Peptisolv IV

White to whitish lyophilized powder.
Each vial contains: Omeprazole (as sodium) 40 mg.
Diluent: Each ampoule contains: Water for Injection 10 mL.

Pharmacotherapeutic Group: Proton pump inhibitors.
Pharmacology: Pharmacodynamics: Mechanism of action: Omeprazole is a racemic mixture of two active enantiomers that reduces gastric acid with a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cells. It has rapid action on acid secretion and reversibly inhibits gastric acid secretion with once-daily dosage.
Omeprazole is a weak base; it rapidly concentrates in the acidic media in the parietal cell where it is transformed to its active form to inhibit H+, K+-ATPase-acid pump enzyme which is the final step of gastric acid production. This effect on the final step of gastric acid production is dose-dependent and thus, irrespective of the stimulus, both basal and stimulated acid secretion are inhibited.
All pharmacodynamic effects observed can be explained by the effects of omeprazole on acid secretion.
Effect on gastric acid secretion: Intravenous omeprazole produces a dose-dependent gastric acid inhibition in humans. In order to rapidly achieve similar gastric acidity reduction to the one achieved by repeated oral dosing with 20 mg intravenously, a first dose of 40 mg is recommended. Both I.V. injection and I.V. infusion result in a rapid decrease in gastric acidity and approximately 90% decrease within 24 hours.
Inhibition of acid secretion is related to the area under the plasma concentration time curve (AUC), not with the actual plasma concentration of omeprazole.
No tachyphylaxis was observed during treatment with omeprazole.
Effect on Helicobacter pylori: Helicobacter pylori is associated with peptic ulcer disease, including gastric and intestinal ulcers. H. pylori is a primary factor forthe development of gastritis. H. pylori, together with gastric acid are major factors for the development of peptic ulcer disease. H. pylori is also a primary factor for the development of atrophic gastritis related with an increased risk of gastric cancer.
Omeprazole and antimicrobial agents provide H. pylori eradication, rapid symptomatic improvement, high rates of mucosal healing, and long-term improvement in peptic ulcer disease, which reduces complications, including gastrointestinal bleeding and need for anti-secretory treatments.
Other effects related to acid inhibition: Gastric glandular cysts may occur with increased frequency during long-term treatment. Such changes are physiological and occur as a result of inhibition of acid secretion; they appear to be benign and reversible. Decreased gastric acidity due to any reason, including proton pump inhibitors, causes an increase in the number of bacteria normally present in the gastrointestinal system. Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections with Salmonella and Campylobacter and potentially Clostridium difficile in hospitalized patients.
During treatment with anti-secretory medical products, serum gastrin is increased as a response to reduced acid secretion. Chromogranin A (CgA) also increases due to reduced gastric acidity. Increased CgA levels may interfere with investigations for neuroendocrine tumors. In order to avoid this, omeprazole treatment should be withheld 5 days before CgA measurements. In case CgA and gastrin levels do not return to normal within 5 days, measurements should be repeated after 14 days of omeprazole treatment interruption.
During long-term treatment with omeprazole, an increased count of chromaffin-like cells (ECL), possibly related to increased serum gastrin levels, was observed in some patients (children and adults). The findings were considered to be of no clinical relevance.
Pharmacokinetics: Distribution: The apparent volume of distribution in healthy subjects is approximately 0.3 L/kg body weight. Omeprazole is 97% bound to plasma proteins.
Biotransformation: Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The major part of the metabolism is dependent on polymorphically expressed specific isoform CYP2C19, which is responsible for the formation of the major metabolite hydroxyomeprazole in plasma. The remaining part is dependent on the other specific isoform CYP3A4, responsible for the formation of omeprazole sulphone. As a result of high affinity of omeprazole to CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interaction between omeprazole and other CYP2C19 substrates. However, due to the low affinity of omeprazole to CYP3A4, there is no potential to inhibit the metabolism of other CYP3A4 substrates. Additionally, omeprazole has no inhibition effect on the main CYP enzymes.
Elimination: Total plasma clearance following a single dose is 30-40 L/hour. Plasma elimination half-life of omeprazole is shorter than one hour after both single and repeated once-daily oral dosing. Omeprazole is eliminated between doses. Approximately 80% of an intravenously administered dose is eliminated in the urine as metabolites, and the remainder is eliminated in feces mainly by bile secretion.
The area under the plasma-time curve (AUC) for omeprazole increases by repeated administrations, probably as a result of decreased systemic clearance due to CYP2C19 enzyme inhibition caused by omeprazole and/or its metabolites (e.g. sulphone).
None of the metabolites was found to have any effect on gastric acid secretion.
Patient characteristics: Renal impairment: Omeprazole pharmacokinetics, including systemic bioavailability and elimination rate, remain unchanged in patients with renal function impairment.
Hepatic impairment: AUC is increased in patients with impaired liver functions, however, once-daily oral dosing of omeprazole administration have not caused any accumulation.
Elderly: Metabolism rate of omeprazole is slightly reduced in the elderly (aged 75-79 years).
Children: There is limited experience with I.V. use in children.
Poor metabolizers: Approximately 3% of the Caucasian population and 15-20% of the Asian population have functional CYP2C19 enzyme deficiency, and they are called the weak metabolizers. Omeprazole metabolism is probably catalyzed mainly by CYP3A4 in these subjects. After repeated once-daily 20 mg omeprazole administration, mean AUC was 5 to 10 times higher in weak metabolizers compared to those with functional CYP2C19 enzymes. Mean peak plasma concentrations were 3 to 5 times higher. These findings do not affect omeprazole pathology.

