Geerdin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEERDIN (GEERDIN)

Composition:

Active substance: rabeprozole;

One enteric-coated tablet contains sodium rabeprozole 10 mg or 20 mg;

Excipients:

for the 10 mg dose: light magnesium oxide, mannitol (E 421), hypromellose, talc, sodium croscarmellose, Sancel pH 102, magnesium stearate, ethylcellulose, methylene chloride, propylene glycol, hypromellose phthalate, diethyl phthalate, polyethylene glycol 6000, titanium dioxide (E 171), iron oxide/yellow iron oxide (E 172);

for the 20 mg dose: light magnesium oxide, mannitol (E 421), hypromellose, talc, sodium croscarmellose, Sancel pH 102, magnesium stearate, ethylcellulose, methylene chloride, propylene glycol, hypromellose phthalate, diethyl phthalate, polyethylene glycol 6000, titanium dioxide (E 171), iron oxide/red iron oxide (E 172).

Pharmaceutical form. Enteric-coated tablets.

Main physico-chemical properties:
10 mg dose: light yellow (brownish), round, biconvex, enteric-coated tablets;
20 mg dose: red-brown, round, biconvex, enteric-coated tablets.

Pharmacotherapeutic group. Drugs affecting the digestive tract and metabolism. Drugs used in disorders related to acid imbalance. Antiulcer agents and drugs for treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprozole. ATC code A02BC04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Sodium rabeprozole belongs to the class of antisecretory compounds substituted benzimidazoles. It has no anticholinergic properties and is not a histamine H2-receptor antagonist, but it inhibits gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme at the secretory surface of gastric parietal cells (the acid, or proton pump). The effect is dose-dependent and results in inhibition of both basal and stimulated acid secretion, regardless of the stimulus.

Sodium rabeprozole has weakly basic properties and is rapidly absorbed at all dosage levels, concentrating in parietal cells. Sodium rabeprozole is converted into its active sulfenamide form via protonation and thereby reacts with accessible cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg sodium rabeprozole, antisecretory effect is observed within 1 hour and reaches maximum within 2–4 hours. The inhibition of basal acid output and food-stimulated acid secretion 23 hours after the first dose of sodium rabeprozole was 69% and 82%, respectively, with the duration of effect lasting up to 48 hours. The efficacy of sodium rabeprozole in suppressing acid secretion slightly increases during daily administration of one tablet, but stable suppression of acid secretion is achieved within 3 days after initiation of treatment. After discontinuation of sodium rabeprozole, secretory activity returns to normal within 2–3 days.

Reduction of gastric acidity, independent of any factors, including proton pump inhibitors such as rabeprozole, increases the number of bacteria in the gastrointestinal tract. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile.

Effect on serum gastrin concentration. Serum gastrin concentration may increase during the first weeks of therapy but typically returns to baseline levels within 1–2 weeks after discontinuation of treatment.

Other effects. Currently, there are no data on systemic effects on the central nervous system (CNS), cardiovascular, or respiratory systems caused by sodium rabeprozole. Oral administration of 20 mg sodium rabeprozole daily for 2 weeks did not affect thyroid function, carbohydrate metabolism, or blood concentrations of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone, or growth hormone.

Studies in healthy volunteers showed no clinically significant interactions between rabeprozole and amoxicillin.

Rabeprozole does not negatively affect plasma levels of amoxicillin and clarithromycin when administered concomitantly for the purpose of eradicating H. pylori infection in the upper gastrointestinal tract.

Pharmacokinetics.

Absorption. Geeridin – enteric-coated tablets of sodium rabeprozole.

Absorption of sodium rabeprozole begins only after the tablet passes through the stomach. Sodium rabeprozole is rapidly absorbed from the intestine. Peak plasma concentration of rabeprozole is reached approximately 3.5 hours after a 20 mg dose. Peak plasma concentration (Cmax) and AUC of rabeprozole show a linear relationship within the dose range of 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%, primarily due to first-pass metabolism. Furthermore, bioavailability does not increase with repeated administration of sodium rabeprozole. In healthy volunteers, the plasma half-life is approximately 1 hour (ranging from 0.7 to 1.5 hours), and total clearance is estimated at 283±98 mL/min.

