Pantoprazole-sofarma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE-SOPHARMA

Composition:

Active substance: pantoprazole;

One vial contains 44.94 mg of pantoprazole sodium sesquihydrate, equivalent to 40 mg of pantoprazole;

Excipients: disodium edetate, sodium hydroxide, nitrogen.

Pharmaceutical form. Powder for solution for injection.

Basic physico-chemical characteristics: white or almost white porous lyophilized powder.

Pharmacotherapeutic group.
Proton pump inhibitors. ATC code A02BC02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells.

Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H+-K+-ATPase, thereby blocking the final step of gastric hydrochloric acid production. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. As with other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole treatment reduces gastric acidity and thereby increases gastrin levels proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following both oral and intravenous administration of the drug.

Pantoprazole use increases fasting gastrin levels. With short-term use, levels in most cases do not exceed the upper normal limit. With long-term treatment, gastrin levels increase approximately twofold in most cases. Excessive increases, however, occur only in isolated cases. As a result, prolonged treatment may occasionally be associated with mild or moderate increases in the number of specific endocrine cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been observed in humans.

Based on animal study results, a potential effect of long-term (over 1 year) pantoprazole treatment on thyroid gland endocrine parameters cannot be completely ruled out.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect test results in the diagnosis of neuroendocrine tumors.

Available published data indicate that PPI use should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA. This is necessary to allow CgA levels, which may be slightly elevated after PPI treatment, to return to the normal range.

Pharmacokinetics

Pharmacokinetics are not altered after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion.

Distribution

Plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is approximately 0.15 L/kg.

Biotransformation

The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation. Another metabolic pathway involves oxidation via the enzyme CYP3A4.

Elimination

The terminal half-life is approximately 1 hour, and clearance is approximately 0.1 L/h/kg. Several cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the half-life does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), with the remainder excreted in feces. The main metabolite in both plasma and urine is desmethylpantoprazole, which is conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups

Slow metabolizers

Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19 and are referred to as slow metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the enzyme CYP3A4. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in slow metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment

Dose reduction is not recommended when prescribing pantoprazole to patients with renal impairment (including patients on dialysis). As in healthy volunteers, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are removed by dialysis. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, so accumulation does not occur.

Hepatic impairment

Although in patients with liver cirrhosis (Child-Pugh classes A and B), the half-life values increase to 7–9 hours and AUC values increase 5–7 times, the maximum serum concentration increases only slightly, by 1.5 times, compared to healthy volunteers.

Elderly patients

The slight increase in AUC and Cmax observed in elderly volunteers compared to younger volunteers is not clinically significant.

Pediatric patients

After single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical Characteristics

Indications

• Gastroesophageal reflux disease (GERD);
• Gastric and duodenal ulcer;
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications

Hypersensitivity to the active substance or to other benzimidazole derivatives or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction

Medicinal products whose absorption is pH-dependent

Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of other medicinal products where gastric pH is an important determinant of bioavailability after oral administration, for example, certain azole antifungal agents such as ketoconazole, itraconazole, posaconazole, and other medicinal products such as erlotinib.

HIV protease inhibitors

Concomitant use of pantoprazole with HIV protease inhibitors whose absorption depends on an acidic intragastric pH, such as atazanavir, is not recommended due to a significant reduction in their bioavailability (see section "Special warnings and precautions for use"). If concomitant use of HIV protease inhibitors with PPIs cannot be avoided, careful clinical monitoring (e.g., for viral load) is recommended. The pantoprazole dose should not exceed 20 mg daily. Dose adjustment of the HIV protease inhibitor may be necessary.

Coumarin anticoagulants (phenprocoumon or warfarin)

Concomitant administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or the International Normalized Ratio (INR). However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concurrently. Elevated INR and prolonged prothrombin time may lead to clinically relevant bleeding and even death. Monitoring of INR and prothrombin time is therefore recommended during concomitant use.

Methotrexate

There have been reports that concomitant administration of high doses of methotrexate (e.g., 300 mg) and PPIs led to increased blood levels of methotrexate in some patients. Therefore, when high doses of methotrexate are administered, for example in oncological diseases and psoriasis, temporary discontinuation of pantoprazole therapy is recommended.

Studies on other interactions

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with other metabolic pathways involving oxidation by the CYP3A4 enzyme.

Studies on interactions with medicinal products that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

An interaction between pantoprazole and other medicinal products or compounds metabolized via the same enzyme system cannot be excluded.

Results from several interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol). Pantoprazole does not affect P-glycoprotein, which is associated with digoxin absorption.

No interactions were observed with concomitantly administered antacids.

Interaction studies have also been conducted with concomitant administration of pantoprazole and certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions between these drugs were observed.

Medicinal products that inhibit or induce CYP2C19

CYP2C19 inhibitors such as fluvoxamine may increase the systemic exposure to pantoprazole. A dose reduction should be considered in patients receiving high doses of pantoprazole long-term or in patients with impaired liver function.

Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized via these enzyme systems.

Interaction between medicinal products and laboratory tests

False-positive results in certain urine screening tests for tetrahydrocannabinol have been reported in patients treated with pantoprazole. Alternative confirmatory testing methods should be considered to verify positive results.

Special precautions for use

Gastric malignancies

Symptomatic response to pantoprazole may mask symptoms of gastric malignancy and thus may delay its diagnosis. In the presence of any alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded.

Additional investigations should be considered if symptoms persist despite adequate therapy.

Hepatic impairment

In patients with severe hepatic impairment, liver enzymes should be monitored during therapy. If liver enzymes increase, treatment must be discontinued (see section "Method of administration and dosage").

Concomitant use with HIV protease inhibitors

Concomitant use of pantoprazole with HIV protease inhibitors such as atazanavir, whose absorption is pH-dependent, is not recommended due to a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal infections caused by bacteria

Treatment with pantoprazole may lead to a slight increase in the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesaemia

Rare cases of severe hypomagnesaemia have been reported in patients treated with PPIs such as pantoprazole for at least three months, and in most cases, for a year or longer. Hypomagnesaemia may develop unexpectedly and insidiously, with serious clinical manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Undesirable effects"). 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.

For patients requiring long-term treatment or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesaemia (e.g., diuretics), serum magnesium levels should be measured before initiating PPI therapy and periodically during treatment.

Risk of bone fractures

Long-term use (more than one year) of high-dose PPIs may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies indicate that PPIs may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Undesirable effects"), potentially life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about the signs and symptoms of these skin reactions, and closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy considered.

Subacute cutaneous lupus erythematosus (SCLE)

The use of PPIs has been associated with very rare cases of SCLE. If skin lesions develop, particularly in sun-exposed areas, and especially if accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of pantoprazole should be considered. Development of SCLE during previous treatment with a PPI may increase the risk of SCLE with subsequent use of other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumours. To avoid this interference, pantoprazole treatment should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal after the initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI therapy.

Information on excipients. Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Available data on the use of pantoprazole in pregnant women (from 300 to 1000 pregnancy outcomes) indicate no embryonal or foetal/neonatal toxicity of pantoprazole. Animal studies have shown reproductive toxicity. As a precautionary measure, pantoprazole should be avoided during pregnancy.

Breastfeeding

Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient information on excretion of pantoprazole into human breast milk, but excretion has been reported. A risk to newborns/infants cannot be excluded. Therefore, when deciding whether to discontinue breastfeeding or to discontinue/abstain from pantoprazole therapy, the benefit of breastfeeding for the child and the benefit of pantoprazole therapy for the woman should be considered.

Fertility

In animal studies, pantoprazole did not impair fertility.

Ability to influence reaction speed when driving or operating machinery

Pantoprazole has no effect or a negligible effect on reaction speed and the ability to drive vehicles or operate machinery.

Adverse reactions such as dizziness and visual disturbances may occur (see section "Undesirable effects"). In such cases, patients should not drive vehicles or operate machinery.

Method of Administration and Dosage

The drug should be administered as prescribed by a physician and under appropriate medical supervision.

Intravenous administration of pantoprazole is recommended only when oral administration is not feasible. Data are available on intravenous use for up to 7 days. Therefore, as soon as oral administration becomes possible, intravenous pantoprazole therapy should be discontinued and 40 mg of pantoprazole orally should be initiated.

Method of Administration

Adults

Gastric and duodenal ulcer, reflux esophagitis

The recommended dose is 40 mg of pantoprazole (1 vial) once daily administered intravenously.

Zollinger-Ellison syndrome and other hypersecretory conditions

For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the recommended initial dose is 80 mg of pantoprazole daily. The dose may then be titrated upwards or downwards as needed, depending on gastric acid secretion parameters. For doses exceeding 80 mg daily, the dose should be divided into two administrations. Temporary dose increases above 160 mg may be considered, but should not be used longer than necessary to achieve adequate acid control.

In cases where rapid acid reduction is required, an initial dose of 2 × 80 mg pantoprazole is sufficient for most patients to achieve the desired acid output level (<10 mEq/h) within one hour.

Transition from intravenous to oral administration should be performed as soon as the patient's clinical condition allows.

Special Patient Categories

Patients with hepatic impairment

Patients with severe liver dysfunction should not exceed a daily dose of 20 mg pantoprazole (½ vial of 40 mg pantoprazole) (see section "Special Warnings and Precautions for Use").

Patients with renal impairment

Dose adjustment is not required in patients with impaired renal function (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required for elderly patients (see section "Pharmacokinetics").

Paediatric population

The safety and efficacy of 40 mg pantoprazole for injection, powder for solution, in children under 18 years of age have not been established. Therefore, 40 mg pantoprazole for injection, powder for solution, is not recommended for use in patients under 18 years of age until further data are available.

