Heliprosan

№ _____________________ INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HELIPROZAN (HELIPROZAN)

Composition:

Active substance: vonoprazan;

One film-coated tablet contains vonoprazan fumarate 13.36 mg or 26.72 mg, equivalent to vonoprazan 10 mg or 20 mg;

Excipients: mannitol, microcrystalline cellulose, hydroxypropylcellulose, fumaric acid, sodium croscarmellose, magnesium stearate;

Film coating of the 10 mg tablet: hypromellose, polyethylene glycol, titanium dioxide (E 171), talc, iron oxide yellow (E 172);

Film coating of the 20 mg tablet: hypromellose, polyethylene glycol, titanium dioxide (E 171), iron oxide red (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: round, biconvex, film-coated tablets without a score line, coated with a film ranging in color from light yellow to orange-yellow;

20 mg tablets: oval, biconvex, film-coated tablets without a score line, coated with a film ranging in color from light pink to pink.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Vonoprazan. ATC code A02BC08.

Pharmacological Properties

Pharmacodynamics

Vonoprazan is a potassium-competitive acid blocker and does not require acid activation. It competitively and reversibly inhibits H+, K+-ATPase with respect to potassium ions. Vonoprazan remains at the acid-producing sites in gastric parietal cells for a prolonged period, resulting in sustained suppression of gastric acid secretion. Thus, the drug significantly reduces the risk of injury to the mucosa of the upper gastrointestinal tract.

Vonoprazan does not exhibit anti-Helicobacter activity and does not inhibit H. pylori or H. pylori urease. The role of vonoprazan in H. pylori eradication lies in increasing gastric pH, which likely enhances the antibacterial activity of amoxicillin, clarithromycin, and metronidazole used in combination therapy.

Pharmacokinetics

Absorption. Pharmacokinetic parameters and blood concentration profiles of vonoprazan in healthy men after single oral administration of a 20 mg dose on an empty stomach and after food intake were as follows: AUC0–48 — 222.1±69.7 ng×h/mL, T1/2 — 7.7±1.0 h, Cmax — 24.3±6.6 ng/mL, Tmax — 1.5 (1.0, 3.0) h. The effect of food intake on pharmacokinetics was almost negligible.

With repeated administration of the drug for 7 days at doses of 10 mg or 20 mg once daily, AUC and Cmax of vonoprazan on Day 7 in healthy men increased with dose escalation, and this increase was slightly greater than dose-proportional. Blood concentrations of vonoprazan remained stable from Day 3 to Day 7 of administration, suggesting steady state is reached by Day 3. Additionally, based on accumulation assessment after repeated dosing, pharmacokinetic parameters AUC and T1/2 indicate that the pharmacokinetics of vonoprazan are time-independent.

Distribution. [14C]Vonoprazan added to human plasma at concentrations of 0.1–10 µg/mL showed protein binding of 85.2–88.0% (in vitro).

Metabolism. Vonoprazan is primarily metabolized by CYP3A4 and partially by CYP2B6, CYP2C19, and CYP2D6. Metabolism also occurs via sulfotransferase SULT2A1 (in vitro). Vonoprazan exhibits time-dependent inhibitory effects on CYP2B6, CYP2C19, and CYP3A4/5 (in vitro). Furthermore, vonoprazan concentration-dependently slightly induces CYP1A2 but has almost no effect on the activity of CYP2B6 and CYP3A4/5 (in vitro).

Excretion. After oral administration of radiolabeled vonoprazan at a dose of 15 mg in healthy men, 98.5% of the administered radioactivity was excreted within 168 hours, with 67.4% in urine and 31.1% in feces.

Renal impairment. Compared to patients with normal renal function, patients with mild, moderate, and severe renal impairment showed 1.3–2.4 times higher AUC0–∞ and 1.2–1.8 times higher Cmax of vonoprazan, with worsening renal function associated with increased values of these parameters. In patients with end-stage renal disease, AUC0–∞ and Cmax were 1.3 and 1.2 times higher, respectively, compared to patients with normal renal function.

Hepatic impairment. Compared to patients with normal hepatic function, patients with mild, moderate, and severe hepatic impairment showed 1.2–2.6 times higher AUC0–∞ and 1.2–1.8 times higher Cmax of vonoprazan.