Distribution. In humans, the plasma protein binding of sodium rabeprozole is approximately 97%.

Metabolism and excretion. Like other members of the proton pump inhibitor class, rabeprozole is metabolized by the hepatic cytochrome P450 (CYP450) drug metabolism system. In vitro studies with human liver microsomes have shown that sodium rabeprozole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprozole does not induce or inhibit CYP3A4. However, since in vitro findings cannot always be extrapolated to in vivo situations, these results suggest that interaction between rabeprozole and cyclosporine is not expected. In humans, the main metabolites present in plasma are thioether (M1) and carboxylic acid (M6), while minor metabolites present at low concentrations include sulfone (M2), dimethylthioether (M4), and mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has slight antisecretory activity, but it is not present in plasma.

After a single 20 mg dose of 14C-labeled sodium rabeprozole, unchanged rabeprozole was not detected in urine. Approximately 90% of the administered dose was eliminated in urine, primarily as two metabolites: mercapturic acid conjugate (M5) and carboxylic acid (M6); the remainder of the dose was recovered in feces.

Gender differences. Since the single 20 mg dose of sodium rabeprozole is adjusted according to body weight and height, gender differences do not affect pharmacokinetic parameters.

Renal impairment. In patients with end-stage chronic renal failure undergoing maintenance hemodialysis (creatinine clearance <5 mL/min/1.73 m²), the disposition of sodium rabeprozole was very similar to that in healthy volunteers. AUC and Cmax of sodium rabeprozole were increased by approximately 35% compared to healthy volunteers. Mean elimination half-life was 0.82 hours in healthy volunteers, 0.95 hours in hemodialysis patients, and 3.6 hours in post-dialysis patients. Drug clearance in patients with renal impairment on hemodialysis was approximately twice that in healthy volunteers.

Hepatic impairment. After a single 20 mg dose of sodium rabeprozole in patients with moderate chronic liver disease, AUC was doubled and the elimination half-life of rabeprozole was increased 2–3 times compared to healthy volunteers. Thus, with daily administration of 20 mg for 7 days, AUC should increase by at least 1.5 times and changes in peak plasma concentrations (Cmax) by up to 1.2 times. The elimination half-life of sodium rabeprozole in patients with liver disease was 12.3 hours compared to 2.1 hours in healthy volunteers. Pharmacodynamic response (gastric content pH-metry) was similar between the two patient groups in terms of therapeutic parameters.

Elderly patients. Elimination of sodium rabeprozole is slightly reduced in elderly patients. After 7 days of 20 mg daily administration in elderly subjects, AUC was approximately twice as high, Cmax increased by 60%, and T1/2 increased by 30% compared to young healthy volunteers. However, it should be noted that there are no signs of sodium rabeprozole accumulation.

Polymorphism of CYP2C19. After 7 days of treatment with 20 mg sodium rabeprozole daily in patients with slow CYP2C19 metabolism, AUC (area under the curve) and T1/2 (elimination half-life) were approximately 1.9 and 1.6 times higher, respectively, compared to patients with rapid metabolism; meanwhile, Cmax increased by only 40%.

Chromogranin A. During treatment with antisecretory drugs, plasma gastrin concentration increases in response to reduced acid secretion. Chromogranin A (CgA) also increases due to reduced gastric acidity. Elevated CgA levels may interfere with testing for neuroendocrine tumors. To avoid false results, treatment with rabeprozole should be discontinued 5–14 days before measuring CgA.

Clinical characteristics.

Indications.

