Zigosis

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZYGOSIS (ZYGOSIS)

Composition:

Active substance: pantoprazole;

1 vial contains 45.11 mg of pantoprazole sodium sesquihydrate, equivalent to 40 mg of pantoprazole;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilized powder for solution for injection.

Main physico-chemical properties: lyophilized powder of white or almost white color.

Reconstituted solution: clear yellowish solution, free from visible particles.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Pantoprazole.

ATC code A02BC02.

Pharmacological Properties.

Pharmacodynamics.

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 hydrochloric acid production in the stomach. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. Pantoprazole, like other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby 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 hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term treatment, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. However, excessive elevation occurs only in isolated cases. As a consequence, in some cases during prolonged treatment, a mild or moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach may be observed (similar to adenomatoid hyperplasia). However, according to available studies, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal experiments, has not been observed in humans.

Based on animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, due to reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect diagnostic test results for neuroendocrine tumors. Available published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.

Pharmacokinetics.

Absorption

Pantoprazole is rapidly absorbed, and maximum plasma concentration (C_max) is achieved after a single oral dose of 40 mg. On average, peak serum concentration of approximately 2–3 µg/mL is reached about 2.5 hours after administration; serum concentration remains stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or peak serum concentration, and therefore does not affect bioavailability. However, food intake increases only the variability of the lag time.

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; other metabolic pathways include oxidation via CYP3A4.

Elimination

The terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been reported. 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 (approximately 80%), with the remainder excreted in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups

Poor metabolizers. Approximately 3% of Europeans lack functionally active CYP2C19 enzyme and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely catalyzed primarily by the CYP3A4 enzyme. After a single 40 mg dose, mean AUC was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). Mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage adjustment recommendations are required for pantoprazole administration in patients with renal impairment (including dialysis patients). As in healthy individuals, the elimination half-life of pantoprazole in these patients is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination remains rapid, and no accumulation occurs.

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

Elderly patients. The slight increase in AUC and C_max 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.

• Moderate to severe reflux esophagitis.
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger–Ellison syndrome and other hypersecretory conditions.

Contraindications.

Hypersensitivity to the active substance, to benzimidazole derivatives, or to any component of the medicinal product. Pantoprazole, like other proton pump inhibitors (PPIs), is contraindicated with atazanavir.

Interaction with other medicinal products and other forms of interactions.

Medicinal products whose absorption depends on pH. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (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), whose absorption is pH-dependent, is not recommended due to a significant reduction in their bioavailability (see section "Special precautions for use").

If concomitant use of HIV protease inhibitors with PPIs cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary.

Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use 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 prolonged prothrombin time in patients receiving concomitant PPIs and warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary when these drugs are used together.

Methotrexate. There have been reports that concomitant administration of high-dose methotrexate (e.g., 300 mg) and PPIs increases methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized by the same enzyme system cannot be ruled out.

Results from several studies on potential interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), nor does it affect P-glycoprotein, which is involved in digoxin absorption.

No interaction was observed with concomitantly administered antacids.

Studies have also been conducted on the interaction of pantoprazole with certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions were observed between these drugs.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in patients with hepatic impairment. 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.

Special precautions for use.

Malignant gastric neoplasms. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in case of suspected or confirmed gastric ulcer, malignancy must be ruled out.

If symptoms persist despite adequate therapy, further investigation is required.

Hepatic impairment

Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the drug must be discontinued (see section "Dosage and administration").

HIV protease inhibitors

PPIs are not recommended for concomitant use with HIV protease inhibitors (such as atazanavir), whose absorption is pH-dependent, 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

Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug slightly increases the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Sodium. The drug contains less than 1 mmol of sodium (23 mg) per vial, i.e., it is essentially "sodium-free."

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients treated with PPIs, such as pantoprazole, for at least 3 months, and in most cases, for over a year. Serious clinical manifestations of hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. In most cases, patients' condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients planned for long-term therapy or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), measurement of magnesium levels is recommended before initiating PPI treatment and periodically during therapy.

Bone fractures

PPIs, particularly when used at high doses and for prolonged periods (more than 1 year), are associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPIs 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 adequate amounts of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE). PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, especially in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Zigosys should be considered. Development of SCLE during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid this interference, treatment with Zigosys should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI therapy.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetal/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Zigosys in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. A risk to newborns or infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with Zigosys should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment with Zigosys for the woman.

