Nolpaza® control
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nolpaza® control (Nolpaza® control)
Composition:
Active substance: pantoprazole;
One gastro-resistant tablet contains 20 mg of pantoprazole as pantoprazole sodium sesquihydrate;
Excipients: mannite (E 421), crospovidone, sodium carbonate, sorbitol (E 420), calcium stearate, hypromellose, povidone (K 25), titanium dioxide (E 171), yellow iron oxide (E 172), propylene glycol, methacrylate copolymer dispersion, talc, macrogol 6000.
Pharmaceutical form. Gastro-resistant tablets.
Main physicochemical properties: light yellow-brown, oval, slightly biconvex tablets coated with a film coating.
Pharmacotherapeutic group. Drugs for the treatment of acid-related disorders. Proton pump inhibitors. ATC code A02BC02.
Pharmacological properties.
Pharmacodynamics.
Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically targeting the proton pump of parietal cells.
Pantoprazole is transformed into its active form in an acidic environment, specifically within parietal cells, where it inhibits the enzyme H+-K+-ATPase, thereby blocking the final step of gastric acid production. This inhibition is dose-dependent and suppresses both basal and stimulated acid secretion.
Treatment with pantoprazole, as with other proton pump inhibitors and H2-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The efficacy of the drug is equivalent following either oral administration or intravenous infusion.
Pantoprazole use leads to increased fasting gastrin levels. With short-term treatment, these levels usually do not exceed the upper normal limit. With long-term therapy, gastrin levels typically increase approximately twofold. Marked elevation, however, occurs only in isolated cases. As a result, with prolonged treatment, a mild or moderate increase in the number of gastric enterochromaffin-like (ECL) cells (adenomatoid hyperplasia) may be observed in a small number of cases. Nevertheless, according to studies conducted to date, the development of neuroendocrine tumor precursor cells observed in animal experiments has not been observed in humans. However, with long-term (more than 1 year) treatment, the potential influence of pantoprazole on thyroid endocrine parameters cannot be excluded.
During treatment with antisecretory agents, serum gastrin levels rise in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data indicate that proton pump inhibitor therapy should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.
Pharmacokinetics.
Distribution. Plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is about 0.15 L/kg.
Bioavailability. Pantoprazole is completely and rapidly absorbed after oral administration. The absolute bioavailability of the tablet formulation is approximately 77%. On average, maximum serum concentrations (Cmax) of about 1–1.5 µg/mL are reached approximately 2.0–2.5 hours (tmax) after a single 20 mg oral dose, and these values remain consistent with repeated dosing. Concomitant food intake does not affect bioavailability (AUC or Cmax) but increases the variability of the lag time (tlag).
Elimination. The terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. A few cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition).
The majority of pantoprazole metabolites are excreted in urine (about 80%), with the remainder eliminated in feces. The main metabolite in both plasma and urine is desmethylpantoprazole, conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.
Characteristics in special patient populations
Poor metabolizers. Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19 and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers compared to individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing recommendations.
Renal impairment. No dose adjustment recommendations are required for patients with impaired renal function, including those on dialysis. As in healthy volunteers, the elimination half-life of pantoprazole remains short. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains efficient, and no accumulation occurs.
Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the elimination half-life of pantoprazole increases to 3–7 hours and AUC increases 3–6 times, the maximum serum concentration increases only slightly—by 1.3 times compared to healthy volunteers.
Elderly patients. A slight increase in AUC and Cmax observed in elderly volunteers compared to younger volunteers is not clinically significant.
Clinical characteristics.
Indications.
For short-term treatment of gastroesophageal reflux disease and its symptoms (such as heartburn, acid regurgitation) in adults.
Contraindications.
Hypersensitivity to pantoprazole or to any component of the medicinal product.
Concomitant use of pantoprazole with HIV protease inhibitors such as atazanavir and nelfinavir, whose absorption depends on gastric pH, is contraindicated due to a significant reduction in their bioavailability (see section «Interaction with other medicinal products and other types of interactions»).
Interaction with other medicinal products and other types of interactions.
Medicinal products with pH-dependent absorption pharmacokinetics
Pantoprazole may reduce the absorption of drugs whose bioavailability depends on gastric pH (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).
HIV protease inhibitors
Concomitant use of pantoprazole with HIV protease inhibitors such as atazanavir and nelfinavir, whose absorption depends on gastric acidity, is contraindicated due to a significant reduction in their bioavailability (see section «Contraindications»).
