ACTION AND MECHANISM

- Anti-peptic ulcer, H+/K+ pump inhibitor. Omeprazole is a benzimidazole that acts as a specific, non-competitive, and irreversible inhibitor of the proton pump (PPI) or H+/K+ ATPase, located on the surface of the gastric parietal cell. Blocking this proton pump prevents gastric acid production, both basally and in response to a stimulus, regardless of the stimulus (acetylcholine, gastrin, or histamine).

Omeprazole is a racemic mixture of two stereoisomers, S-omeprazole (esomeprazole, pharmacologically active) and R-omeprazole (no activity on acid production).

Omeprazole is a weakly base-like prodrug that, after absorption, is distributed throughout the body, particularly into the lumen of the secretory canaliculi of the parietal cell. There, in the presence of an acidic medium, it undergoes a non-enzymatic chemical reaction, yielding the active form, a completely hydrophilic sulfonamide derivative, which tends to accumulate in the canaliculi and bind to the proton pump via disulfide bonds with the cysteine residues of the luminal alpha chain.

Due to the formation of covalent bonds, the only way for the parietal cell to recover its secretory activity is by synthesizing new pumps, which takes a long time and explains the long duration of the effects of PPIs, which can last up to 4 days after the administration of a single dose, despite their low t1/2.

Administration of a 20 mg dose of omeprazole resulted in a 70% reduction in pentagastrin-induced acid secretion 24 h after administration.

The effects on acid production begin to appear within 2 hours, although it may take up to 5 days to achieve maximum antiulcer activity. Its effects can be prolonged, and some studies have shown an inhibition of acid secretion of 26% (20 mg) and 48% (24 hours) after administration.

SPECIAL WARNINGS

- It is recommended to confirm the healing of ulcerations by endoscopy before discontinuing treatment.

- PPIs may mask the symptoms of digestive tumors of the esophagus or stomach. Close monitoring is recommended for patients treated with a PPI for prolonged periods, exceeding 1 year. If the patient experiences symptoms such as significant and unexplained weight loss, frequent vomiting, dysphagia, hematemesis, or melena, a differential diagnosis is recommended.

- In the event of severe and prolonged diarrhea, possible Clostridium difficile infection will be investigated.

- Long-term treatment with PPIs has rarely resulted in severe cases of hypomagnesemia, which may be associated with hypocalcemia. If the patient experiences symptoms such as weakness, dizziness, tetany, seizures, or cardiac arrhythmia, magnesium levels should be measured. If hypomagnesemia persists, treatment should be discontinued and a magnesium supplement should be administered.

- Antiulcer drugs may interfere with the diagnosis of neuroendocrine tumors by increasing levels of the specific marker chromogranin A (CgA), leading to false negatives. Discontinue the antiulcer drug at least 5 days before the test, and if levels have not normalized, repeat the test 14 days after discontinuation.

- Monitoring:

* Baseline and periodic magnesium levels in patients treated for long periods with omeprazole, treated with digoxin or with drugs that could cause hypomagnesemia, such as diuretics.

PATIENT ADVICE

- Do not stop treatment until your doctor tells you to, even if symptoms have disappeared. Stopping treatment too early could cause symptoms to return.

- Tell your doctor about any medications you are taking.

- Tell your doctor and/or pharmacist if you experience any of these symptoms:

* Intense and/or persistent diarrhea.

* Significant and unexplained weight loss, frequent vomiting, difficulty swallowing, or presence of blood in vomit or stool.

* Unexplained tiredness, dizziness, muscle stiffness, seizures or cardiac arrhythmias.

* Appearance of skin lesions, especially in areas exposed to the sun, accompanied by joint pain.

CONTRAINDICATIONS

- Hypersensitivity to omeprazole, any other PPI, or any other component of the medication.

- Co-treatment with nelfinavir (see Interactions – Protease inhibitors).

ADVANCED AGE

No specific problems have been described in the elderly that require dosage adjustment.

EFFECTS ON DRIVING

It doesn't appear to have any significant side effects. Dizziness is uncommon, and blurred vision and vertigo are rarely seen.

PREGNANCY

Animal safety : Omeprazole did not cause teratogenicity when administered to pregnant rats or rabbits at doses of 345 and 172 DMRH, although an increase in fetal mortality was recorded.

Safety in humans : The gestational safety of PPIs (including lansoprazole, omeprazole, and pantoprazole) has been evaluated in several clinical trials and meta-analyses, and no teratogenic effects or embryotoxicity have been found, although these cannot be completely ruled out, especially in the case of rare or delayed-onset fetal adverse reactions. However, based on information obtained from animal studies, the risk is not considered very high.

Omeprazole crosses the placenta. It is recommended to use it with caution, restricting its use to situations where there are no safer therapeutic alternatives and the benefits outweigh the potential risks.

