Zurcal for Symptomatic gastro esophageal reflux disease and For long term management and prevention of relapse

 
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Zurcal 20 & 40mg
Pantoprazole

COMPOSITION :

Zurcal 20 mg Gastro-resistant Tablet:
Each Tablet contains: Active ingredient
22.6 mg pantoprazole sodium sesquihydrate equivalent to 20 mg pantoprazole.
Zurcal40 mg Gastro-resistant Tablet:
Each Tablet contains: Active ingredient:
45.1 mg pantoprazole sodium sesquihydrate equivalent to 40 mg pantoprazole.
Excipients:
Sodium carbonate,mannitol 0 der, Crospovidone ,PVP K90 ,calcium stearate, hydroxyl propyl methyl cellulose ES ,povidone K 2S ,polyethylene glycol 6000, titanium dioxlde ,ferrtc oxide yellow, eudragit L 100-55 ,tween 80 ,sodium lauryl sulphate, triethyl citrate and sodium hydroxide.

PHARMACOLOGICAL PROPERTIES :

Pharmacotherapeutic group
Proton pump inhibitor
Pharmacodynamic properties
Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific action on the proton pumps of the parietal cells. 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. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase in 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, the substance can affect 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 level doubled 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
carcinoid 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 the resul in animal studies.
Pharmacokinetic properties
Absorption
Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 20 mg oral dose. On average at about 2.0h-2.5 h p.a. the maximum serum concentration of about t-t.suq/m! are achieved, and these values remain constant after multiple administration . Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole is virtually linear after both oral and intravenous administration. The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake offood had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.
Distribution
Pantoprazole’s serum protein binding is about 98%. Volume of distribution is about 0.1 SI/kg.

Metabolism and elimination
The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation other metabolic pathway include oxidation by CY3A4. Terminal half-life is about 1 h and clearance is about 0.1 I/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific activation of pantoprazole in 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 are excreted with the feces. 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 h) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects
Approximately 3% of the European population lack a functional CP2C, 9 enzyme called poor metabolisers.ln 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 subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentration were increased by about 60%.
These findings have no implications for the posology of pantoprazole. No dose reduction is requested when pantoprazole is
administered to patients with restricted kidney function (incl. dialysis patients). As with healthy subjects, pantoprazole’s half-life is short. Only very small amounts of pantoprazole are delayed. Although the main metabolite has a moderately delayed half-life (2-3 h), excretion is still rapid and thus accumulation does not occur.
Although for patients with liver cirrhosis (classes A and B according to Child) the half-lifetime 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 t.S compared with healthy subjects. A slight increase in AUC and C max in elderly volunteers compared with younger counterparts is also not clinically
relevant.
Children
Following single oral doses of 20 or 40 mg pantoprazole to children aged 5 – 16 years AUC and C max were in the range of corresponding values in adults. Following single IV doses of 0.8 or 1.6 mg/kg pantcprazole 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

THERAPEUTIC INDICATIONS :

Zurcal20 mg Gastro-resistant Tablet:
Adults and adolescents 12 years of age and above: Symptomatic gastro-esophageal reflux disease For long-term management and prevention of relapse in reflux esophagitis
Adults: Prevention of gastro-duodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment
Zurcal40 mg Gastro-resistant Tablet:
Adults and adolescents 12 years of age and above Reflux esophagitis
Adults: Eradication of Helicobacter pylori (H.Pylori) in combination
e with appropriate antibiotic therapy in patients with H. pylori
associated ulcers. Gastric & duodenal ulcer Zollinger-Ellison-Syndrome and other pathological hyper-secretory conditions

POSOLOGY AND METHOD OF ADMINISTRATION :