Omeprazole is indicated for the following indications: Treatment of duodenal ulcers.
Prevention of relapse of duodenal ulcers.
Treatment of gastric ulcers.
Prevention of relapse of gastric ulcers.
Helicobacter pylori (H. pylori) eradication in peptic ulcer, in combination with appropriate antibiotics.
Treatment of NSAID-associated gastric and duodenal ulcers.
Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk.
Treatment of reflux esophagitis.
Long-term treatment of patients with healed reflux esophagitis.
Symptomatic treatment of gastro-esophageal reflux disease.
Treatment of Zollinger-Ellison syndrome.

Alternative to oral therapy: Patients who cannot use oral treatment can be treated with daily intravenous 40 mg of omeprazole.
Zollinger-Ellison syndrome: Dosing should be adjusted individually. The recommended initial dose is 60 mg daily, however, more frequent and higher doses may be required. In case the daily dose exceeds 60 mg, it should be divided to be given twice daily.
Method of administration: IV. injection.
Omeprazole should be administered with a gradual intravenous injection. Omeprazole should not be added to infusion solutions. The reconstituted solution should be given at a maximum rate of 4 ml per minute over at least 2.5 minutes. The solution should be administered within 4 hours after reconstitution.
For instructions on reconstitution of the product before administration.
Additional information on special populations: Renal impairment: Dose adjustment is not necessary in patients with renal impairment.
Hepatic impairment: In patients with hepatic impairment, a daily dose of 10-20 mg may be sufficient.
Pediatric population: There is limited experience with IV. use in children.
Geriatric population: Dose adjustment is not necessary for elderly patients aged 65 years or over.

There is limited experience with omeprazole overdose in humans. In the literature, up to 560 mg doses have been described and a few reports were received where a single oral dose of omeprazole exceeded 2,400 mg (120 times the usual recommended dose). Nausea, vomiting, dizziness, abdominal pain, diarrhea and headache were reported. Additionally, apathy, depression, and confusion were described in isolated cases.

Omeprazole is contraindicated in subjects with hypersensitivity to omeprazole, substituted benzimidazoles, or to any of the excipients.
Omeprazole, like other proton pump inhibitors, should not be used concomitantly with nelfinavir.