Coumarin anticoagulants (phenprocoumon or warfarin)
Although no interaction was observed during clinical studies when co-administered with phenprocoumon and warfarin, isolated cases of changes in INR (International Normalized Ratio) have been reported during post-marketing surveillance. Therefore, in patients receiving coumarin anticoagulants (e.g., phenprocoumon and warfarin), monitoring of prothrombin time/INR is recommended at the beginning and end of treatment, as well as in case of irregular pantoprazole therapy.
Methotrexate
There have been reports of increased blood levels of methotrexate in some patients when high-dose methotrexate (e.g., 300 mg) is co-administered with proton pump inhibitors. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.
Other interaction studies
Pantoprazole is metabolized in the liver via the cytochrome P450 enzyme system.
Studies with most of these agents have not revealed clinically relevant interactions with carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glyburide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline, and oral contraceptives containing levonorgestrel and ethinylestradiol. However, interaction between pantoprazole and other drugs metabolized via the same enzyme system cannot be excluded.
No interaction has been observed with concomitantly administered antacid agents.
Studies on the interaction between pantoprazole and concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions between these drugs were observed.
Effect of the medicinal product on laboratory parameters
False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm results.
Special precautions for use.
Patients should consult a physician if:
- they experience unintentional significant weight loss, anaemia, gastrointestinal bleeding, dysphagia, recurrent vomiting, or vomiting with blood, as pantoprazole may mask symptoms and delay diagnosis of more serious conditions. In such cases, the risk of a malignant tumour should be ruled out. If symptoms persist despite adequate ongoing treatment, further investigation is required;
- they have a history of gastric or duodenal ulcer, or previous gastrointestinal surgery;
- they have been receiving symptomatic treatment for dyspepsia or heartburn for 4 weeks or longer;
- they have jaundice, hepatic insufficiency, or liver disease;
- they suffer from other serious conditions negatively affecting general health;
- they are over 55 years of age and experience new or recently changed symptoms of dyspepsia or heartburn.
Patients with chronic recurrent symptoms of dyspepsia or heartburn should undergo regular medical evaluation. Patients aged 55 years or older who take any over-the-counter medications for dyspepsia or heartburn daily should inform their physician.
Patients should not take any other proton pump inhibitor or H2-receptor blocker concurrently.
If endoscopic examination or urease breath test is required, patients should consult their physician prior to taking pantoprazole.
Patients should be aware that pantoprazole tablets are not intended for immediate relief of symptoms. Symptom relief may occur approximately 1 day after starting treatment with pantoprazole, but up to 7 days may be needed to achieve complete resolution of heartburn symptoms. Patients should not use pantoprazole as a preventive agent.
Liver function impairment. Patients with severe liver dysfunction should have liver enzyme levels monitored regularly. If liver enzymes increase, treatment with the drug should be discontinued.
HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir, nelfinavir), whose absorption depends on intragastric pH, is contraindicated due to a significant reduction in their bioavailability.
Gastrointestinal infections caused by bacteria. Reduced gastric acidity due to any agent, including proton pump inhibitors, increases the number of gastric bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents slightly increases the risk of gastrointestinal infections caused by microorganisms such as Salmonella, Campylobacter, or Clostridium difficile.
Concomitant use with NSAIDs. The use of Nolpaza® Control for prevention of gastric and duodenal ulcers caused by long-term NSAID use should be limited to patients prone to frequent ulcer recurrences. Risk assessment should consider individual risk factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.
Vitamin B12 absorption. Pantoprazole, like all drugs that inhibit gastric acid production, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term therapy, or if corresponding clinical symptoms occur.
Long-term treatment. This medicinal product is intended for short-term treatment (up to 4 weeks). For long-term treatment, especially exceeding 1 year, patients should remain under continuous medical supervision.
Hypomagnesaemia. Rare cases of severe hypomagnesaemia have been reported in patients receiving proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, and in most cases, after one year. Serious clinical manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may occur and develop insidiously. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see section "Special precautions for use"). In cases of hypomagnesaemia (and associated hypocalcaemia and/or hypokalaemia), the condition of most patients improved after magnesium replacement therapy and discontinuation of PPI treatment.
Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesaemia (e.g., diuretics), should have magnesium levels measured before starting PPI treatment and periodically during therapy.
Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may slightly increase the risk of hip, wrist, and spine fractures, particularly in elderly patients or those with other risk factors. Observational studies suggest that PPI use may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.
Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during pantoprazole use, which may be life-threatening or fatal. The frequency of these reactions is unknown (see section "Adverse reactions").
