ACTION AND MECHANISM

- Anti-peptic ulcer, H+/K+ pump inhibitor. Pantoprazole 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 basal and in response to a stimulus, regardless of the stimulus (acetylcholine, gastrin, or histamine).

Pantoprazole 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, giving rise to 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.

The effects on acid production begin to appear after 15–30 minutes (IV) or 2.5 hours, and may last for up to 24 hours. Some studies have shown that basal hydrochloric acid secretion does not return to normal until 7 days after discontinuing pantoprazole.

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.

- Prolonged treatment with PPIs (> 3 months) may rarely result in severe hypomagnesemia, which may be associated with hypocalcemia and/or hypokalemia. If the patient experiences symptoms such as weakness, dizziness, tetany, seizures, or cardiac arrhythmia, magnesium levels should be determined. If hypomagnesemia occurs, the patient should be notified immediately, treatment should be discontinued, and a magnesium supplement should be administered. The physician should consider performing periodic blood tests to monitor blood magnesium levels.

- 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:

* Liver function tests (transaminases, bilirubin) in patients with severe liver function (Child-Pugh class C).

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

- Co-administration with NSAIDs: The use of pantoprazole for the prevention of gastroduodenal ulcers induced by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and are at high risk of developing gastrointestinal complications. This increased risk should be assessed based on individual risk factors, e.g., advanced age (>65 years), a history of gastric or duodenal ulcer, or upper gastrointestinal bleeding.

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.

- If you are on "on-demand" treatment (administered when symptoms appear), inform your doctor and/or pharmacist of any changes in your usual symptoms.

- 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 pantoprazole, any other PPI, or any other component of the medication.

ADVANCED AGE

No specific problems have been reported in the elderly that would require dosage adjustment. However, it should be noted that in patients over 65 years of age, a physiological reduction in liver function may occur.

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: Administration in rats and rabbits at doses higher than those recommended for humans was not associated with teratogenic or embryotoxic effects.

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.

It is unknown whether pantoprazole can cross the placenta, but due to its low molecular weight, this passage is possible. Other PPIs such as omeprazole are able to cross this barrier. However, due to its high plasma protein binding and low t1/2, the amount that could reach the fetus is not estimated to be very high.

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

Effects on fertility: Pantoprazole did not adversely affect fertility in animals. No specific studies on its effects on fertility have been conducted.

PHARMACOKINETICS

Pantoprazole 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.

It has linear pharmacokinetics at doses between 10-80 mg.

INDICATIONS

- Short-term treatment of [GASTROESOPHAGEAL REFLUX] symptoms, such as [GASTRIC HYPERACIDITY] or acid regurgitation in adults.

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. Reductions in the antiplatelet effect have been reported in patients receiving omeprazole. Pantoprazole does not appear to interact with clopidogrel, although caution is recommended when using it, with careful monitoring of the effect of clopidogrel.

- 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 given its serious effects, caution is advised in elderly patients treated with high doses. Monitoring plasma digoxin levels is recommended.

- Enzyme inducers/inhibitors. Pantoprazole 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. Combining these drugs with nelfinavir or atazanavir is not recommended. If this combination is unavoidable, it is recommended to increase the atazanavir dose from 300 to 400 mg and not exceed the pantoprazole dose of 20 mg/24 h. However, this dose increase did not fully counteract the effect on atazanavir plasma levels, so it is advisable to assess the patient's response.

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. Temporarily discontinuing the antiulcer agent may be advisable in patients treated with high doses of methotrexate.

No drug interactions have been found when combined with antacids, metoprolol or theophylline.

LACTATION

Animal Safety: Animal studies have shown the excretion of pantoprazole in breast milk.

Safety in humans: Pantoprazole is excreted in milk in small amounts, becoming undetectable 6 hours after administration. It is estimated that the dose received by a nursing infant would be approximately 0.14% of the dose administered to the mother. The potential consequences for the nursing infant are unknown, although it should be noted that PPIs are acid-labile at acid pH, which is why they are administered orally in gastro-resistant forms. It is recommended to discontinue breastfeeding or avoid its administration based on the benefit of breastfeeding for the child and the benefit of treatment with pantoprazole for the mother.