General
Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.
Recommended dose:
Adults and adolescents 12 years of age and above: Zurcal 20 11 mg Gastro-resistant Tablet: Symptomatic gastro-esophageal reflux disease The recommended oral dosage is one Zurcal 20 mg
gastro-resistant tablet per day. Symptoms relief are generally accomplished within 2-4 weeks. If this is not sufficient, symptoms relief will normally be achieved within a further 4 weeks. When symptom relief has been achieved, reoccurring symptoms can be controlled using an on-demand a regimen of 20 mg once daily, when required. A switch to continuous therapy may be considered in case satisfactory symptom control cannot be maintained with on-demand treatment.
Long term management and prevention of relapse in reflux esophagitis :
For long-term management, a maintenance dose of one qastro-reststant tablet Pantoprazole 20 mg per day is recommended, increasing to 40 mg pantoprazole per day if relapse occurs. Pantoprazole 40 mg is available for this case. After healing of the relapse the dosage can be reduced to 20 5 mg pantoprazole.
Zurcal 40 mg Gastro-resistant Tablet:
Reflux esophagitis
One tablet of Pantoprazole per day In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually ) required for the treatment of reflux esophagitis. If this is not sufficient healing will usually be achieved within a further 4 weeks.
Adults:
Zurcal 20 mg Gastro-resistant Tablet:
Prevention of gastro-duodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment The recommended oral dose is one ZURCAL Gastro-resistant tablet (contains 20 mg) per day.
Zurcal 40 mg Gastro-resistant Tablet:

Eradication of “H- pylori” in combination with two appropriate antibiotics
In Hellcobacter pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination therapy should be achieved. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori:
a)Twice daily one ZURCAL Gastro-resistantTablet (contains 40 mg)
+ Twice daily 1000 mg amoxicillin
+ Twice daily 500 mg clarithromycin b)Twice daily one ZURCAL gastro-resistant tablet (contains 40 mg)
+ Twice daily 400-500 mg metronidazole (or 500 mg tinidazole)
+ Twice daily 250-500 mg clarithromycin c)Twice daily one ZURCAL gastro-resistant tablet (contains 40mg)
+ Twice daily 1000 mg amoxycillin
+ Twice daily 400-500 mg metronidazole (or 500 mg tinidazolel
In combination therapy for eradication of h. pylori infection, the second pantoprazole 40 mg tablet should be taken1 hour before the evening meal. The combination therapy is implemented for 7 days in general and can be prolonged for further 7 days to a total duration up to two weeks. If to insure healing of the ulcers, further treatment with pantoprazole is indicated, the dosage recommendation for duodenal and gastric ulcers should be considered.
If combination therapy is not an option, e.g. if the patient has tested negative for Helicobacter pylori, the following dosage guidelines apply for ZURCAL monotherapy:
Treatment of gastric ulcer:
One ZURCAL gastro-resistant tablet (contains 40 mg) per day In individual cases the dose may be doubled (increase to 2 tablets pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric and duodenal ulcer. If this is not sufficient, healing will usually be achieved within a further 4 weeks.
Treatment of duodenal ulcer:
One Zurcal gastro-resistant tablet (contains 40 mg) per day In individual cases the dose may be doubled (increase to 2 tablets pantoprazole daily) especially when there has been no response to other treatment.
A duodenal ulcer generally heals within 2 weeks. If a 2-week t period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Zollinger-Ellison syndrome and other pathological hypersecretory conditions
For the long-term management of Zollinger-Ellison-Syndrome and other pathological hyper-secretory conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of ZURCAL 40
mg). 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.
Treatment duration in Zollinger-Ellison-Syndrome and other
pathological hyper-secretory conditions is not limited and should be adapted according to clinical needs.

Special populations
Children below 12 years of age Pantoprazole is not recommended for use in children below 12 years of age due to limited data in this age group.

Hepatic Impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment. Pantoprazole must not be used in combination treatment 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.
Rena/lmpairment
No dose adjustment is necessary in patients with impaired renal function. Dosage in impaired renal patients and elderly Pantoprazole must not be used in combination treatment for eradication of H.pylori in patients with impaired renal dysfunction since currently no data are available on the efficacy and safety of Pantoprazole in combination treatment of these patients.
Elderly
No dose adjustment is necessary in elderly patients.

