INSTRUCTION
for medical use of the medicinal product

PANOCID 40

Composition:

Active substance: 1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg;

Inactive substances: mannitol (E 421), sodium carbonate anhydrous, crospovidone, hydroxypropyl methylcellulose, calcium stearate, dye IC-S-329 (hydroxypropyl methylcellulose, polyethylene glycol), dye ENS-II-041 (methacrylate copolymer (type C), polyethylene glycol, talc, titanium dioxide ( E 171), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated, gastro-resistant tablets.

Basic physical and chemical properties: round biconvex yellow gastro-resistant tablets.

Pharmaceutical group. Drugs for the treatment of peptic ulcers and gastroesophageal reflux disease. Proton pump inhibitors.

ATC Code: А02В С02.

Pharmacological properties.

Pharmacodynamics.

An inhibitor of Н⁺-К⁺-ATPase of parietal cells disturbs the transfer of hydrogen ions from the parietal cells into the stomach lumen and blocks the final stage of hydrophilic secretion of hydrochloric acid. It reduces basal and stimulated (regardless of the type of stimuli - acetylcholine, histamine, gastrin) secretion of hydrochloric acid. In duodenal ulcer, which is associated with Helicobacter pylori, such reduction of gastric secretion increases the sensitivity of microorganisms to antibiotics. Pantoprazole has antimicrobial activity against Helicobacter pylori and promotes the anti-helicobacter effect of other drugs.

Pharmacokinetics.

After the intake, the drug is rapidly and completely absorbed; about 90 to 95% of the drug binds with plasma proteins. Pantoprazole is metabolized in the liver by enzyme cytochrome P450. The maximum serum concentration is achieved in 2.5 hours. The effect lasts for 24 hours. Approximately 71% of the drug is excreted by the kidneys and 18% – in feces.

Clinical particulars.

Indications.

Adults and adolescents up from 12 years of age.

- Reflux oesophagitis.

Adults.

- Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated stomach and duodenum ulcers.

- Duodenal ulcer.

- Stomach ulcer.

- Zollinger-Ellison-Syndrome and other hypersecretory pathological conditions.

Contraindications.

Hypersensitivity to the active substance, substitutes of benzimidazoles or to any of the other excipients.

Interaction with other medicinal products and other forms of interaction.

Effect of pantoprazole on the absorption of other medicinal products. Pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability (e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib).

HIV medications (atazanavir). Co-administration of atazanavir and other HIV medications which absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicinal agents. Therefore, co-administration of proton pump inhibitors and atazanavir is not recommended.

Coumarin anticoagulants (phenprocoumon and warfarin). Although no interaction during concomitant prescription of phenprocoumon and warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalized Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon and warfarin), monitoring of prothrombin time/INR is recommended after the treatment initiation, termination or during irregular use of pantoprazole.

Methotrexate. Concomitant use of high doses of methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore, in patients treated with high-doses of methotrexate, for example in patients with cancer and psoriasis, a temporary termination of treatment with pantoprazole has to be considered.

Other interactions. 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 including oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinyl oestradiol did not reveal any clinically significant interactions.

Results of a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.

No interactions with concomitantly administered antacids were found.

Interaction studies have also been performed on concomitant administration of pantoprazole and certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions of these drugs were found.

Precautions for use.

Liver Impairment. In patients with severe liver impairment, the liver enzymes level should be monitored regularly, especially during the long-term treatment with pantoprazole. In case of increase of the liver enzymes level, the treatment should be discontinued .

Combination therapy. During the combination therapy, the instructions for medical use of of the respective medicinal products should be followed.

Presence of alarm symptoms. In the presence of any alarm symptoms (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further clinical tests should be carried out if symptoms persist despite adequate treatment.

