Controloc

Pantoprazole.

Controloc 20 mg tab: One gastro-resistant tablet contains Pantoprazole sodium sesquihydrate 22.6 mg (equivalent to pantoprazole 20 mg) for oral use.
Controloc 40 mg tab: One gastro-resistant tablet contains: Pantoprazole sodium sesquihydrate 45.1 mg (equivalent to pantoprazole 40 mg) for oral use.
Controloc IV: One vial contains Pantoprazole sodium 42.3 mg (equivalent to pantoprazole 40 mg).
Excipients/Inactive Ingredients: Controloc tab: Core: Anhydrous sodium carbonate, Mannitol, Crospovidone, Povidone K90, Vegetable calcium stearate.
Coating: Hypromellose 2910, Povidone K25, Titanium dioxide (E171), Yellow ferric oxide (E172), Propylene glycol, Methacrylic Acid - Ethyl Acrylate Copolymer (1:1), Sodium laurilsulfate, Polysorbate 80, Triethyl citrate.
Printing ink brown: shellac, red, black and yellow iron oxide (E172), Concentrated ammonia solution.
Controloc IV: Disodium edetate, Sodium hydroxide.
This medicinal product contains less than 1 mmol (23 mg) per vial.

Pharmacotherapeutic Group: Proton pump inhibitors. ATC Code: A02BC02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps in the parietal cells.
Pantoprazole is converted to its active form in the acidic environment of the parietal cells where it inhibits the H+, K+- ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose dependent and affects both basal and stimulated acid secretion. In most patients, freedom from gastric acid-related symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and consequently increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.
The fasting gastrin values increase with pantoprazole. During short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase has only been observed in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (similar to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see Preclinical safety data as follows) have not been observed in humans.
An influence of long-term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid based on data observed in animal studies.
Pharmacokinetics: Absorption: Both oral and I.V. administration of pantoprazole in the dose range of 10 mg to 80 mg result in linear serum pharmacokinetics.
Controloc tab: After ingestion, pantoprazole is rapidly absorbed into the bloodstream. On average the maximum serum concentrations (C_max) of 1 to 1.5 μg/mL (pantoprazole 20 mg tablet) or 2 to 3 μg/mL (pantoprazole 40 mg tablet) are achieved at about 2 to 2.5 hours after administration. After single and repeated administration of pantoprazole, the pharmacokinetic characteristics of pantoprazole are very similar.
The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no relevant influence either on the AUC or on the C_max and, thus, bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.
With pantoprazole granules, the peak serum concentration of 1.9 mg/l is reached after 2-2.5 hours in the fasting state. The AUC is about 5.5 mgh/l. Concomitant food intake reduces both AUC and the peak serum concentration and delays the time to peak concentration. This effect is reduced by taking pantoprazole Granules 30 minutes before breakfast.
Distribution: Pantoprazole's serum protein binding is about 98%, and in keeping with this, pantoprazole has a low volume of distribution (about 0.15 l/kg) and limited tissue distribution.
Metabolism: Pantoprazole is rapidly eliminated from the circulation and extensively metabolized in the liver. Metabolism occurs via oxidation by the CYP enzyme system, predominantly by CYP2C19 and CYP3A4 (Phase I metabolism, which is saturable). Pantoprazole undergoes further biotransformation by conjugation with sulphate, which involves the cytoplasmic enzyme sulphotransferase (phase II metabolism, which is not saturable), and which presents the main metabolism of pantoprazole.
Excretion and elimination: About 80% of the metabolites of pantoprazole are eliminated via the renal route, the rest via the feces. None of the metabolites are considered as biologically active. The main metabolite in both the serum and urine is desmethylpantoprazole, which is conjugated with sulphate. T1/2 of the main metabolite is about 1.5 hour (which is not much longer than that of pantoprazole, 1 hour).
Special populations: Impaired renal function: In patients with impaired renal function (including dialysis), pantoprazole showed no prolonged elimination half-life and no accumulation when compared with healthy subjects. No dose adjustment is necessary in patients with impaired renal function.
Impaired hepatic function: In comparison with healthy subjects, after oral administration of 40 mg pantoprazole sodium to patients with liver cirrhosis classified as Child-Pugh A and B, serum elimination half-lives of pantoprazole increased to between 3 and 6 hours (pantoprazole 20 mg tablet) or 7 to 9 hours (pantoprazole 40 mg tablet and powder) and AUC values increased by a factor of 3 to 5 (pantoprazole 20 mg tablet) or 5 to 7-fold (pantoprazole 40 mg tablet and powder). Maximum serum concentrations, C_max, in these patients increased only slightly (1.3-fold after oral administration, 1.5-fold after I.V. application) relative to healthy subjects. The observed pharmacokinetic changes did not lead to relevant accumulation following once-daily dosing.
Age, Gender, Race: As with other clinically used PPIs, a small percentage of the population (about 3% Caucasians, 20% Asians) shows slower elimination of pantoprazole (T_1/2 being up to 10 hours as compared with 1hour). Such persons are known as poor metabolizers as a result of a deficiency of the CYP2C19 enzyme. In these individuals the metabolism of pantoprazole is probably mainly catalyzed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole.
Results from several studies in children/adolescents from birth to 16 years indicate that the pharmacokinetics of pantoprazole is similar to those in adults when appropriately adjusted by patient weight, despite somewhat decreased clearance in patients less than 1 year old. Similar to adults, pediatric patients who were poor metabolizers of CYP2C19, exhibited reduced clearance that was more than 70% lower than the typical value.
Compared with younger subjects, slight increases in AUC and C_max were noted after single and repeated oral administration of pantoprazole to healthy elderly subjects (age >65 years). However, no dose adjustment is necessary in elderly patients.
Drug Interactions: Pantoprazole is metabolized in the liver via the CYP enzyme system. An interaction of pantoprazole with other drugs or compounds, which are metabolized using the same enzyme system, cannot be ruled out. Nevertheless, in specific tests pantoprazole did not affect the clearance of several compounds metabolized by CYP enzymes. Vice-versa, all drugs that were tested regarding their potential influence on the pharmacokinetics of pantoprazole had no relevant effect.
No detectable interactions between pantoprazole and any other commonly prescribed co-medication tested so far were found.
Metabolism of pantoprazole occurs via oxidation by the CYP enzyme system, predominantly by CYP2C19 and CYP3A4. Interaction studies with drugs also metabolized by these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin, and an oral contraceptive containing levonorgestrel and ethinyl estradiol did not reveal clinically significant interactions. Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol) does not interfere with p-glycoprotein related absorption of digoxin. There were no interactions with concomitantly administered antacids. Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In the two-year carcinogenicity studies in rats, neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and it can be concluded that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high dose treatment. In the two-year rodent studies, an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.
Animal Toxicology and/or Pharmacology: A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects to the thyroid glands are expected.
In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg. Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, the concentration of pantoprazole in the fetus is increased shortly before birth.