In case any alarming symptom occurs (e.g., significant unintentional weight loss, recurrent vomiting, difficulty in swallowing, melena or hematemesis etc.) or when a gastric ulcer is diagnosed or suspected, treatment should not be initiated before malignancy is excluded, since treatment may delay diagnosis by symptom relief.
Co-administration of omeprazole with atazanavir is not recommended. If combination of atazanavir with proton pump inhibitors is inevitable, close clinical monitoring (e.g. virus load) for combinations with 100 mg of ritonavir and up to 400 mg doses of atazanavir is recommended while omeprazole dose should not exceed 20 mg.
Omeprazole, like all acid blocking agents, can reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered in patients with limited body stores or risk factors due to reduced vitamin B12 absorption during long-term treatment. Omeprazole is a CYP2C19 inhibitor. Potential interactions with drugs that metabolize through CYP2C19 should be considered on initiating or ending treatment with omeprazole. An interaction between clopidogrel and omeprazole has been observed. Clinical significance of this interaction is not clear.
As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.
Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter.
Bone fractures: Reports from various observational studies suggest that treatment with proton pump inhibitors (PPI) is associated with increased risk of hip, wrist or spine fractures as a result of osteoporosis. Risk of fractures is increased in patients on high doses, described as taking multiple daily doses or prolonged PPI treatment (one year or longer). Patients should receive PPI treatment at the lowest adequate dose for the minimum duration.
Hypomagnesemia: Symptomatic or asymptomatic hypomagnesemia has been rarely reported in patients treated with a PPI for at least 3 months and in most cases for one year. Serious adverse events include tetany, arrhythmias and convulsions. Management of hypomagnesemia requires magnesium replacement and discontinuation of PPI treatment in the majority of cases. For patients expected to receive prolonged treatment or those taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), healthcare professionals might monitor magnesium levels before initiating PPI treatment and during follow-up.
Interference with tests for neuroendocrine tumors: Serum chromogranin A (CgA) levels increase secondary to drug-related reductions in gastric acid levels. Increased CgA levels may cause false positive results in diagnostic tests for neuroendocrine tumors. PPI treatment should be temporarily stopped before CgA level evaluation, and tests should be repeated if baseline CgA levels are high. If serial tests are performed (e.g., for monitoring), tests should be performed at the same laboratory to avoid reference range variations.
Particularly, patients treated for longer than one year should be regularly monitored.
This medicinal product contains less than 1 mmol (23 mg) of sodium per dose; thus, it is essentially "sodium free".
Effects on the ability to drive and use of machines: Omeprazole does not affect the ability to drive and use machines. Adverse drug reactions, including dizziness and visual impairment, may occur. Affected patients should not drive or use machines.

Pregnancy: Animal studies on effects on pregnancy and/or embryonal/fetal development and/or delivery and/or postnatal development are insufficient.
Potential risk for humans is unknown.
Three prospective epidemiological studies (including over 1,000 exposures) indicate no adverse effects of omeprazole on pregnant women and health of the fetus or newborn child.
Omeprazole should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus.
Lactation: Omeprazole passes into the breastmilk however, it is unlikely to affect the child when used at therapeutic doses. It should be preferred to avoid using during lactation.
Reproduction ability/Fertility: No studies have been performed on the effects on reproduction/fertility.

The most common adverse effects (in 1-10% of patients) are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.
The following adverse effects were reported from clinical trials and post-marketing experience. None was found to be dose-related. The undesirable effects are listed as follows according to system organ class with frequencies described as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to 1/1,000); very rare (<1/10,000); unknown (cannot be estimated from the available data).
Blood and lymphatic system disorders: Rare: Leukopenia, thrombocytopenia.
Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock.
Metabolism and nutritional disorders: Rare: Hyponatremia.
Unknown: Hypomagnesemia; severe hypomagnesemia may cause hypocalcemia.
Psychiatric disorders: Uncommon: Insomnia.
Rare: Agitation, confusion, depression.
Very rare: Aggression, hallucinations.
Nervous system disorders: Common: Headache.
Uncommon: Dizziness, paresthesia, somnolence.
Rare: Taste disturbance.
Eye disorders: Rare: Blurred vision.
Ear and labyrinth disorders: Uncommon: Vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: Bronchospasm.
Gastrointestinal disorders: Common: Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting.
Rare: Dry mouth, stomatitis, gastrointestinal candidiasis.
Unknown: Microscopic colitis.
Hepatobiliary disorders: Uncommon: Increased liver enzymes.
Rare: Hepatitis with or without jaundice.
Very rare: Hepatic impairment, encephalopathy in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders: Uncommon: Dermatitis, pruritus, rash, urticaria.
Rare: Alopecia, photosensitivity.
Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Musculoskeletal, connective tissue and bone disorders: Uncommon: Hip, wrist or spinal fractures.
Rare: Arthralgia, myalgia.
Very rare: Muscular weakness.
Renal and urinary disorders: Rare: Interstitial nephritis.
Reproductive system and breast disorders: Very rare: Gynecomastia.
General disorders and administration site conditions: Uncommon: Malaise, peripheral edema.
Rare: Excessive sweating.
Irreversible visual impairment has been reported following intravenous treatment with omeprazole, especially at high doses, in isolated cases with critical disease. However, no causal relation with omeprazole treatment was confirmed.

