Pantoprazole

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St. John’s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment.

A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment.

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of other medicinal products where gastric is an important determinant of oral availability e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability.

If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Pantoprazole reduces levels of dasatinib.

Pantoprazole may decrease the absorption of enoxacin.

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.

Pantoprazole may increase the bioavailability and serum levels of orally administered topotecan.

Pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B₁₂ absorption on long-term therapy or if respective clinical symptoms are observed.

Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in older people or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Pantoprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/ neonatal toxicity of pantoprazole. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion into human milk but excretion into human milk has been reported. A risk to the newborn/infant cannot be excluded.

Therefore, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Pantoprazole should be made taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy to woman.

Fertility

There was no evidence of impaired fertility following the administration of pantoprazole in animal studies.

Pantoprazole has no or negligible influence on the ability to drive and use machines.

Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADR is injection site thrombophlebitis. Diarrhoea and headache occurred in approximately 1% of patients.

The list below shows adverse reactions reported with pantoprazole, ranked under the following frequency classification: 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), not known (cannot be estimated from the available data).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse Reaction frequency and therefore they are mentioned with a “not known” frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions with pantoprazole in clinical trials and post-marketing experience:

Blood and lymphatic system disorders

Rare: Agranulocytosis

Very rare: Thrombocytopenia; Leukopenia; Pancytopenia

Immune system disorders

Rare: Hypersensitivity (including anaphylactic reactions and anaphylactic shock)

Metabolism and nutrition disorders

Rare: Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes

Not known: Hyponatraemia, Hypomagnesaemia, Hypocalcaemia¹; Hypokalaemia

Psychiatric disorders

Uncommon: Sleep disorders

Rare: Depression (and all aggravations)

Very rare: Disorientation (and all aggravations)

Not known: Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)

Nervous system disorders

Uncommon: Headache, Dizziness

Rare: Taste disorders

Not known: Parasthesia

Eye disorders

Rare: Disturbances in vision/blurred vision

Gastrointestinal disorders

Common: Fundic gland polyps (benign)

Uncommon: Diarrhoea; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort

Hepatobiliary disorders

Uncommon: Liver enzymes increased (transaminases, γ-GT)

Rare: Bilirubin increased

Not known: Hepatocellular injury; Jaun-dice; Hepato-cellular failure

Skin and subcutaneous tissue disorders

Uncommon: Rash/exanthema/eruption; Pruritus

Rare: Urticaria; Angioedema

Not known: Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity; Subacute cutaneous lupus erythematosus

Musculo-skeletal and connective tissue disorders

Uncommon: Fracture of the hip, wrist or spine

Rare: Arthralgia; Myalgia

Not known: Muscle spasm²

Renal and urinary disorders

Not known: Interstitial nephritis (with possible progression to renal failure)

Reproductive system and breast disorders

Rare: Gynaecomastia

General disorders and administration site conditions

Common: Injection site thrombo-phlebitis

Uncommon: Asthenia, fatigue and malaise

Rare: Body temperature increased; Oedema peripheral

¹ Hypocalcemia in association with hypomagnesemia
² Muscle spasm as a consequence of electrolyte disturbance