Controloc 20 mg tab: Pediatric: Symptomatic treatment of gastroesophageal reflux disease (GERD); Reflux esophagitis.
Adult: Symptomatic treatment of gastroesophageal reflux disease (GERD); For long-term management and prevention of relapse in reflux oesophagitis; Prevention of gastroduodenal ulcers induced by non-selective non-steriodal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAIDs treatment.
Controloc 40 mg tab: Pediatric: Reflux esophagitis.
Adult: Reflux esophagitis; In combination with two appropriate antibiotics (see Dosage & Administration) for the eradication of Helicobacter pylori in patients with peptic ulcers with the objective of reducing the recurrence of duodenal and gastric ulcers caused by this microorganisms; Duodenal ulcer; Gastric ulcer; Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.
Controloc IV: Duodenal ulcer; Gastric ulcer; Moderate and severe Reflux esophagitis; Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

Controloc 20 mg tab: General instructions: Controloc 20 mg gastro-resistant tablets should not be chewed or crushed, and should be swallowed whole with some water. (See Table 1.)

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Special Patient Populations: Elderly patients: No dose adjustment is necessary in elderly patients.
Pediatric patients: Controloc is not recommended for use in children below 5 years of age due to limited data on safety and efficacy in this age group.
Impaired hepatic function: A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment.
Impaired renal function: No dose adjustment is necessary patients with impaired renal function.
Controloc 40 mg tab: Tablets should not be chewed or crushed, and should be swallowed whole with some water. (See Table 2.)

