion (4 mgIh or 8
mg/h) over 23.5 hours.
Special patient populations
Poor metabolisers : Approximately 2.9 tl.5% of the population lacks a func:lionaI CYP2C19 enzyme and IS called poor metabolisers. in these individuals. the metabolism 01 Esomeprazole Is probably ITI3IOIy catalysed by CYP3A4. MM repeated once daily administration 0140 mg oral Esomeprazole. the mean total exposure was approximately 100% higher 11\ poor metaboltsers than in subjects with a functional CYP2C19 enzyme (extensIVe
metaboli:sen;). Mean peak plasma concentrations were inaeased by about 60%. Similar differences have been seen lor intravenous
administration of Esomeprazole. These findjngs have no implications for the posology of Esomeprazole.
Following a single oral dose of 40 mg Esomeprazole the mean total exposure Is approximately 30% higher In females than In males. No gender difference Is seen after repeated once dally administration. Similar dltl’orences have been obSONed for Intravenous administration of Esomeprazole. These findings neve no Implications lor the posology of Esomeprazole.
The metabolism of Esorneprazole In patients wfth mild to moderate livor dysfunction may be Impaired. The metabolic rate is deaeased in patients with severe liver dysfunction resulting in a doubling of the total exposure of Esomeprazol8. Therefore a maximum dose of 20 mg should nee be exceeded In GERD.patients with severe dysfunction. For patients with bleeding ulcers and severe liver impa,rment, following an Initial bolus dose of 80 mg. a maximum continoous intravenous infusion dose of 4 mgr1t for 71.5 houI’S may be sufficient Esorneprazole or its major metaboites do not show any tendency to aexumulale with once deily dosing.
No studies have been performed in patients with decreased renal funcoon. Since the kidney is responsible for !he exaetion of the metabolites of Esomeprazde but not tor !he elimination of the parent compound, the metabolism of Esorne9f1lZoIe is not expected to be changed in patients with impaIred renal function.
The metabolism of Esomepra:ole is not significanttychanoed In eIderty subjects (71.8() years of age).
The table below desaibes the syslemlc exposure to Esomep!’aZOle following the intravenous &dmInistralioo as a 3-minuta injection in paediatric patients and adult healthy subjects The values in the table are geometric means (range). The 2Q mg dose for adutls was given as a JO.minute infusion. The c max was measured 5 minutes post dose In aW paediatric groups and 7 minutes coet-ccse in aduHs on the 40 mg dose, and after stop of Infusm in adults on the20 mg dose
A patient in the age group 0 up to 1 month was defined as a patient with corrected age of >32 complete weeks and <44 complete weeks
where corrected age was the sum oftha gestational age and the age afta!’ bInh in complete weeks. A patienl in the age group 1 to 11 months had a corrected age of >44 complete weeks Two patients excluded, 1 most ~kely a CYP2C19 poor metaboliser and 1 on concomitant treatment with a CYP3A4 inhibitor.
Model based predictions indicate that cmax following intravenous administration of Eaomeprazole as a 10 minute, 20 minute and 30 minute Infusions will be reduced by on average 37% 10 49%, 54% to 66% and 61% to 72%. respectively, across all ege and dose groups compared to when the dose Is admin!s!ered as a 3 minute injection.
6. Pharmaceutical particulars
6.1 list of exciplents
Sodium hydroxide (for pH adjustment)
This medicinal product must not be used with other medicinal products except those mentioned in section 6.6.
6.3 Shelf lit.
2 years in all climate zones.
SheIf-life 24 hours after reconstitution with 5% Dextrose & NaCl & lactated Ringer store at temperature not exceeding 30 C
6.4 Spacial precautions for storage
Store at temperature not exceeding 3O”C before and after reconstitution
6.5 Nature and contents of container
Carton box containing colorless (Type 1 ) glass vial containing 22.8 mg for Megaprazote 20 mg or 44 mg for Megapmzole 40 mg lyophilized powder dosed with elastomeric Closure bromobutyl rubber stopper with aluminum over seal tampered with plastic p0lypropylene flipping – off closure)+inner leaflet
6.6 Special precautions for disposal and other handling
The reconstituted solution should be inspected visually for particulate matter and discoklration prior to administration. Only Clear solution should be used. For single use only.
If the entire reconsllMed contanl of the vial Is not required, any unused solution should be disposed of In accordance with local requirements. The reconstituted solution ‘or Infusion Is dear and COIouriess to very slightly yellow.
7. Produced by :
Chemipharm Pharmaceutical lndustries
6th OctolMr – Egypt