Effects on fertility : No specific studies have been conducted on its effects on fertility.

PHARMACOKINETICS

Omeprazole is a prodrug, and after absorption and distribution to the parietal cell, it is transformed by a chemical reaction catalyzed in an acid medium into the active sulfonamido derivative.

INDICATIONS

- [GASTROESOPHAGEAL REFLUX]:

* Treatment of erosive reflux esophagitis.

* Symptomatic treatment of GERD.

* Long-term prevention of recurrence in patients with healed esophagitis.

INTERACTIONS

- Oral anticoagulants. Cases of increased INR have been reported in patients treated with an anticoagulant and a PPI. Caution is recommended when using this medication, with INR monitoring.

- Clopidogrel. High-dose omeprazole may decrease the effect of clopidogrel by inhibiting the CYP2C19-mediated conversion to its active metabolite (although there may be another mechanism, as clopidogrel has several metabolic pathways). It is recommended to avoid combining omeprazole with clopidogrel. Pantoprazole, and to a lesser extent lansoprazole and rabeprazole, may be safer alternatives.

- Disulfiram. A case of catatonic reaction has been reported when combined with omeprazole.

- Drugs with pH-dependent absorption. The increase in pH produced by antiulcer drugs could modify the absorption of certain medications by promoting or reducing their dissolution in the aqueous medium of the gastric contents. Thus, an increase in the absorption of digoxin has been observed, as well as a reduction in the absorption of azole antifungals (itraconazole, ketoconazole, posaconazole), mycophenolate mofetil, rilpivirine, vitamin B12, and tyrosine kinase inhibitors (dasatinib, erlotinib, gefitinib, lapatinib, nilotinib, pazopanib).

Digoxin toxicity is rare, but due to its serious effects, caution is advised in elderly patients treated with high doses. Monitoring plasma digoxin levels is recommended.

- Enzyme inducers/inhibitors. Omeprazole is metabolized by CYP2C19 and, to a lesser extent, by CYP3A4, so its plasma levels could be modified by potent inhibitors (fluconazole, fluvoxamine, ticlopidine) or inducers (rifampicin) of both isoenzymes. There are also certain risks with drugs that affect only one isoenzyme, especially CYP2C19, which is the most common. Dosage adjustment is not considered necessary, as the effect would be similar to that observed in slow metabolizers, but it could be more significant in cases of severe liver failure and long-term treatment.

- Protease inhibitors (PIs). PPIs may alter plasma levels of certain PIs, either by increasing pH or by inhibiting CYP2C19.

Significant reductions in plasma levels of nelfinavir and atazanavir have been reported. Co-administration with nelfinavir is contraindicated, and combination with atazanavir is not recommended. If this combination cannot be avoided, increasing the atazanavir dose from 300 to 400 mg is recommended. However, this dose increase did not fully counteract the effect on atazanavir plasma levels, so the patient's response should be assessed.

An increase in saquinavir levels of up to twofold has been described.

Finally, no significant pharmacokinetic changes were observed when combined with amprenavir, darunavir, fosamprenavir, lopinavir or tipranavir.

- Methotrexate. PPIs may increase serum methotrexate levels.

- CYP2C19 substrates. Omeprazole is a moderate inhibitor of CYP2C19, so it may increase the plasma levels of drugs metabolized by this system, such as certain tricyclic antidepressants (clomipramine, imipramine), cilostazol, citalopram, diazepam, phenytoin, voriconazole, or warfarin. It may be necessary to reduce the doses of these drugs, especially in the case of on-demand PPI therapy.

In the case of phenytoin and warfarin, it would also be advisable to monitor their plasma levels when starting and ending treatment with omeprazole.

- Tacrolimus. Increased serum levels of tacrolimus have been reported when administered with omeprazole.

No drug interactions have been found when combined with antacids, beta-blockers (metoprolol, propranolol), domperidone, fluoroquinolones or theophylline.

LACTATION

Animal Safety : Administration to lactating rats (35-345 MDRH) was associated with reduced pup weight gain.

Safety in humans : Omeprazole is excreted in breast milk, reaching levels of 7% of maternal total daily intake. The potential consequences for the nursing infant are unknown, although it should be noted that PPIs are acid-labile, which is why they are administered orally in gastro-resistant forms. It is recommended to discontinue breastfeeding or avoid their administration.

CHILDREN

Omeprazole has been used orally for the treatment of reflux esophagitis and symptomatic treatment of esophagitis in children aged 1 year and older who weigh at least 10 kg, as well as for the eradication of H. pylori in children and adolescents aged 4 years and older.

Its use is not recommended for indications other than those established in the approved indications or at ages other than those established in the approved indications.

RULES FOR CORRECT ADMINISTRATION

- Gastro-resistant capsules: Swallow whole with half a glass of liquid. Do not chew, crush, or break them.