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 reaction speed when driving or operating machinery. However, the possible development 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.

Method of Administration and Dosage

Adults. The drug should be used by adults only as prescribed and under direct medical supervision.

Intravenous administration of pantoprazole is recommended only when oral administration is not possible. Data are available on intravenous treatment duration of up to 7 days. Therefore, whenever clinically feasible, a transition from intravenous administration of Zigosis to oral administration of pantoprazole preparations should be implemented.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer

The recommended dose is 40 mg of pantoprazole (1 vial) per day administered intravenously.

Treatment of Zollinger–Ellison syndrome and other hypersecretory conditions

For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the recommended initial dose of the medicinal product Zigosis is 80 mg per day. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. A temporary increase in the dose of pantoprazole up to 160 mg may be considered, but the duration of use should be limited only to the period necessary for adequate control of acid secretion.

If rapid reduction of acidity is required, an initial dose of 2×80 mg is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Preparation for Use

Dissolve the powder in 10 mL of 0.9% sodium chloride solution provided in the vial. The solution may be administered directly or after dilution with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass bottles.

After reconstitution, the chemical and physical stability of the drug is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately.

The medicinal product Zigosis must not be prepared or mixed with solvents other than those specified above.

Intravenous administration of the drug should be performed over 2–15 minutes.

The vial is intended for single use only. Prior to administration, vials should be visually inspected (particularly for changes in color or presence of precipitate). The reconstituted solution should be clear and yellowish in color. Any unused portion or drug with altered physicochemical properties (e.g., change in color, presence of precipitate) must be disposed of according to local regulations.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of the medicinal product Zigosis, lyophilized powder 40 mg) (see section "Special Warnings and Precautions for Use").

Renal impairment. Dose adjustment is not required in patients with renal impairment. However, Zigosis should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are currently no data on efficacy and safety of such use in this patient population.

Elderly patients do not require dose adjustment.

Children.

Zigosis, lyophilized powder for injection solution, is not recommended for use in children (under 18 years of age), as data on safety and efficacy in this age group are limited. Available pharmacokinetic data are described in the "Pharmacokinetics" section; however, dosage recommendations cannot be provided.

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is extensively protein-bound, it is not a drug that can be readily eliminated by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no recommendations for specific antidotal therapy.

Adverse Reactions

Adverse reactions occurred in approximately 5% of patients. The most common adverse reactions were thrombophlebitis at the injection site. Diarrhea and headache occurred in approximately 1% of patients.

Adverse reactions are classified by frequency of occurrence as follows:

• Common (> 1/100 and < 1/10)
• Uncommon (> 1/1000 and < 1/100)
• Rare (> 1/10,000 and < 1/1000)
• Very rare (< 1/10,000)
• Frequency not known (cannot be estimated from 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); change in body weight
Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia¹, hypokalemia

Psychiatric disorders

Uncommon: sleep disorders
Rare: depression (including exacerbation)
Very rare: confusion (including exacerbation)
Frequency not known: hallucinations, confusion (especially in patients predisposed to such disorders), as well as exacerbation of these symptoms if previously present

Nervous system disorders

Uncommon: headache, dizziness
Rare: taste disturbances
Frequency 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
Frequency not known: microscopic colitis

Hepatobiliary disorders

Uncommon: increased liver enzymes (transaminases, γ-GT)
Rare: increased bilirubin levels
Frequency not known: hepatocellular injury, jaundice, hepatocellular failure

Skin and subcutaneous tissue disorders

Uncommon: skin rash, exanthema, pruritus
Rare: urticaria, angioneurotic edema
Frequency not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions")

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the femur, wrist, spine (see section "Special precautions")
Rare: arthralgia, myalgia
Frequency not known: muscle spasms²

Renal and urinary disorders

Frequency not known: interstitial nephritis (with possible development of renal failure)

Reproductive system and breast disorders

Rare: gynecomastia

General disorders

Common: thrombophlebitis at the injection site
Uncommon: asthenia, fatigue, malaise
Rare: increased body temperature, peripheral edema

¹ Hypocalcemia concurrent with hypomagnesemia
² Muscle spasms as a result of electrolyte imbalance

Shelf life. 2 years

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.
Lyophilized powder for solution for injection, 40 mg; 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.
Polifarma Ilac San. Ve Tic. A.S.

Manufacturer's address.
Vakıflar OSB Mahallesi, Sanayi Caddesi, No: 22/1 Ergene/Tekirdag, Turkey