• Active duodenal ulcer;
• active benign gastric ulcer;
• erosive or ulcerative gastroesophageal reflux disease (GERD);
• long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD);
• symptomatic treatment of mild to very severe gastroesophageal reflux disease (symptomatic treatment of GERD);
• Zollinger–Ellison syndrome;
• in combination with appropriate antibacterial therapeutic regimens for eradication of Helicobacter pylori (H. pylori) in patients with gastric and duodenal peptic ulcers.

Contraindications.

Hypersensitivity to sodium rabeprazole, substituted benzimidazoles, or any other component of the drug.

Pregnancy or breastfeeding period.

Interaction with other medicinal products and other forms of interactions.

CYP-450 system

Sodium rabeprazole is metabolized by the hepatic enzyme system CYP-450, specifically CYP2C19 and CYP3A4.

Studies have shown that sodium rabeprazole has no pharmacokinetic or clinically significant interactions with warfarin, phenytoin, theophylline, or diazepam, each of which is metabolized by CYP-450.

Interactions caused by inhibition of gastric acid secretion

Sodium rabeprazole causes strong and prolonged reduction in gastric acid production. Therefore, rabeprazole may interact with drugs whose absorption depends on the pH of gastric contents. Concomitant administration of sodium rabeprazole and ketoconazole or itraconazole may lead to decreased plasma concentrations of the latter, while administration with digoxin may lead to increased digoxin concentration. Thus, individual patients receiving these drugs together with Geerdin should be monitored by a physician to determine the need for dose adjustment.

Antacids

During clinical trials, patients took antacids as needed concomitantly with sodium rabeprazole; in a specific study, no interaction between sodium rabeprazole and antacids such as aluminum or magnesium hydroxide was observed.

Atazanavir

Concomitant administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers led to a significant reduction in atazanavir exposure. Atazanavir absorption is pH-dependent. Although no studies have been conducted, similar results are expected with other proton pump inhibitors. Proton pump inhibitors, including rabeprazole, should not be used in combination with atazanavir (see section "Special precautions for use").

Methotrexate

Case reports, published data from population pharmacokinetic studies, and retrospective analyses suggest that concomitant use of methotrexate and proton pump inhibitors (particularly at high doses) may lead to increased serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal studies have been conducted.

Clopidogrel

Concomitant administration of clopidogrel and rabeprazole in healthy volunteers had no clinically significant effect on concentrations of the active metabolite of clopidogrel. Dose adjustment is not required.

Food

Studies have shown that consumption of low-fat food does not affect the absorption of sodium rabeprazole. Administration of sodium rabeprazole with fatty food may delay absorption by 4 hours or more, but maximum concentration and extent of absorption remain unchanged.

Cyclosporine

In vitro studies have shown that sodium rabeprazole inhibits cyclosporine metabolism. This level of inhibition is comparable to that of omeprazole.

Table 1

Special precautions for use.

Hypersensitivity.

Caution should be exercised when prescribing rabeprozole to patients with known hypersensitivity to drugs. The risk of developing cross-hypersensitivity reactions with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Use in elderly patients

Sodium rabeprozole is metabolized exclusively in the liver. Since physiological liver function may decline with age, adverse reactions may occur in elderly patients. Therefore, elderly patients should be monitored closely and dosing recommendations and treatment duration guidelines should be strictly followed.

General recommendations

Symptomatic improvement with rabeprozole therapy does not exclude the presence of gastric or esophageal malignancy; therefore, the presence of malignant tumors should be ruled out before initiating Geerdin.

Patients undergoing long-term treatment (particularly those treated for more than one year) should be regularly monitored.

Patients should be advised that Geerdin tablets must not be chewed or crushed, but should be swallowed whole.

Geerdin is not recommended for use in children, as there is no experience with use in this patient group.

Blood disorders

Post-marketing reports have described blood abnormalities (thrombocytopenia and neutropenia). In most cases, no other etiology was identified; blood changes were uncomplicated and resolved after discontinuation of rabeprozole.

Abnormal liver enzyme values have been observed both during clinical trials and in the post-marketing period. In most cases, no other etiology was identified; blood changes were uncomplicated and resolved after discontinuation of rabeprozole.