If the patient has difficulty swallowing the capsules, they can be opened and sucked out, or the contents can be suspended in half a glass of still water, fruit juice, or soft foods such as yogurt or applesauce. The suspension with the granules should be drunk immediately or within 30 minutes. Then, fill the glass halfway with water and drink the contents. The granules should not be chewed or crushed.

Administration with food : preferably administer on an empty stomach, first thing in the morning.

POSOLOGY

"ORAL ADMINISTRATION"

- Adults:

DOSAGE IN LIVER FAILURE

Normally a dose of 10-20 mg/24 h is sufficient.

DOSAGE IN KIDNEY FAILURE

No dosage adjustment required.

PRECAUTIONS

- [LIVER FAILURE]. Hepatic impairment may increase exposure by reducing the hepatic first-pass effect and decrease elimination by reducing metabolism. However, omeprazole has been shown not to accumulate in these patients when administered once daily. Caution is advised. Patients with hepatic impairment may require a lower maintenance dose.

- [DIGESTIVE INFECTIONS]. The increase in gastric pH produced by antiulcer agents may promote colonization of the digestive tract by certain pathogenic microorganisms, such as Salmonella, Campylobacter, and even Clostridium difficile in hospitalized patients. A differential diagnosis of [PSEUDOMEMBRANOUS COLITIS] is recommended in patients treated with an antiulcer agent who develop severe diarrhea.

- [CYANOCOBALAMIN DEFICIENCY]. The increase in pH produced by antiulcer drugs could decrease the absorption of cyanocobalamin, so it is recommended to take it into account in people with low stores of this vitamin, such as in patients with [MALNUTRITION] or strict vegetarian diets without supplementation of this vitamin, or situations in which its absorption could be reduced, such as [CHRONIC ALCOHOLISM], [INTESTINAL MALABSORPTION] or situations that could lead to malabsorption, such as [INFLAMMATORY BOWEL DISEASE] or major surgical procedures of the digestive system.

- [HYPOMAGNESEMIA]. Treatment with PPIs has been associated with severe cases of hypomagnesemia, which may be associated with [HYPOCALCEMIA]. Its frequency has not been estimated, but it is considered rare. However, the widespread use of these drugs should be taken into account, so their clinical impact could be significant. Most patients who presented hypomagnesemia were on long-term treatment (at least 3 months and primarily 1 year).

Magnesium levels should be monitored at the start of treatment and periodically throughout the course of treatment in patients on long-term treatment with PPIs, digoxin, or drugs that could cause hypomagnesemia, such as diuretics.

If symptoms of hypomagnesemia appear, such as fatigue, dizziness, tetany, delirium, seizures, or cardiac arrhythmia, magnesium levels will be determined. Hypomagnesemia responds to discontinuation of the PPI and magnesium supplementation.

- [OSTEOPOROSIS]. The administration of PPIs at high doses and for prolonged periods (> 1 year) has been associated with an increased risk of hip, wrist, and vertebral fractures, especially in elderly individuals and those with risk factors. Therefore, women with osteoporosis are advised to receive treatment and adequate calcium and vitamin D intake.

- [PNEUMONIA]. Treatment with PPIs has been associated with cases of pneumonia, including community-acquired pneumonia (CAP), interstitial pneumonia, and nosocomial pneumonia. The risk appears to be higher in patients recently started treatment (especially for < 2 days) than in patients with long-term treatment.

- [SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS] (SCLE). PPIs have been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions appear, particularly in sun-exposed areas, accompanied by arthralgia, consider discontinuing treatment. Patients with SCLE due to a PPI may experience this condition again if they receive a different PPI.

- Analytical interferences. The increase in gastric pH induced by antiulcer drugs may increase plasma levels of gastrin (which usually return to baseline within 4 weeks of discontinuing treatment) and chromogranin A (CgA).

CgA is a specific marker for neuroendocrine tumors, so antiulcer agents may cause false positives when used in diagnostic tests. Therefore, any antiulcer agent should be discontinued at least 5 days before CgA testing. If CgA levels have not normalized within this period, the test should be repeated 14 days after discontinuing the antiulcer agent.

- Long-term treatment. Antiulcer drugs eliminate symptoms associated with acid disorders, which are common in malignant conditions such as stomach cancer or esophageal cancer. Therefore, there is a risk of delaying the diagnosis of these conditions.

It is recommended that patients receiving prolonged treatment, lasting more than one year, undergo regular monitoring and be advised to report the presence of other symptoms associated with these neoplasms, such as significant and unexplained weight loss, recurrent vomiting, dysphagia, or vomiting blood or stool. If a serious digestive process is suspected, a differential diagnosis is recommended.

- Renal impairment: [ACUTE TUBULOINTERSTITIAL NEPHRITIS] has been observed in patients taking omeprazole and may occur at any time during omeprazole treatment (see section 4.8). Acute tubulointerstitial nephritis may progress to renal failure.