CHILDREN

Safety and efficacy in children and adolescents under 18 years of age have not been evaluated, so its use is not recommended.

RULES FOR CORRECT ADMINISTRATION

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

Administration with food : administer 1 hour before one of the main meals.

POSOLOGY

"ORAL ADMINISTRATION"

- Adults:

DOSAGE IN LIVER FAILURE

- Mild to moderate hepatic impairment (Child-Pugh classes A and B): no dosage adjustment required.

- Severe hepatic impairment (Child-Pugh class C): maximum dose 20 mg/24 h.

DOSAGE IN RENAL FAILURE

No dosage adjustment required.

PRECAUTIONS

- [DIGESTIVE INFECTIONS]. The increase in gastric pH produced by antiulcer drugs could 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 drug who develop severe diarrhea.

- 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, receive 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.

- [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 who have just 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 can 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 drugs could lead to false positives when used in diagnostic tests. Therefore, any antiulcer drug should be discontinued at least 5 days before CgA testing. If CgA levels have not normalized during this period, the test should be repeated 14 days after discontinuing the antiulcer drug.

- [LIVER FAILURE]. Pantoprazole is primarily eliminated by hepatic metabolism, so drug accumulation may occur. However, no accumulation has been observed after daily administration, and in fact, dosage adjustment does not appear necessary. Use with caution is advised, especially in patients with severe hepatic impairment (Child-Pugh class C), in whom liver function (transaminase levels) should be monitored. If a significant increase occurs, discontinue pantoprazole.

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ADVERSE REACTIONS

Pantoprazole is generally well tolerated, and in clinical trials only 5% of patients experienced any adverse reactions, which were generally mild and transient. Adverse reactions to pantoprazole appear to be dose-independent.

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: infrequent [NAUSEA] and [VOMITING], [ABDOMINAL PAIN], [DIARRHEA], [CONSTIPATION], [FLATULENCE], [ABDOMINAL DISTENTION], [DRY MOUTH].

- Liver: uncommon [elevated transaminases] (AST, ALT and GGT); rare [hyperbilirubinemia]; frequency unknown [jaundicity], [liver failure], [hepatitis].

- Cardiovascular: uncommon [ELECTROCARDIOGRAM DISTURBANCES]; frequency unknown [THROMBOPHLEBITIS].

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

- Respiratory: frequency unknown [PNEUMONIA].

- Genitourinary: uncommon [ERECTILE DYSFUNCTION]; rare [GYNECOMASTIA]; frequency unknown [INTERSTIAL NEPHRITIS].

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

- Allergic: rare [HYPERSENSITIVITY REACTIONS], including [ANAPHYLAXIS].

- Musculoskeletal: uncommon [HIP FRACTURE], [VERTEBRAL FRACTURE] or wrist; rare [ARTHRALGIA], [MYALGIA]; frequency unknown [RHABDOMYOLYSIS].

- Ophthalmological: rare [VISION DISORDERS], such as [BLURRED VISION].

- Hematological: uncommon [eosinophilia]; rare [agranulocytosis]; very rare [thrombocytopenia], [leukopenia], [pancytopenia]; frequency unknown [neutropenia].

- Metabolic: rare [HYPERCHOLESTEROLEMIA], [HYPERTRIGLYCERIDEMIA], [WEIGHT GAIN], [WEIGHT LOSS]; frequency unknown [HYPONATREMIA], [HYPOMAGNESEMIA], [HYPOCALCEMIA], [HYPOKALAEMIA], [HYPERGLYCEMIA]; [CYANOCOBALAMIN DEFICIENCY].

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 magnesium supplementation.

- General: infrequent [MALE FEELING], [ASTHENIA], [FATIGUE]; rare [FEVER], [MALLEOLAR EDEMA].

OVERDOSE

Symptoms : Doses of up to 240 mg (iv) have been administered over a 2-minute period without adverse reactions.

Measures to be taken :

- Antidote: There is no specific antidote.

- General elimination measures: it is not expected to be easily dialyzable due to its high plasma protein binding.

- Monitoring: clinical status of the patient.

- Treatment: symptomatic.