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Special Patient Populations: Elderly patients: No dose adjustment is necessary in elderly patients.
Pediatric patients: Controloc is not recommended for use in children below 5 years of age due to limited data on safety and efficacy in this age group.
Impaired renal function: No dose adjustment is necessary in patients with impaired renal function.
Pantoprazole 40 mg must not be used in combination treatment (e.g. amoxicillin, clarithromycin) for eradication of H. pylori in patients with impaired renal function, since currently no data are available on the efficacy and safety of pantoprazole in combination treatment for these patients.
Impaired hepatic function: A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment (see Precautions).
Pantoprazole 40 mg must not be used in combination treatment (e.g. amoxicillin, clarithromycin) for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients (see Precautions).
Controloc IV: The intravenous administration of Controloc i.v. is recommended only if oral application is not appropriate.
Recommended dosage: Duodenal ulcer, gastric ulcer, moderate and severe reflux esophagitis: The recommended intravenous dosage is one vial (40 mg pantoprazole) Controloc i.v. per day.
Long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions: Patients should start their treatment with a daily dose of 80 mg Controloc i.v.. Thereafter, the dosage can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dosage above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.
In case of rapid acid control is required, a starting dose of 2 x 80 mg Controloc i.v. is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients. Transition from Controloc i.v. to the oral formulation of Controloc should be performed as soon as it is clinically justified.
Method of administration and General instructions: A ready-to-use solution is prepared by injecting 10 ml of physiological sodium chloride solution into the vial containing the dry substance. This solution may be administered directly or may be administered after mixing with 100 ml physiological sodium chloride solution or 5% glucose.
After preparation the solution must be used within 12 hours.
Controloc i.v. should not be manufactured or mixed with solvents other than those stated.
As soon as oral therapy is possible, treatment with Controloc i.v. should be discontinued and 40 mg pantoprazole p.o. (by mouth) should be administered instead.
The drug should be administered intravenously over 2-15 minutes.
Keep the vial in the outer carton in order to protect from light.
Special Patient Populations: Paediatric patients: The experience in children is limited. Therefore, Controloc i.v. 40 mg powder for solution for injection is not recommended for use in patients below 18 years of age.
Impaired hepatic function: A daily dose of 20 mg pantoprazole (half a vial of 40 mg Controloc I.V.) should not be exceeded in patients with severe liver impairment (see Precautions).
In addition, pantoprazole 40 mg must not be used in combination treatment (e.g. amoxicillin, clarithromycin) for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients (see Precautions).
Impaired renal function: No dose adjustment is necessary in patients with impaired renal function.
In addition, pantoprazole 40 mg must not be used in combination treatment (e.g. amoxicillin, clarithromycin) for eradication of H. pylori in patients with impaired renal function, since currently no data are available on the efficacy and safety of pantoprazole in combination treatment for these patients.
Elderly patients: No dose adjustment is necessary in elderly patients.

Controloc 20 mg tab: Systemic exposure with up to 240 mg intravenously over 2 minutes was well tolerated.
As pantoprazole is extensively protein bound, it is not readily dialyzable.
In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.
Controloc 40 mg tab: In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.
Controloc IV: Systemic exposure with up to 240 mg i.v. were administered over two minutes and well tolerated.
In the case of overdosage with clinical signs of intoxication, the usual rules of intoxication therapy apply.

Hypersensitivity to the active ingredients, or to any of the excipients of the product or the combination product.