Effects of omeprazole on pharmacokinetics of other drugs: Medicinal products with pH-dependent absorption: Absorption of medicinal products that depend on gastric pH for absorption may decrease or increase depending on the reduced gastric acidity during treatment with omeprazole.
Nelfinavir, Atazanavir: Plasma levels of atazanavir and nelfinavir decrease when used concomitantly with omeprazole.
Concomitant administration of omeprazole with nelfinavir is contraindicated. Concomitant use with omeprazole (40 mg once daily) have reduced mean nelfinavir exposure approximately by 40% and its pharmacologically active metabolite M8 mean exposure approximately by 75-90%. The interaction also involves CYP2C19 inhibition.
Concomitant use of omeprazole with nelfinavir is not recommended. In healthy volunteers, concomitant use of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg has reduced atazanavir exposure by 75%. Increasing atazanavir dose to 400 mg does not compensate for the impact of omeprazole on atazanavir exposure.
Co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg resulted in approximately 30% reduction in atazanavir exposure compared to once-daily atazanavir 300 mg/ritonavir 100 mg administration in healthy volunteers.
Digoxin: Concomitant use of Omeprazole (20 mg daily) and digoxin have increased digoxin bioavailability by 10% in healthy volunteers. Digoxin toxicity was rarely reported. However, caution must be exercised in elderly patients when omeprazole is given in high doses. Subsequently, therapeutic monitoring for digoxin should be encouraged.
Clopidogrel: Results of studies conducted on healthy volunteers showed that there is pharmacokinetic (PK)/pharmacodynamics (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg once daily). When clopidogrel and omeprazole were co-administered, mean exposure to the active metabolite of clopidogrel was decreased by 46% and mean reduction in maximum inhibition of platelet aggregation was 16%.
In both observational and clinical studies, inconsistent data on clinical outcomes of PK/PD interaction in terms of important cardiovascular events have been reported. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.
Other medicinal products: The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and therefore clinical efficacy may be impaired. Concomitant use with posaconazole and erlotinib should be avoided.
Medicinal products metabolized by CYP2C19: Omeprazole is a moderate inhibitor of CYP2C19 which is the major metabolizing enzyme of omeprazole. Therefore, metabolism of other drugs metabolized by CYP2C19 enzyme, such as diazepam, phenytoin, warfarin (R-warfarin) and other vitamin K antagonists and cilostazol may be reduced.
Cilostazol: In a cross-over study with 40 mg of omeprazole given to healthy subjects, Cmax and AUC values for cilostazol were increased by 18% and 26% respectively and values for one of its active metabolites increased by 29% and 69%, respectively.
Phenytoin: Monitoring phenytoin plasma concentrations is recommended during the first two weeks after initiating omeprazole treatment; if phenytoin dose is adjusted, monitoring and further dose adjustment should be made after omeprazole treatment is ended.
Unknown mechanism: Saquinavir: Approximately 70% increase in plasma levels of saquinavir, a well-tolerated agent in HIV-infected patients, was reported with concomitant use of omeprazole and saquinavir/ritonavir.
Tacrolimus: Increased plasma levels of tacrolimus were reported with concomitant use of omeprazole and tacrolimus. Assisted monitoring of renal functions (creatinine clearance) besides tacrolimus concentrations should be performed and tacrolimus dosage should be adjusted if necessary.
Methotrexate: In some patients, increased methotrexate levels were reported when co-administered with proton pump inhibitors. Temporary discontinuation of omeprazole may be required during high-dose methotrexate administration.
Effects of other drugs on the pharmacokinetics of omeprazole: CYP2C19 and/or CYP3A4 inhibitors: Since omeprazole is metabolized by CYP2C19 and CYP3A4, drugs such as clarithromycin and voriconazole known to be inhibited by CYP2C19 or CYP3A4 or both may cause increased serum omeprazole levels by decreasing the metabolism rate of omeprazole. Concomitant use of omeprazole and voriconazole resulted in more than twofold increase in omeprazole exposure. Dose adjustment for omeprazole is not required during short-term concomitant use since omeprazole is well tolerated at high doses. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is necessary.

Incompatibilities: No known incompatibility exists if used as recommended.
Special Precautions for Disposal and Other Handling: Any unused product or waste material should be disposed of in accordance with the "Directive on Control of Medical Waste" and "Directive on the Control of Packaging and Packaging Waste". Unused Omeprazole should not be disposed via wastewater or household waste to protect the environment.

Store at temperatures not exceeding 30°C. Protect from light.
Vials kept in the outer carton can be stored up to 24 hours at normal room temperature below 25°C, provided they are protected from light.
Reconstituted solution can be stored 4 hours at room temperature below 25°C and 12 hours in the refrigerator.

Antacids, Antireflux Agents & Antiulcerants

A02BC01 - omeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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