CONTRAINDICATIONS :

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients

SPECIAL WARNINGS AND PRECAUTIONS FOR USE :

Hepatic Impairment
In patients with severe liver impairment, the liver enzymes should be monitored regularly during therapy, particularly on long-term use. In the case of a rise of thEt liver enzymes, the treatment should be discontinued.
Co-administration with NSAIDs
The use of Pantoprazole 20 mg as a preventive of gastro-duodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (N5AIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop
gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (>65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.
In presence of alarm symptoms
In the presence of any alarm symptom(e.g. significant unintentional weight loss , recurrent vomiting, dysphagia, hematemesis, anemia or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with atazanavir
Co-administration of atazanavir with proton pump inhibitors is not recommended. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.

Influence on vitamin B 12 absorption
Pantoprazole, as all acid-blocking medicines, may reduce the
absorption of vitamin 812 (cyanocobalamin) due to hypo- or
achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin 812 absorption on long-term therapy or if respective clinical symptoms are observed.

Long term treatment
In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Gastrointestinal infections caused by bacteria
Pantoprazole, like all proton pump inhibitors (PPls), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

Bone Fracture
“Several published observational studies suggest that proton pump inhibitor (PPIl 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-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk fOI osteoporosis-related fractures should be managed according to the established treatment guidelines.”

Hypomagnesaemia
Prescription proton pump inhibitor (PP!) drugs may cause low serum magnesium levels (hypomagnesaemia) if taken for prolonged periods of time (in most cases, longer than one year), magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.
low serum magnesium levels can result in serious adverse events including muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms. Treatment of Hypomagnesaemia     generally     requires magnesium supplements.
Treatment in patients taking a PPI and who have hypomagnesaemia may also require stopping the PPL For patients expected to be on prolonged treatment or who take PPls with digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Effect of pantoprazole on the absorption of other medicinal product because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g. some azote antifungals as ketoconazote, itraconazole, posaconazole and other medicine as erlotinib. HIV medications (atazanavir)
Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and tnight impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended.
Coumarin anticoagulants (phenprocoumon or warfarin)
Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (lNR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time / INR is recommended after initiation, termination or during irregular use of pantoprazole.
Methotrexate
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy.
Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPls, such as omeprazole, esomeprazole, and pantoprazole with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPls, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.
Other interactions 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 include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing
levonorgestrel and ethinyl oestradiol did not reveal clinically
significant interactions. Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of active substances metabolised by CYPl A2 (such as caffeine,
theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2El (such as ethanol) or 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.

PREGNANCY AND LACTATION :

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

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES :

Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

UNDESIRABLE EFFECTS :

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhea and headache, both occurring in approximately 1 % of patients. The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:
Very common (“1110); common (1/100 to <1110); uncommon
(“1/1,000 to <11100); rare (“1/10,000 to
<111,000); very rare «1/10,000), not known (cannot be
estimated from the available data). For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse Reaction frequency and therefore they are mentioned with a “not known” frequency.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

POST MARKETING REPORTS :

“Musculoskeletal: Bone fracture”

OVERDOSE :

There are no known symptoms of over-dosage in man. Doses up to 240 mg administered intravenously over two minutes were 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.

PACKAGE AND SPECIAL PRECAUTIONS FOR STORAGE :

Package:
Zurcal20 mg Gastro-resistant Tablet: Carton box containing one or 2 or 3 or 4 strips (AUAL) each strip of 7 gastro resistant tablets and an insert leaflet.
Zurcal40 mg Gostro-resistant Tablet: Carton box containing one or 2 or 3 or 4 strips (AUAL) each strip of 7 gastro resistant tablets and an insert leaflet.
Special precautions for storage:
Store at temperature not exceeding 300c, in a dry place
Keep out of the reach and sight of children.
Do not use after the expiry date which is stated on the label.
The expiry date refers to the last day of that month.

Manufactured by :

AUG Pharma

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