Hepatic impairment

In a dedicated study, no significant difference in the frequency of adverse effects was observed in patients with mild or moderate hepatic impairment receiving sodium rabeprozole compared to the control group matched for sex and age. Physicians should exercise caution when prescribing Geerdin at the beginning of therapy to patients with severe hepatic impairment, as there are no clinical data on the use of sodium rabeprozole in this patient group.

During treatment with Geerdin, periodic hematological and biochemical testing is recommended.

Concomitant use of atazanavir and Geerdin is not recommended (see section "Interaction with medicinal products and other types of interactions").

Renal function impairment

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking rabeprozole. It may occur at any time during rabeprozole therapy (see section "Adverse reactions") and may progress to renal failure.

If TIN is suspected, rabeprozole should be discontinued and appropriate treatment initiated immediately.

Gastrointestinal infection risk

Treatment with proton pump inhibitors, including sodium rabeprozole, may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile (see section "Pharmacodynamics").

Fracture risk

Proton pump inhibitors, particularly when used at high doses and for prolonged periods (more than 1 year), may increase the risk of fractures of the hip, wrist, and spine, predominantly in elderly patients or patients with other existing risk factors. Observational studies suggest that proton pump inhibitors may increase the overall fracture risk by 10–40%. The risk may also be elevated due to other factors. Patients at risk of osteoporosis should receive appropriate treatment and take vitamin D and calcium supplements.

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors for at least 3 months, in most cases for over a year. Severe manifestations of hypomagnesemia may include weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. In most patients, hypomagnesemia resolved after discontinuation of proton pump inhibitors and with magnesium replacement therapy.

Patients undergoing long-term treatment or those receiving concomitant therapy with proton pump inhibitors and drugs such as digoxin or other agents that may cause hypomagnesemia (e.g., diuretics) should have their blood magnesium levels monitored before starting treatment and periodically during therapy.

Concomitant use with methotrexate

Published data suggest that concomitant use of proton pump inhibitors and methotrexate (mainly at high doses) may increase methotrexate or its metabolite levels in blood serum, potentially leading to methotrexate-related toxicity. When high-dose methotrexate is required, discontinuation of proton pump inhibitor therapy should be considered.

Effect on vitamin B12 absorption

Sodium rabeprozole, like all agents that suppress gastric acid secretion, 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 treatment, or in the presence of relevant clinical symptoms.

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 accompanied by arthralgia, patients should seek immediate medical attention, and physicians should consider discontinuing Geerdin therapy. Subacute cutaneous lupus erythematosus following prior treatment with a proton pump inhibitor may increase the risk of developing subacute cutaneous lupus erythematosus upon use of other proton pump inhibitors.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with testing for neuroendocrine tumors. To avoid false results, treatment with rabeprozole should be discontinued at least 5 days before measuring CgA (see section "Pharmacokinetics"). If CgA and gastrin levels have not returned to reference ranges after initial testing, the test should be repeated 14 days after discontinuation of rabeprozole.

Thyroid function

Monitoring of thyroid function is recommended during Geerdin therapy.

Special considerations for breath testing

Results of C-urea breath tests may be falsely negative during treatment with proton pump inhibitors such as rabeprozole, and antibiotics such as amoxicillin, clarithromycin, and metronidazole. Therefore, breath tests to detect Helicobacter pylori should not be performed earlier than 4 weeks after discontinuation of these agents.

Treatment of non-erosive reflux disease with rabeprozole

Treatment of non-erosive reflux disease is indicated in patients with recurrent reflux symptoms, particularly heartburn and acid regurgitation (approximately twice a week). Rabeprozole therapy may mask symptoms of malignancy (e.g., gastric or intestinal cancer) and other gastrointestinal disorders. Therefore, such conditions should be excluded before initiating rabeprozole.

When prescribing rabeprozole for patients with reflux disease without erosions, the physician should assess treatment efficacy after 2 weeks of therapy. If symptoms do not resolve, reflux disease may not be the cause. In such cases, the physician should consider alternative treatment approaches.

