Rabimac

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT RABIMAK

Composition:

Active substance: rabeprazole;

1 tablet contains 10 mg or 20 mg of sodium rabeprazole;

Excipients: tablets of 10 mg: mannite (E 421), low-substituted hydroxypropylcellulose, heavy magnesium oxide, povidone, sodium hydroxide, talc, magnesium stearate, ethylcellulose, iron oxide red (E 172), titanium dioxide (E 171), methacrylic acid copolymer dispersion, triethyl citrate;

tablets of 20 mg: mannite (E 421), low-substituted hydroxypropylcellulose, heavy magnesium oxide, povidone, sodium hydroxide, talc, magnesium stearate, ethylcellulose, iron oxide yellow (E 172), titanium dioxide (E 171), methacrylic acid copolymer dispersion, triethyl citrate.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties:

tablets of 10 mg: round, biconvex, enteric-coated tablets, pink in color, smooth on both sides;

tablets of 20 mg: round, biconvex, enteric-coated tablets, yellow in color, smooth on both sides.

Pharmacotherapeutic group.

Drugs affecting the digestive tract and metabolism. Drugs for treatment of conditions associated with acid disorders. Anti-ulcer drugs and drugs for treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprazole. ATC code A02BC04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Sodium rabeprazole belongs to the class of antisecretory compounds substituted benzimidazoles, has no anticholinergic properties and is not a histamine H2-receptor antagonist, but 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. Animal studies have shown that after administration, sodium rabeprazole rapidly disappears from both blood plasma and gastric mucosa. Sodium rabeprazole has weakly basic properties, is rapidly absorbed at all dosage levels, and accumulates in parietal cells. Sodium rabeprazole is converted into its active sulfenamide form via protonation, thereby reacting with accessible cysteine residues of the proton pump.

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

Reduction of gastric acidity, regardless of the cause, including proton pump inhibitors such as rabeprazole, 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. After administration of 10 or 20 mg sodium rabeprazole once daily for 3–4 months, serum gastrin concentration increases during the first 2–8 weeks of therapy, reflecting inhibition of acid secretion. Gastrin concentrations generally return to baseline levels within 1–2 weeks after discontinuation of treatment.

Examination of biopsy specimens from the fundus and antral region of the stomach in many patients who received rabeprazole or a comparator drug for 8 weeks revealed no histological changes, no significant gastritis, no increased frequency of atrophic gastritis, intestinal metaplasia, or spread of H. pylori infection. During long-term treatment lasting 36 months, no significant changes were observed in the results of these analyses.

Other effects. Currently, there are no data on systemic effects on the central nervous system (CNS), cardiovascular or respiratory systems caused by the use of sodium rabeprazole. Oral administration of 20 mg sodium rabeprazole daily for 2 weeks does 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 have demonstrated the absence of clinically significant interactions between rabeprazole and amoxicillin.

Rabeprazole has no negative effect on plasma levels of amoxicillin and clarithromycin when used concomitantly for eradication of H. pylori infection in the upper gastrointestinal tract.

Pharmacokinetics.

Absorption. Rabimac – enteric-coated tablet. Absorption of sodium rabeprazole begins only after the tablet passes through the stomach. Sodium rabeprazole is rapidly absorbed from the intestine. Peak plasma concentrations of rabeprazole are reached approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of rabeprazole are linear within the dose range of 10–40 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 rabeprazole. The elimination half-life from plasma 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 extent of binding of sodium rabeprazole to plasma proteins is approximately 97%.

Metabolism and excretion. Like other members of the proton pump inhibitor class, rabeprazole is metabolized by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes have shown that sodium rabeprazole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprazole 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 rabeprazole 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 rabeprazole, unchanged rabeprazole 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). Additionally, two unidentified metabolites were found in toxicological studies in laboratory animals. The remaining portion of the dose was recovered in feces.

Gender differences. Since the single 20 mg dose of sodium rabeprazole is adjusted for 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 distribution of sodium rabeprazole was very similar to that in healthy volunteers. AUC and Cmax of sodium rabeprazole were approximately 35% higher in these patients 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 hemodialysis patients was approximately twice that in healthy volunteers.