Bone fracture: PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-doses; defined as multiple daily doses, and long-term PPI therapy (a year or longer.)
Clostridium difficile: PPI therapy may be associated with an increased risk of Clostridium difficile infection.
Hypomagnesemia: Has been rarely reported in patients treated with PPIs for at least three months (in most cases after a year of therapy). Serious consequences of hypomagnesemia include tetany, arrhythmia, and seizure.
Hepatic Impairment: In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes, the treatment should be discontinued. (See Dosage & Administration.)
HIV Protease Inhibitors: Co-administration of Pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir, nelfinavir; due to significant reduction in their bioavailability.
Methotrexate: Concomitant use with high dose methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.
Gastric malignancy: Symptomatic response to pantoprazole does not preclude the presence of gastric malignancy.
Influence on vitamin B12 absorption: Controloc tab: Daily treatment with any acid-suppressing medication over a prolonged period of time (several years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Cyanocobalamin deficiency should be considered in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, individuals with reduced body stores or risk factors for reduced vitamin B12 absorption (such as the elderly) on long-term therapy or if relevant clinical symptoms are observed.
Controloc IV: In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.
Controloc tab: Interference with Laboratory Tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, proton pump inhibitor treatment should be stopped 14 days before CgA measurements.
Subacute Cutaneous Lupus Erythematosus (SCLE): Proton pump inhibitors are associated in rare cases with the occurrence of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping the product.
Effects on ability to drive and use of machines: Controloc tab: Pantoprazole is not expected to adversely affect the ability to drive or use machines.
Adverse drug reactions such as dizziness and visual disturbances may occur (see Adverse Reactions). If affected, patients should not drive or operate machines.
Controloc IV: There are no known effects on the ability to drive, use machines.
Adverse drug reactions such as dizziness and visual disturbances may occur (see Adverse Reactions). If affected, patients should not drive or operate machines.

Pregnancy: There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.
Lactation: Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore a decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with pantoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of pantoprazole therapy to women.

Controloc tab: See Table 3.

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Controloc IV: The table as follows lists adverse reactions reported with pantoprazole, ranked under the following frequency classification: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 4.)

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Other interaction studies: Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways which include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, including carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin, and an oral contraceptive containing levonorgestrel and ethinyl estradiol did not reveal clinically significant interactions.
An interaction of pantoprazole with other drugs or compounds, which are metabolized using the same enzyme system, cannot be excluded.
Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol) does not interfere with p-glycoprotein related absorption of digoxin. There were no interactions with concomitantly administered antacids.
Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically relevant interactions were found.
Effects of Pantoprazole on Other Medicinal Products: HIV Protease Inhibitors: Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir, nelfinavir; due to significant reduction in their bioavailability.
Drugs with pH-Dependent Absorption Pharmacokinetics: Pantoprazole may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability.
Methotrexate: Concomitant use with high dose methotrexate may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.
Clopidogrel: Concomitant administration of pantoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole.
Coumarin anticoagulants (phenprocoumon or warfarin): Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenoprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenoprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.
Controloc tab: Effects of other medicinal products on Pantoprazole: Drugs that Inhibit or Induce CYP2C19: Inhibitors of CYP2C19, such as fluvoxamine, would likely increase the systemic exposure of pantoprazole. Inducers of CYP2C19 may decrease the systemic exposure to pantoprazole.
Controloc IV: Drugs that Inhibit or Induce CYP2C19 (tacrolimus, fluvoxamine): Concomitant administration of pantoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, would likely increase the systemic exposure of pantoprazole.

Controloc tab: Incompatibilities: Not applicable.
Controloc IV: Instructions for use/handling: Special precautions for disposal: A ready-to-use solution is prepared by injecting 10 mL of physiological sodium chloride (0.9%) solution for injection into the vial containing the powder. The appearance of the product after reconstitution is a clear yellowish solution. This solution may be administered directly or may be administered after mixing it with 100 mL physiological sodium chloride (0.9%) solution for injection or glucose (5%) solution for injection. Glass or plastic containers should be used for dilution.
After reconstitution, or reconstitution and dilution, chemical and physical in use stability has been demonstrated for 12 hours at 25 °C. From a microbiological point of view, the product should be used immediately. Pantoprazole should not be prepared or mixed with solvents other than those stated.
The medicinal product should be administered intravenously over 2 to 15 minutes.
The contents of the vial is for single use only. Any product that has remained in the container or whose visual appearance has changed (e.g., if cloudiness or precipitation is observed) should be disposed in accordance with local requirements.
Incompatibility: Controloc I.V. must not be mixed with other medicinal products except those mentioned in the previous text.

Controloc IV: Controloc i.v. should be stored below 25°C and protected from light.

Antacids, Antireflux Agents & Antiulcerants

A02BC02 - pantoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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