Eradication of Helicobacter pylori

When rabeprozole is prescribed for Helicobacter pylori eradication, attention must be paid to contraindications, special precautions for use, clinically significant adverse reactions, and other warnings stated in the medical instructions for other medicinal products used in eradication regimens.

Maintenance therapy with rabeprozole for reflux esophagitis

Rabeprozole may be prescribed as maintenance therapy for reflux esophagitis only in patients with recurrent disease. Rabeprozole should not be prescribed to patients who do not require maintenance therapy. Discontinuation of treatment is recommended if health improves through dietary changes, reduced alcohol intake, or in the absence of disease exacerbations over a prolonged period. Careful monitoring, including periodic endoscopy, is indicated during maintenance therapy.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the safety of rabeprozole use during pregnancy.

Reproductive studies in animals did not reveal evidence of impaired fertility or fetal harm associated with sodium rabeprozole; however, slight placental penetration was observed in rats. Geerdin is contraindicated during pregnancy.

Breastfeeding

Sodium rabeprozole penetrates into the milk of rats. It is unknown whether sodium rabeprozole passes into human breast milk. Appropriate studies have not been conducted.

Geerdin should not be prescribed to women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Based on the pharmacodynamics of sodium rabeprozole and its known adverse reaction profile, Geerdin is not expected to negatively affect the ability to drive vehicles or operate potentially hazardous machinery. However, if drowsiness or visual disturbances occur, patients are advised to avoid driving and operating machinery.

Method of Administration and Dosage

Adults, including elderly patients.

Active duodenal ulcer and active benign gastric ulcer: The recommended dose for these conditions is 20 mg once daily in the morning.

In most patients with active duodenal ulcer, healing occurs within 4 weeks. However, some patients may require additional treatment with Geerdin for another 4 weeks. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some patients may need to continue Geerdin treatment for an additional 6 weeks.

Erosive or ulcerative gastroesophageal reflux disease (GERD): The recommended dose for these conditions is 20 mg once daily for 4–8 weeks.

Long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD): For long-term management, maintenance doses of Geerdin 10 mg or 20 mg once daily may be used (depending on treatment efficacy).

Symptomatic treatment of moderate to very severe GERD: Patients without esophagitis should be prescribed Geerdin 10 mg once daily. If symptoms persist after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms resolve, ongoing symptom control can be achieved with an "on-demand" regimen: 10 mg once daily as needed.

Zollinger–Ellison syndrome: The dose should be individually adjusted.

The recommended initial dose is 60 mg once daily. The dose may be gradually increased up to 120 mg daily if clinically necessary. A single daily dose of up to 100 mg may be used. If a daily dose of 120 mg is required, the dose should be divided into two administrations of 60 mg each. The duration of treatment depends on clinical need.

Some patients with Zollinger–Ellison syndrome have been treated with sodium rabeprazole for up to 1 year.

H. pylori eradication: Patients with H. pylori should receive appropriate combination therapy with Geerdin and antibiotics. A 7-day regimen is recommended:

Geerdin 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.

For indications requiring once-daily dosing, Geerdin tablets should be taken in the morning before meals. Although administration in the morning or food intake has not been shown to affect the action of sodium rabeprazole, this dosing schedule is more favorable for treatment. Geerdin tablets must not be chewed or crushed; they should be swallowed whole.

Renal and hepatic impairment. Dose adjustment of Geerdin is not required in patients with renal or hepatic impairment. For information on the use of Geerdin in patients with severe hepatic impairment, see section "Special Warnings and Precautions for Use."

Children

Sodium rabeprazole is not recommended for use in children, as there is insufficient experience with its use in this age group.

Overdose.