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

Elderly patients. Elimination of sodium rabeprazole is somewhat reduced in elderly patients. After 7 days of administration of 20 mg sodium rabeprazole daily, 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 were no signs of accumulation of sodium rabeprazole.

Polymorphism of CYP2C19. After administration of 20 mg sodium rabeprazole daily for 7 days in patients with slow CYP2C19 metabolism, AUC and 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%.

Clinical characteristics.

Indications.

• Active duodenal peptic 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 moderate 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.

The drug is contraindicated in patients with hypersensitivity to sodium rabeprazole, substituted benzimidazoles, or to any other ingredient of the drug.

Pregnancy or breastfeeding period.

Interaction with other medicinal products and other types of interactions.

CYP450 system

Sodium rabeprazole is metabolized by the hepatic enzyme system CYP450, specifically CYP2C19 and CYP3A4.

Studies have shown that sodium rabeprazole does not have pharmacokinetic or clinically significant interactions with warfarin, phenytoin, theophylline, or diazepam, each of which is metabolized by CYP450.

Interactions caused by inhibition of gastric acid secretion

Sodium rabeprazole causes strong and prolonged reduction in gastric acid production. Thus, 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 concentration of the latter. Therefore, individual patients receiving these drugs concomitantly with Rabimak should be under medical supervision to determine the need for dose adjustment.

Antacids

During clinical trials, patients received antacids as needed concomitantly with Rabimak; in a specific study, no interaction between the drug and antacids such as aluminium 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 resulted in 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.

Metotrexate

Case reports of adverse reactions, 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 to healthy volunteers did not have a 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.

Medicinal products not recommended for concomitant use with rabeprazole

Medicinal product	Signs of interaction	Mechanism and risk factors
Atazanavir sulfate	The therapeutic effect of atazanavir may be reduced	Due to its antisecretory effect, rabeprazole increases gastric pH, reduces the solubility of atazanavir sulfate, and thereby decreases its plasma concentration

Medicinal products that should be prescribed with caution

Medicinal product	Signs of interaction	Mechanism and risk factors
Digoxin Methyldigoxin	Blood concentration levels of digoxin and methyldigoxin may increase	Due to its antisecretory effect, rabeprazole may increase gastric pH, leading to enhanced absorption of digoxin and methyldigoxin
Itraconazole Gefitinib	Blood concentration levels of itraconazole and gefitinib may decrease	Due to its antisecretory effect, rabeprazole may increase gastric pH, resulting in reduced absorption of itraconazole and gefitinib
Antacids containing aluminium hydroxide/magnesium hydroxide	The concentration of rabeprazole may decrease when co-administered with antacids.

Special precautions for use

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

Use in elderly patients

Rabeprazole 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 closely monitored, and dosing and duration of treatment recommendations should be strictly followed.

Symptomatic improvement with rabeprazole therapy does not exclude the presence of a malignant tumor of the stomach or esophagus. Therefore, malignancy should be ruled out before initiating rabeprazole treatment.

Patients undergoing long-term treatment (especially those treated for more than 1 year) should be regularly monitored.

The risk of developing cross-sensitivity reactions when used with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

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

Rabeprazole is not recommended for use in children due to lack of experience with this patient group.

Cases of blood pathology (thrombocytopenia and neutropenia) have been reported. In most cases, no other etiology was identified; hematological changes were uncomplicated and resolved after discontinuation of rabeprazole.

Abnormalities in liver enzymes have been observed both during clinical trials and in the post-marketing period. In most cases, no other etiology was identified; abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

In clinical studies, no significant difference in the frequency of adverse effects was observed in patients with mild or moderate hepatic impairment compared to the control group matched for gender and age. Physicians should exercise caution when prescribing rabeprazole to patients with severe hepatic impairment during the initial stages of therapy, as there are no clinical data on the use of the drug in this patient group.

Concomitant use of atazanavir and rabeprazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors for at least 3 months, and in most cases, for over 1 year. Serious manifestations of hypomagnesemia may include weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, which may occur unexpectedly and remain undiagnosed. In most patients, hypomagnesemia resolved after discontinuation of proton pump inhibitors and magnesium replacement therapy.

Patients receiving long-term concomitant treatment with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics) should have serum magnesium levels monitored before starting treatment and periodically during therapy.

