Centrapraz

White to off white coloured sterile lyophilized mass after reconstitution with sterile water for injection, it forms white to off white coloured solution.
Each vial contains: Pantoprazole (as sodium sesquihydrate) 40 mg.
Each ampoule contains: Sodium Chloride BP 90 mg (0.9% w/v).

Pharmacotherapeutic group: Proton pump inhibitors.
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 of the parietal cells.
Pharmacodynamic effects: Pantoprazole is converted to its active form in the acidic environment in 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 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 thereby 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 under pantoprazole. On 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, however, occurs only 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 (simple 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 have not been observed in humans.
An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also, CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
Pharmacokinetics: General pharmacokinetics: Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole is linear after both oral and intravenous administration.
Distribution: Pantoprazole's serum protein binding is about 98%. Volume of distribution is about 0.15 L/kg.
Biotransformation: The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway includes oxidation by CYP3A4.
Elimination: Terminal half-life is about 1 hour and clearance is about 0.1 L/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).
Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of Pantoprazole.
Special populations: Poor metabolisers: Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of Pantoprazole is probably mainly catalysed 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 metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of Pantoprazole.
Renal impairment: No dose reduction is recommended when Pantoprazole is administered to patients with impaired renal function (incl. dialysis patients). As with healthy subjects, Pantoprazole's half-life is short. Only very small amounts of Pantoprazole are dialyzed. Although the main metabolite has a moderately delayed half-life (2-3 h), excretion is still rapid and thus accumulation does not occur.
Hepatic impairment: Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5-7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects.
Older people: A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.
Pediatric population: Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2-16 years there was no significant association between Pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

For the treatment of gastroesophageal reflux disease, peptic ulcer, and pathological hypersecretory states such as Zollinger-Ellison syndrome. It is also used in prophylaxis of Non-Steroidal Anti-Inflammatory Drug-associated ulceration.

Pantoprazole may be administered intravenously through a dedicated line or through a Y-site.
The intravenous line should be flushed before and after administration of Pantoprazole for injection with either water for injection 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection. Or as prescribed by the physician.
Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome: The dosage of Pantoprazole for Injection in patients with pathological hypersecretory conditions associated with Zollinger-Ellison syndrome or other neoplastic conditions varies with individual patients. The recommended adult dosage is 80 mg every 12 hours. The frequency of dosing can be adjusted to individual patient needs based on acid output measurements.
In those patients who need a higher dosage, 80 mg every 8 hours is expected to maintain acid output below 10 mEq/h. Daily doses higher than 240 mg or administered for more than 6 days have not been studied. Transition from oral to I.V. and from I.V. to oral formulations of gastric acid inhibitors should be performed in such a manner to ensure continuity of effect of suppression of acid secretion. Patients with Zollinger-Ellison syndrome may be vulnerable to serious clinical complications of increased acid production even after a short period of loss of effective inhibition.

Experience in patients taking very high doses of Pantoprazole is limited. There has been spontaneous reports of overdosage with Pantoprazole, including a suicide in which Pantoprazole 560 mg and undetermined amounts of chloroquine and zopiclone were also ingested. There have also been spontaneous reports of patients taking similar amounts of Pantoprazole (400 mg and 600 mg) with no adverse effects. Pantoprazole is not removed by hemodialysis. In case of overdose, treatment should be symptomatic and supportive.
Single intravenous doses of Pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) were lethal to mice, rats and dogs.

Pantoprazole is contraindicated in patients with known hypersensitivity to the active substance or any excipients.

General: Hepatic effects: Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered intravenous Pantoprazole is unknown. Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric malignancy. As with any other intravenous product containing edetate disodium (the salt form of EDTA) which is a potent chelator of metal ions including zinc, zinc supplementation should be considered in patients treated with Pantoprazole who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously.
Use in Women: No gender-related differences in the safety profile of intravenous Pantoprazole were seen in international trials involving 166 men and 120 women with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 221 women treated with oral Pantoprazole in U.S. clinical trials were similar to those found in men. The incidence rates of adverse events were also similar between men and women.
Laboratory Tests: There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including Pantoprazole. An alternative confirmatory method should be considered to verify positive results.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation section for further information.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: No age-related differences in the safety profile of intravenous Pantoprazole were seen in international trials involving 86 elderly (≥65 years old) and 200 younger (<65 years old) patients with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 107 elderly patients (≥65 years old) treated with oral Pantoprazole in U.S. Clinical trials were similar to those found in patients under the age of 65. The incidence rates of adverse events and laboratory abnormalities in patients under the age of 65 years and older were similar to those associated with patients younger than 65 years of age.

Pregnancy: Teratogenic Effects: Pregnancy Category: B.
Teratology studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) and have revealed no evidence of impairment fertility or harm to the fetus due to Pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Lactation: Pantoprazole and its metabolites are expected in the milk. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for Pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.

Safety Experience with Intravenous Pantoprazole: Intravenous Pantoprazole has been studied in clinical trials in several populations including patients with GERD and a history of erosive esophagitis, patients with Zollinger-Ellison syndrome, patients involved in clinical trials for other disorders which may respond to proton pump inhibitor therapy, and healthy subjects. Adverse experiences occurring in >1% of patients treated with intravenous Pantoprazole (n=836) in domestic or international clinical trials are shown as follows by body system. In most instances, the relationship to Pantoprazole was unclear.
Respiratory system: Rhinitis.
Head-to-head comparative studies between Pantoprazole and other oral proton pump inhibitors (oral or I.V.), or H2 receptor antagonists (oral or I.V.) have been limited. The available information does not provide sufficient evidence to distinguish the safety profile of these regimens.

Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates) and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of Pantoprazole were not significantly altered. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2 would not significantly affect the pharmacokinetics of Pantoprazole. In vivo studies also suggest that Pantoprazole does not significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam and oral contraceptives levonorgestrel/ethinyl estradiol]) metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2. Therefore, it is expected that Pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes.
Dosage adjustment of such drugs is not necessary when they are co-administered with Pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with Pantoprazole.
Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once daily dosing with high doses of Pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.

Direction for Reconstitution: Dissolve the content of the vial in diluent. If any particle is visible after dissolving the contents, do not use the solution.
Pantoprazole is compatible with the following solutions: Water for Injection 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, or Lactated Ringer's Injection USP.
Midazolam HCl has been shown to be incompatible with Y-site administration of Pantoprazole may not be compatible with products containing zinc. When Pantoprazole is administered through a Y-site, and immediately stop use if precipitation or discoloration occurs.
Treatment with Pantoprazole Injection should be discontinued as soon as the patient is able to be treated with Pantoprazole delayed release tablets.
Parenteral route of administration other than intravenous is not recommended. No dosage adjustment is necessary in patients with renal impairment, hepatic impairment, or for elderly patients. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients. No dosage adjustment is necessary in patients undergoing hemodialysis.
Fifteen Minute Infusion: Pantoprazole for Injection should be reconstituted with 10 mL of diluent and further diluted (admixed) with 100 mL of 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, or Lactated Ringer's Injection USP, to a final concentration of approximately 0.4 mg/mL. The reconstituted solution may be stored for up to 4 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light. Pantoprazole for admixtures should be administered intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min.

Store at temperatures not exceeding 30°C.
Storage Condition and Shelf-life after Reconstitution: 2°C-8°C for 24 hours and 21°C-25°C for 4 hours.

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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