PRECAUTIONS RELATED TO EXCIPIENTS

- This medicinal product contains sucrose. Patients with hereditary [FRUCTOSE INTOLERANCE], glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicinal product.

ADVERSE REACTIONS

Omeprazole's adverse reactions appear to be dose-independent. The most common are digestive in nature, as well as headache.

In the trials conducted, the safety profile in children was similar to that reported in adult patients. There are no long-term safety data in children, nor data on effects on growth.

Adverse reactions are described according to each frequency interval, considering very frequent (>10%), frequent (1-10%), unfrequent (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

- Digestive: common [NAUSEA] and [VOMITING], [ABDOMINAL PAIN], [CONSTIPATION], [DIARRHEA], [FLATULENCE]; rare [DRY MOUTH], [STOMATITIS], [CANDIDIASIS]; frequency unknown [PANCREATITIS].

- Hepatic: uncommon [elevated transaminases]; rare [hepatitis] with or without [jaundicity]; very rare [liver failure], [liver encephalopathies] in patients with pre-existing liver disease; frequency unknown [cholestasis].

- Cardiovascular: frequency unknown [ARTERIAL HYPERTENSION], [PALPITATIONS], [ANGINA PECTORIUM], [RAYNAUD'S SYNDROME].

- Neurological/psychological: common [HEADACHE]; uncommon [DIZZINESS], [PARESTHESIA], [DROWSY], [INSOMNIA]; rare [NERVOUSNESS], [CONFUSION], [DEPRESSION], [DYSGEUSIA]; very rare [HALLUCINATIONS], [AGGRESSIVENESS]; frequency unknown [ATAXIA].

- Respiratory: common [COUGH], [RESPIRATORY INFECTION]; rare [BRONCHIAL SPASM]; frequency unknown [PNEUMONIA].

- Genitourinary: rare [INTERSTITIAL NEPHRITIS]; very rare [GYNECOMASTIA]; frequency unknown [GALACTORRHEA], [INCREASE IN SERUM CREATININE].

- Dermatological: uncommon [DERMATITIS], [PRURITUS], [SKIN RASHES], [URTICARIA]; rare [ALOPECIA], [PHOTOSENSITIVITY REACTIONS]; very rare [ERYTHEMA MULTIFORME], [TOXIC EPIDERMAL NECROLYSIS], [STEVENS-JOHNSON SYNDROME]; frequency unknown [ANGIOEDEMA]; frequency unknown [SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS].

- Allergic: rare [HYPERSENSITIVITY REACTIONS], with [FEVER], [ANGIOEDEMA] or [ANAPHYLAXIS], and [LUPUS ERYTHEMATOSUS].

- Musculoskeletal: common [BACK PAIN]; uncommon [HIP FRACTURE], [VERTEBRAL FRACTURE] or wrist; rare [MUSCLE PAIN], [MYALGIA]; very rare [MYASTHENIA]; frequency unknown [RHABDOMYOLYSIS].

- Ophthalmological: rare [BLURRED VISION]; frequency unknown [OPTIC NEURITIS], [OPTIC NEUROPATHY].

- Optic: uncommon [VERTIGO].

- Hematological: rare [leukopenia], [thrombocytopenia]; very rare [agranulocytosis], [pancytopenia]; frequency unknown [neutropenia], [hemolytic anemia] or [megaloblastic anemia].

- Metabolic: rare [HYPONATREMIA]; frequency unknown [HYPOMAGNESEMIA], [HYPERCALCEMIA], [HYPOGLYCEMIA], [HYPOKALAEMIA], [CYANOCOBALAMIN DEFICIENCY], [WEIGHT GAIN].

Hypomagnesemia may present with [ASTHENIA], [DIZZINESS], [TETANY], [DELIRIUM], [SEIZURES], or [CARDIAC ARRHYTHMIA], among others. If symptoms appear, magnesium levels will be determined. Hypomagnesemia responds to discontinuation of the PPI and administration of magnesium supplements.

- General: common [ASTHENIA], [FEVER]; uncommon [MALEOLAR EDEMA], [MALAISE]; rare [HYPERHIDROSIS].

OVERDOSE

Symptoms : Single doses of up to 2,400 mg, equivalent to 120 MRHD, have been administered. No serious or irreversible adverse reactions have been reported, and in most cases, patients presented with symptoms such as nausea and vomiting, abdominal pain, diarrhea, dizziness, headache, depression, apathy, or confusion.

Measures to be taken :

- Antidote: There is no specific antidote.

- General elimination measures: administer activated charcoal in cases of very severe poisoning, although this is not usually necessary. It is not expected to be readily dialyzable due to its high plasma protein binding.

- Monitoring: clinical status of the patient.

- Treatment: symptomatic.