Current available data are described in the "Pharmacokinetics" section; however, recommendations for use cannot be made.

Preparation for Administration

The ready-to-use solution is prepared in 10 mL of 0.9% sodium chloride injection solution. See preparation instructions below. The prepared solution may be administered directly or after dilution in 100 mL of 0.9% sodium chloride injection solution or 5% glucose injection solution.

After preparation, the solution must be used within 12 hours.

The medicinal product should be administered intravenously over 2–15 minutes.

Special safety precautions for disposal and handling of unused medicinal product

The solution for immediate use is prepared by adding 10 mL of 0.9% sodium chloride injection solution to the vial containing the powder. The reconstituted product should be a clear, colorless or slightly yellow solution. Glass or plastic containers may be used for dilution.

After reconstitution or dilution, chemical and physical stability has been demonstrated for 12 hours at 25°C. From a microbiological standpoint, the product should be used immediately.

Pantoprazole should not be prepared or mixed with solvents other than those specified.

The vial contents are intended for single use only. Any unused solution in the container or any product with altered appearance (e.g. cloudiness or precipitate) should be disposed of according to local requirements.

Children

Pantoprazole for injection, powder for solution, is not recommended for use in children under 18 years of age due to limited data on safety and efficacy in this age group.

Available data to date are described in the "Pharmacokinetics" section; however, recommendations for use cannot be provided.

Overdose

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is highly protein-bound, it is not readily dialyzable.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no specific antidotes or recommended specific treatments.

Adverse Reactions

Adverse reactions to medicinal products can be expected in approximately 5 % of patients.

The table below lists adverse reactions reported during the use of pantoprazole, classified according to the following frequency classification: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (frequency cannot be determined from available data).

For all adverse reactions reported in the post-marketing period, it is impossible to determine the frequency of occurrence; therefore, they are listed with the frequency term "not known".

Within each frequency category, adverse reactions are listed in order of decreasing severity.

System organ class	Frequency	Adverse reactions
Blood and lymphatic system disorders	uncommon	agranulocytosis
	very rare	leukopenia, thrombocytopenia, pancytopenia
Immune system disorders	uncommon	hypersensitivity reactions (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutrition disorders	uncommon	hyperlipidemia and increased lipid levels (triglycerides, cholesterol), change in body weight
	not known	hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia1, hypokalemia1
Psychiatric disorders	uncommon	sleep disorders
	uncommon	depression (including exacerbation)
	very rare	disorientation (including exacerbation)
	not known	hallucinations, confusion (particularly in patients predisposed to such disorders, and exacerbation of these symptoms if previously present)
Nervous system disorders	uncommon	headache, dizziness
	uncommon	taste disturbances
	not known	paraesthesia
Eye disorders	uncommon	visual disturbances/blurred vision
Gastrointestinal disorders	common	fundic gland polyps (benign)
	uncommon	diarrhea, nausea, vomiting, flatulence, constipation, dry mouth, abdominal pain and discomfort
	not known	microscopic colitis
Hepatobiliary disorders	uncommon	elevated liver enzymes (transaminases, γ-GT)
	uncommon	elevated bilirubin levels
	not known	hepatocellular injury, jaundice, hepatocellular failure
Skin and subcutaneous tissue disorders	uncommon	rash, exanthema, pruritus
	uncommon	urticaria, angioneurotic edema
	not known	Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions")
Musculoskeletal and connective tissue disorders	uncommon	fractures of the femur, wrist or spine (see section "Special precautions")
	uncommon	arthralgia, myalgia
	not known	muscle spasms2
Renal and urinary disorders	not known	tubulointerstitial nephritis (with possible development of renal failure)
Reproductive system and breast disorders	uncommon	gynecomastia
General disorders and administration site conditions	common	thrombophlebitis at injection site
	uncommon	asthenia, fatigue, malaise
	uncommon	increased body temperature, peripheral edema

1Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").

2Muscle spasms as a result of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after reconstitution

After reconstitution or reconstitution and dilution, chemical and physical stability has been demonstrated under conditions of use of the medicinal product for 12 hours at 25 °C.

From a microbiological standpoint, the product should be used immediately.

If not used immediately, the duration and conditions of storage during use are the responsibility of the user.

Storage conditions

Keep out of the reach of children.

Store at a temperature not exceeding 30 °C in the original packaging to protect from light.

For storage conditions of the reconstituted and diluted medicinal product, see the section "Shelf life" after reconstitution.

Incompatibilities

This medicinal product should not be mixed with other medicinal products except those specified in the section "Dosage and administration" ("Special safety precautions for disposal and handling of unused medicinal product").

Packaging

Powder for solution for injection in a vial. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer

Laboratorios Normon S.A.

Manufacturer's address and place of business

Ronda de Valdecarrizo 6, Tres Cantos, 28760, Spain