When prescribing pantoprazole, patients should be informed about the signs and symptoms, and closely monitored for skin reactions. If signs or symptoms suggestive of these severe skin reactions occur, pantoprazole should be discontinued immediately and alternative treatment options considered.
Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus.
If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical attention and discontinuation of Nolpaza® Control should be considered. Development of subacute cutaneous lupus erythematosus in patients previously treated with proton pump inhibitors may increase the risk of recurrence when using other proton pump inhibitors.
Effect on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumours. To avoid this interference, treatment with Nolpaza® Control should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.
Use during pregnancy or breastfeeding.
Pregnancy. Adequate data on the use of pantoprazole in pregnant women are lacking. Reproductive toxicity was observed in animal studies. Preclinical studies showed no evidence of impaired fertility or teratogenic effects. The potential risk to humans is unknown. Pantoprazole should not be used during pregnancy.
Breastfeeding. Pantoprazole and/or its metabolites have been detected in breast milk. The effect of pantoprazole on newborns/infants is unknown. This medicinal product should not be used in women who are breastfeeding.
Fertility. Pantoprazole did not impair fertility in animal studies.
Ability to affect reaction speed when driving or operating machinery.
Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.
Dosage and Administration
Dosage
The recommended dose is 20 mg of pantoprazole (1 tablet) once daily.
It may be necessary to take the tablets for 2–3 days to relieve symptoms. After symptoms have resolved, treatment with the medication should be discontinued. The duration of treatment should not exceed 4 weeks without further medical evaluation (after consultation with a physician).
If no symptom relief occurs after two weeks of continuous treatment, the patient should consult a physician.
Special Patient Groups
No dose adjustment is required for elderly patients or patients with impaired renal or hepatic function.
Administration Method
Nolpaza® Control 20 mg enteric-coated tablets should be swallowed whole, without chewing or breaking, with a small amount of liquid before a meal.
Children
Nolpaza® Control is not recommended for use in children due to insufficient data on safety and efficacy in this age group.
Overdose
There are no reports of overdose in humans.
Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated.
Since pantoprazole is highly protein-bound, it is not effectively removed by dialysis.
In cases of overdose with clinical signs of intoxication, there are no specific antidotes; treatment should be symptomatic and supportive.
Adverse Reactions.
Summary of safety profile.
Adverse reactions have been observed in approximately 5% of patients.
List of adverse reactions.
Undesirable effects are classified by frequency of occurrence into the following categories: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data).
Blood and lymphatic system disorders.
Rare: agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
Immune system disorders.
Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and nutrition disorders.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.
Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia^1, hypokalemia^1.
Psychiatric disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Very rare: confusion (including exacerbation).
Not known: hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms in case of pre-existing conditions).
Nervous system disorders.
Uncommon: headache, dizziness.
Rare: taste disturbances.
Not known: paraesthesia.
Eye disorders.
Rare: visual disturbances/blurred vision.
Gastrointestinal disorders.
Common: fundic gland polyps (benign).
Uncommon: diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort.
Not known: microscopic colitis.
Hepatobiliary disorders.
Uncommon: increased liver enzymes (transaminases, γ-GT).
Rare: increased bilirubin levels.
Not known: hepatocellular injury, jaundice, hepatocellular failure.
Skin and subcutaneous tissue disorders.
Uncommon: skin rashes, exanthema, pruritus.
Rare: urticaria, angioneurotic edema.
Not known: Stevens-Johnson syndrome, Lyell's syndrome, TEN, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use"), phototoxicity, drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders.
Uncommon: fractures of the femur, wrist, spine (see section "Special precautions for use").
Rare: arthralgia, myalgia.
Not known: muscle spasms^2.
Renal and urinary disorders.
Not known: tubulointerstitial nephritis (TIN) (with possible progression to renal failure).
Reproductive system and breast disorders.
Rare: gynecomastia.
General disorders.
Uncommon: asthenia, fatigue, malaise.
Rare: increased body temperature, peripheral edema.
^1 Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").
^2 Muscle spasms as a consequence of electrolyte imbalance.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.
Shelf life. 5 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of the reach of children.
Packaging.
7 tablets in a blister; 1 or 2 blisters in a cardboard box.
14 tablets in a blister; 1 blister in a cardboard box.
Prescription status. Over-the-counter.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and place of business.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia.
Manufacturer.
TAD Pharma GmbH, Germany.
Manufacturer's address and place of business.
Heinz-Lochmann-Straße 5, 27472 Cuxhaven, Germany.