Concomitant use of rabeprazole with methotrexate

Literature data suggest that concomitant use of proton pump inhibitors and methotrexate (predominantly at high doses) may increase serum levels of methotrexate and/or its metabolites, 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 rabeprazole, like all drugs 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 the drug. Previous treatment with a proton pump inhibitor may increase the risk of developing subacute cutaneous lupus erythematosus upon subsequent use of other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with the detection of neuroendocrine tumors. To avoid this effect, treatment with the drug should be discontinued at least 5 days before measuring chromogranin A levels. If chromogranin A and gastrin levels have not returned to the reference range after the initial measurement, the test should be repeated 14 days after discontinuation of PPI therapy.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been observed in patients taking rabeprazole, which may occur at any time during rabeprazole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If ATIN is suspected, rabeprazole should be discontinued and appropriate treatment initiated immediately.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the safety of rabeprazole use during pregnancy. Reproductive toxicity studies in rats and rabbits did not show evidence of impaired fertility or fetal harm associated with sodium rabeprazole, although slight placental transfer was observed in rats.

Rabeprazole (Rabimak) is contraindicated during pregnancy.

Breastfeeding

It is unknown whether sodium rabeprazole passes into human breast milk. Adequate studies have not been conducted. However, sodium rabeprazole has been shown to pass into the milk of rats.

Rabimak should not be administered to women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Based on the pharmacodynamics of sodium rabeprazole and its known adverse effect profile, Rabimak is not expected to negatively affect the ability to drive or operate machinery. However, if drowsiness occurs, patients should avoid driving or 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 for another 4 weeks to achieve healing. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some patients who are unresponsive to treatment may require an additional 6 weeks of therapy.

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 10 mg or 20 mg once daily may be used, depending on the patient's clinical response.

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

Zollinger-Ellison syndrome:

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

H. pylori eradication: patients with H. pylori should receive appropriate combination therapy including this medicinal product. A 7-day regimen is recommended:

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

For indications requiring once-daily dosing, 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 regimen is considered more favorable for treatment. Tablets must not be chewed or crushed; they should be swallowed whole.

Renal and hepatic impairment. Dose adjustment is not required in patients with renal or hepatic impairment. For information on use in patients with severe hepatic impairment, see section "Special precautions for use".

Children.

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

Overdose.

Experience with intentional or accidental overdose 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 associated with overdose are generally minimal and consistent with the known adverse effect profile; they resolve without the need for further medical intervention.

There is no specific antidote for Rabimac. Sodium rabeprazole is highly plasma protein-bound and is not effectively removed by dialysis. In case of overdose, symptomatic and supportive treatment should be administered.

Side effects

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

The following adverse reactions have been reported during clinical trials and in the post-marketing period.

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.

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

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

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

Nervous system disorders: common – headache, dizziness; uncommon – somnolence.

Eye disorders: rare – visual disturbances.

Vascular disorders: not known – peripheral oedema.

Respiratory, thoracic and mediastinal disorders: common – cough, pharyngitis, rhinitis; uncommon – bronchitis, sinusitis.

Gastrointestinal disorders: common – diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fundic gland polyp; uncommon – dyspepsia, dry mouth, eructation; rare – gastritis, stomatitis, taste disturbance; not known – microscopic colitis.

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 (TEN), 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 hip, 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 – gynaecomastia.

General disorders and administration site conditions: common – asthenia, influenza-like illness; uncommon – chest pain, chills, pyrexia.

Investigations: uncommon – increased liver enzymes³; rare – weight gain.

1 Includes facial swelling, hypotension, and dyspnoea.

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 rabeprazole to patients with severe hepatic impairment (see section "Special precautions").

4 See section "Special precautions".

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

Adverse reactions of clinical significance and typical of proton pump inhibitors: visual disturbances, angioneurotic oedema, bronchospasm, confusion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

7 tablets in a strip, 2 strips in a cardboard box.

15 tablets in a blister, 1 or 2 blisters in a cardboard box.

7 tablets in a blister, 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

For 10 mg dosage:

Village Theda, P.O. Lodhimaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India

For 20 mg dosage:

Village Theda, P.O. Lodhimaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India

or

Village Theda, P.O. Lodhimaira, Tehsil Baddi, District Solan Himachal Pradesh - 174101, India (Block No. 1)