Experience with intentional or accidental overdose of the medicinal product is limited. The maximum studied doses did not exceed 60 mg of sodium rabeprazole twice daily or 160 mg of sodium rabeprazole once daily. Symptoms occurring in overdose are generally minimal, typical of the known adverse effect profile, and resolve without need for further medical intervention. There is no specific antidote for rabeprazole. Sodium rabeprazole is highly protein-bound and is not eliminated during dialysis. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

The most commonly reported adverse reactions were headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. The observed adverse effects were generally mild, moderate, and transient.

Frequency is defined as: common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), not known (cannot be estimated from available data).

Infections and infestations: common – infections.

Blood and lymphatic system disorders: rare – neutropenia, leukopenia, thrombocytopenia, leukocytosis; not known – anemia, eosinophilia, erythrocytopenia, lymphopenia.

Immune system disorders: rare – hypersensitivity^1,2.

Metabolism and nutrition disorders: rare – anorexia; not known – hyponatremia, hypomagnesemia⁴.

Psychiatric disorders: common – insomnia; uncommon – nervousness; not known – depression, confusion.

Nervous system disorders: common – headache, dizziness; uncommon – somnolence; not known – weakness in limbs, limb numbness, hypoaesthesia, reduced hand grip strength, speech disorder, disorientation, delirium, coma.

Eye disorders: rare – visual disturbances; not known – increased intraocular pressure.

Cardiac disorders: not known – peripheral edema, arterial hypertension, palpitations.

Respiratory, thoracic and mediastinal disorders: common – cough, pharyngitis, rhinitis; uncommon – bronchitis, sinusitis; not known – glossitis.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fungicidal polyp; uncommon – dyspepsia, dry mouth, belching; not known – microscopic colitis, sensation of fullness and heaviness in the stomach, candidiasis, gastritis, stomatitis, taste disturbance, enteritis, esophagitis, cheilitis, pyrosis, hemorrhoids.

Hepatobiliary disorders: rare – hepatitis, jaundice, hepatic encephalopathy³.

Skin and subcutaneous tissue disorders: uncommon – rash, erythema²; rare – pruritus, sweating, bullous reactions²; very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome; not known – subacute cutaneous lupus erythematosus⁴.

Musculoskeletal and connective tissue disorders: common – non-specific pain, back pain; uncommon – myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist or spine⁴.

Renal and urinary disorders: uncommon – urinary tract infections; rare – tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders: not known – gynecomastia, prolonged erection.

General disorders and administration site conditions: common – asthenia, influenza-like syndrome; uncommon – chest pain, chills, pyrexia; rare – weight gain; not known – thirst, alopecia, malaise.

Investigations: uncommon – increased levels of liver enzymes³ (alanine aminotransferase, aspartate aminotransferase), lactate dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, proteinuria, increased levels of total cholesterol, triglycerides, blood urea nitrogen, increased thyroxine-binding globulin, creatine phosphokinase, uric acid, glucose in urine, hyperammonemia.

1 Includes facial swelling, hypotension, and dyspnea.

2 Erythema, bullous reactions, and hypersensitivity reactions usually resolved after discontinuation of treatment.

3 Hepatic encephalopathy has been observed in isolated cases in patients with liver cirrhosis. Caution is advised when prescribing Gerderin to patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

4 See section "Special Warnings and Precautions for Use".

Adverse reactions with clinical significance: shock and anaphylactic reactions; pancytopenia, leukopenia, agranulocytosis, hemolytic anemia; fulminant hepatitis, hepatic dysfunction, jaundice; interstitial pneumonia; toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; acute renal failure, interstitial nephritis; hyponatremia; rhabdomyolysis.

Adverse reactions with clinical significance associated with proton pump inhibitors: visual disturbances; angioneurotic edema, bronchospasm; confusion.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging and out of reach of children.

Packaging.

7 tablets per blister; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Mepro Pharmaceuticals Private Limited.

Manufacturer's address. Unit II, Q-Road, Phase IV, GIDC, Vadhvan, Surendranagar, Gujarat, 363 035, India.

Marketing Authorization Holder. Milly Healthcare Limited.

Address of Marketing Authorization Holder. 2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.