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 metabolised 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.

Pantoprazole must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of Pantoprazole in combination treatment for these patients.

A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment. In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Pantoprazole must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients.

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenoprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenoprocoumon 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 medicinal products where gastric pH is an important determinant of oral bioavailability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicines such 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.

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.

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, 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.

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

There have been reports of false-positive results in some urine screening tests for tetrahydrocannabinol (THC) in patients receiving pantoprazole. An alternative confirmatory method should be considered to verify positive results.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of pantoprazole.

Animal studies have shown reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of pantoprazole during pregnancy.

Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion of pantoprazole in human milk but excretion into human milk has been reported. A risk to the newborns/infants cannot be excluded. Therefore, a decision on whether to discontinue breast-feeding or to discontinue/abstain from pantoprazole therapy taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy for the women.

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 table below lists 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:

¹ Hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia
² Muscle spasm as a consequence of electrolyte disturbance