Vonoprazan in combination with clarithromycin. In healthy adult men who received 40 mg of vonoprazan 30 minutes after breakfast on Day 1 and Day 8, and 500 mg of clarithromycin twice daily before meals from Day 3 to Day 9, AUC0–∞ and Cmax of vonoprazan increased 1.6 and 1.4 times, respectively, compared to administration without clarithromycin.

Vonoprazan in combination with amoxicillin hydrate and clarithromycin. In healthy adult men who received 20 mg of vonoprazan, 750 mg of amoxicillin, and 400 mg of clarithromycin twice daily for 7 days, AUC0–12 and Cmax of vonoprazan increased 1.8 and 1.9 times, respectively, while AUC0–12 and Cmax of clarithromycin increased 1.5 and 1.6 times, respectively.

Vonoprazan in combination with low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). In healthy adult men who received 40 mg of vonoprazan together with 100 mg aspirin or 60 mg sodium loxoprofen, 25 mg sodium diclofenac, or 10 mg meloxicam twice daily for 7 days, no significant effect of vonoprazan on the pharmacokinetics of aspirin or NSAIDs, or of these drugs on the pharmacokinetics of vonoprazan, was observed.

Vonoprazan in combination with midazolam. In healthy adult men who received a single 2 mg dose of midazolam in the morning and evening on Day 1 and Day 9, and 20 mg of vonoprazan twice daily from Day 2 to Day 10, AUC0–∞ and Cmax of midazolam increased 1.9 times compared to administration without vonoprazan.

Clinical Characteristics

Indications

• For the treatment of gastric and duodenal ulcers, reflux esophagitis, and for the prevention of recurrence of gastric or duodenal ulcer during low-dose acetylsalicylic acid therapy; for the prevention of recurrence of gastric or duodenal ulcer during nonsteroidal anti-inflammatory drug (NSAID) therapy;
• as an adjunctive therapy for H. pylori eradication in the following conditions: gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, after endoscopic treatment of early gastric cancer, and H. pylori-associated gastritis.

Contraindications

• Hypersensitivity to vonoprazan or to any excipient of the medicinal product;
• concomitant use of atazanavir sulfate, nelfinavir, or rilpivirine hydrochloride.

Interaction with other medicinal products and other forms of interaction

Vonoprazan is predominantly metabolized in the liver by cytochrome P450 enzymes CYP3A4, and to a lesser extent by CYP2B6, CYP2C19, and CYP2D6. In addition, the drug weakly inhibits the CYP3A4 enzyme.

The effect of vonoprazan on gastric acid secretion may increase or decrease the absorption of concomitant medications.

Concomitant use of the following drugs is contraindicated

Atazanavir sulfate. Suppression of gastric acid secretion by vonoprazan may reduce the solubility of atazanavir sulfate, thereby potentially decreasing its blood concentration and weakening its efficacy.

Rilpivirine hydrochloride. Reduced absorption of rilpivirine hydrochloride may occur, which could lead to decreased plasma concentrations and reduced effectiveness.

Caution is required when co-administering the following drugs

CYP3A4 inhibitors such as clarithromycin and others. Concomitant use may increase the blood concentration of vonoprazan.

Digoxin, methyldigoxin. Suppression of gastric acid secretion may slow down the hydrolysis of digoxin, leading to increased blood concentration and enhanced effect.

Itraconazole; tyrosine kinase inhibitors such as gefitinib, neratinib, erlotinib; nelfinavir mesylate. Concomitant use may lead to decreased blood concentrations of these drugs and reduced efficacy.

Drugs metabolized by CYP3A4: midazolam and others. Due to weak inhibition of CYP3A4 by vonoprazan, metabolism of these drugs may be slowed, resulting in enhanced pharmacological effects.

Special precautions for use

During prolonged administration of the medicinal product, patient monitoring is required, including regular endoscopic examinations. Maintenance therapy should be avoided in patients who do not require such treatment, and should only be prescribed if there is a risk of recurrence or relapse. In cases of prolonged stable remission with no risk of relapse, dose reduction to 10 mg or intermittent dosing should be considered.

Patients with renal impairment

Heliprazan should be prescribed with caution in patients with kidney disease, as impaired renal function may lead to increased drug concentration in the blood due to delayed elimination.

Patients with hepatic impairment

Heliprazan should be prescribed with caution in patients with liver disease, as impaired liver function may lead to increased drug concentration in the blood due to delayed metabolism and elimination.

Elderly patients

In elderly individuals, functional capacity of the liver, kidneys, and other physiological systems is generally reduced; therefore, Heliprazan should be administered with caution.

