CONTROLOC Gastro-resistant tablet / Solution for injection Ref.[115943] Active ingredients: Pantoprazole

The intravenous administration of Controloc i.v. is recommended only if oral application is not appropriate

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Hepatic Impairment

In patients with severe liver impairment the daily dose has to be reduced to 20 mg pantoprazole. In patients with severe liver impairment, liver enzymes should be monitored during therapy regularly. In the case of a rise of the liver enzymes, the treatment should be discontinued. (See Dosage and Method of Administration).

Gastrointestinal infections caused by bacteria, including Clostridium difficile

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Controloc may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter. In hospitalized patients, PPI therapy may be associated with an increased risk of Clostridium difficile infection.

Published observational studies suggest that proton pump inhibitor (PPI) therapy like pantoprazole may be associated with an increased risk of Clostridium difficile-associated diarrhoea (CDAD), especially in hospitalised patients. This diagnosis should be considered for diarrhoea that does not improve (see 4.8 Undesirable Effects). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with Controloc, refer to Warnings and Precautions sections of those package inserts.

Hypomagnesaemia

Hypomagnesaemia, symptomatic and asymptomatic, has been reported in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious manifestations of hypomagnesamia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias can occur but they may begin insidiously and be overlooked. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia. In most patients, treatment of hypomagnesemia (and hypomagnesemia associated hypocalcemia and/or hypokalemia) required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Undesirable effects].

Bone Fractures

Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines (see Dosage and Administration and Undesirable effects).

Concomitant use with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients (see Drug Interactions).

HIV protease inhibitors

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

Influence on vitamin B₁₂ absorption

Daily treatment with any acid-suppressing medication over a prolonged period of time (several years) may lead to malabsorption of cyanocobalamin (vitamin B₁₂) caused by hypo- or achlorhydria. Cyanocobalamin deficiency should be considered in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, individuals with reduced body stores or risk factors for reduced vitamin B₁₂ absorption (such as the elderly) on long- term therapy or if relevant clinical symptoms are observed

Interference with Laboratory Tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, proton pump inhibitor treatment should be stopped 14 days before CgA measurements.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs (See section 4.8). Discontinue pantoprazole at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE)

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving pantoprazole, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., Antinuclear antibody) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Co‐administration with NSAIDs (Applies to Controloc 20 mg only)

The use of Controloc 20 mg as a preventive of gastroduodenal ulcers induced by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (>65 years), history of gastric or duodenal ulcer or upper gastro-intestinal bleeding.

Combination therapy (Applies to Controloc 40 mg only)

In the case of combination therapy, the prescribing information for the respective drugs must be observed.

Long term treatment (Applies to Controloc 20 mg and 40 mg only)

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Drugs with pH‐Dependent Absorption Pharmacokinetics:

Controloc may reduce or increase the absorption of drugs whose bioavailability is pH-dependent (e.g. ketoconazole)

HIV medications (e.g. atazanavir)

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

It has been shown that co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailibility of atazanavir. The absorption of atazanavir is pH dependent.

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) and prothrombin have been reported during concomitant treatment in the post-marketing period. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of increase prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted (see Warnings and Precautions).

Other interactions studies

Pantoprazole is metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

An interaction of pantoprazole with other drugs or compounds which are metabolized using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin and an oral contraceptive containing levonorgestrel and ethinyl oestradiol.

Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol), or does not interfere with p-glycoprotein related absorption of digoxin.

There were also no interactions with concomitantly administered antacids.

Interaction studies have also been performed by concomitantly administering pantoprazole with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.

Clopidogrel

Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole.

Drugs that Inhibit or Induce CYP2C19

Inhibitors of CYP2C19, such as fluvoxamine, would likely increase the systemic exposure of pantoprazole. Inducers of CYP2C19 may decrease the systemic exposure to pantoprazole.

Pregnancy

The limited data from the use of pantoprazole in pregnant women does not indicate foetal/neonatal toxicity. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Controloc should not be used during pregnancy, unless clearly necessary.

Lactation

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Controloc should be made taking into account the benefit of breastfeeding to the child, and the benefit of Controloc therapy to women.

Pantoprazole is not expected to adversely affect the ability to drive or use machines. Adverse drug reactions, such as dizziness and visual disturbances may occur (see section 4.8). 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 ADRs are diarrhoea and headache, both occurring in approximately 1% of patients.

Table 1 lists adverse drug reactions reported with pantoprazole in clinical studies and post-marketing experience. The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines:

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.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience:

⁺ Applicable to Controloc i.v. only
^* Hypocalcemia and/or hypokalemia may be related to the occurrence of hypomagnesemia (see Special Warnings and Special Precautions for use, 4.4)
^ DRESS: Drug Rash with Eosinophilia and Systemic Symptoms

(Applies to Controloc i.v only)

This medicinal product must not be mixed with other medicinal products except those mentioned in section "Special precautions for disposal".

Drug dependence has not been observed.