Benign gastric polyps have been reported during long-term use of vonoprazan.

Heliprazan may mask symptoms of gastric cancer; therefore, the absence of gastric malignancy should be confirmed prior to initiating treatment.

Treatment with proton pump inhibitors increases the risk of fractures of the hip, wrist, and spine associated with osteoporosis. In particular, fracture risk was increased in patients receiving high-dose treatment over a prolonged period (more than 1 year).

Furthermore, proton pump inhibitors increase the risk of gastrointestinal infection caused by Clostridium difficile.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Heliprazan should be used only if the therapeutic benefit outweighs the potential risk to the pregnant or potentially pregnant woman. Animal studies (in rats) have shown that administration of vonoprazan at high doses (40 mg/day) increases exposure (AUC) by approximately 28 times and leads to reduced fetal and placental weight, external (anal stenosis and tail abnormalities) and internal (ventricular septal defect and subclavian artery abnormalities) malformations.

Breastfeeding

Heliprazan should be avoided in women who are breastfeeding. When deciding whether to continue or discontinue breastfeeding, the therapeutic benefit to the woman and the benefits of breastfeeding to the child should be taken into account. According to animal studies (in rats), vonoprazan passes into breast milk.

Ability to affect reaction speed when driving or operating machinery
There is no information available on the effects of vonoprazan on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Peptic ulcer of the stomach, duodenum

The usual dose for adults is 20 mg of Heliprazan orally once daily. The medicinal product is usually administered for up to 8 weeks for gastric ulcer and up to 6 weeks for duodenal ulcer.

Gastroesophageal reflux disease (GERD)

The usual dose for adults is 20 mg of Heliprazan orally once daily. The medicinal product is usually administered for up to 4 weeks; however, if the effect is insufficient, treatment may be extended up to 8 weeks.

For maintenance therapy of recurrent reflux esophagitis, administer 10 mg once daily orally; in case of inadequate efficacy, 20 mg once daily may be used.

Prevention of recurrence of peptic ulcer of the stomach or duodenum during low-dose aspirin therapy

The usual dose for adults is 10 mg of Heliprazan orally once daily.

Prevention of recurrence of peptic ulcer of the stomach or duodenum during nonsteroidal anti-inflammatory drug (NSAID) therapy

The usual dose for adults is 10 mg of Heliprazan orally once daily.

Adjunctive therapy for eradication of H. pylori

Typically, adults should receive concomitantly 20 mg of Heliprazan, 750 mg of amoxicillin trihydrate, and 200 mg of clarithromycin orally twice daily for 7 days. The dose of clarithromycin may be increased if necessary; however, the upper limit is 400 mg twice daily. In case of failure of triple therapy for H. pylori eradication using a proton pump inhibitor, amoxicillin trihydrate, and clarithromycin, alternative treatment may be prescribed for adults: Heliprazan 20 mg, amoxicillin trihydrate 750 mg, and metronidazole 500 mg, all administered orally twice daily for 7 days.

Children. Clinical trials in children have not been conducted.

Overdose

There is no information regarding overdose with vonoprazan. Vonoprazan is not removed from systemic circulation by hemodialysis. In case of overdose, treatment should be symptomatic and supportive.

Adverse Reactions

Since the following adverse effects may occur, careful monitoring is required, and appropriate measures such as discontinuation of vonoprazan should be taken if any of them are observed.

General disorders: Frequency unknown — shock.

Immune system disorders: 0.1% – <5% — rash, swelling; frequency unknown — anaphylaxis.

Blood system disorders: 0.1% – <5% — eosinophilia; frequency unknown — acute pancytopenia, agranulocytosis, leukopenia, thrombocytopenia.

Hepatobiliary disorders: 0.1% – <5% — increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transferase; frequency unknown — liver function abnormalities.

Skin and subcutaneous tissue disorders: Frequency unknown — toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Gastrointestinal disorders: ≥5% — diarrhea (during H. pylori eradication); 0.1% – <5% — constipation, diarrhea, abdominal fullness, nausea, taste disturbance, stomatitis, abdominal discomfort, bloating; frequency unknown — severe colitis with bloody stools, e.g. pseudomembranous colitis. When amoxicillin trihydrate and clarithromycin are used for H. pylori eradication, severe colitis with bloody stools may occur. If abdominal pain or severe diarrhea occurs, the drug should be discontinued immediately and appropriate measures taken.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business. 74, Kyrylivska St., Kyiv, 04080, Ukraine.