Concomitant administration with atazanavir. Co-administration of atazanavir and proton pump inhibitors is not recommended (see section “Interactions with other medicinal products and other forms of interaction). If the combination of atazanavir and a proton pump inhibitor is unavoidable, close clinical monitoring (e.g. viral load test) is recommended along 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 B12 absorption. 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 В₁₂ (cyanocobalamin) due to the development of hypo- and achlorhydria. This should be considered in patients with reduced body weight or when risk factors for reduced vitamin В₁₂ absorption during long-term therapy are present, or if respective clinical symptoms are observed.

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

Gastrointestinal infections caused by bacteria. Pantoprazole, like other proton pump inhibitors (PPIs), might be expected to increase the amounts of bacteria normally present in the upper gastrointestinal tracts. Treatment with Panocid 40 may lead to a slightly increased risk of gastrointestinal infections caused by such bacteria as Salmonella and Campylobacter or C. Difficile.

Hypomagnesaemia. Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole, during at least three months, and in most cases during a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they might begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after the replacement corrective therapy with magnesium and discontinuation of the PPI administration.

For patients who need prolonged treatment or who take PPIs concomitantly with digoxin or drugs, which may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during the course of treatment.

Bone fracture. Long-term treatment (>1 year) with high doses of proton pump inhibitors, might slightly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10–40%. Some of these fractures might be associated with other risk factors. Patients at risk of osteoporosis development should receive treatment according to the existing clinical guidelines and have a sufficient intake of vitamin D and calcium.

Use during pregnancy and lactation.

Pregnancy.There are no adequate data on the use of pantoprazole in pregnant women. During the studies of reproductive function in animals, embryotoxicity was observed in doses above 5 mg/kg. The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Lactation. There are data on pantoprazole excretion into breast milk. The decision regarding the use of the drug during lactation period should be made after a thorough benefit-risk evaluation.

Effects on reaction rates while driving vehicles or operating other machinery.

Use with caution while driving vehicles and operating machinery. It is necessary to consider that adverse drug reactions such as dizziness and visual disturbances may occur.

Routes of administration and dosage.

Treatment of reflux esophagitis.                                                                                                      

Recommended dose for adults and adolescents up from 12 years of age is one tablet (40 mg) per day. In individual cases the dose may be doubled (increased to 2 tablets of 40 mg per day) especially when there is no response to other treatment for reflux esophagitis.

A 4-week period is usually required for the treatment of reflux esophagitis. If this is not sufficient, healing will usually be achieved within further 4 weeks.

In Helicobacter pylori positive patients and in patients with gastric and duodenal ulcers, eradication of the germ through a combination therapy should be achieved. Depending on the susceptibility pattern for eradication of Helicobacter pylori, the following therapeutic combinations can be recommended for adults:

- 1 tablet of Panocid 40 (40 mg) 2 times a day + amoxicillin 1000 mg 2 times a day + clarithromycin 500 mg 2 times a day;

- 1 tablet of Panocid 40 (40 mg) 2 times a day + metronidazole 400-500 mg (or tinidazole 500 mg) 2 times a day + clarithromycin 250-500 mg 2 times a day;

- 1 tablet of Panocid 40 (40 mg) 2 times a day + amoxicillin 1000 mg 2 times a day + metronidazole  400-500 mg (or tinidazole 500 mg) 2 times a day.

In combination therapy for eradication of H. pylori, the second Panocid 40 tablet should be taken 1 hour before the evening meal. The combination therapy duration is 7 days and can be prolonged for further 7 days to a total duration of up to two weeks. If, to ensure healing of the ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and gastric ulcers should be considered.

If combination therapy is not an option, e.g. if the patient has received negative results for H. pylori, for Panocid 40 monotherapy of gastric and duodenal ulcers the recommended dose is 1 tablet of 40 mg once a day.  In individual cases, the dose may be doubled (2 tablets of 40 mg daily) especially when there has been no response to other treatment.

For the long-term treatment of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions, patients should start their treatment with a daily dose of 80 mg (2 tablets of the preparation). Thereafter, the dose can be adjusted, increased or decreased, as needed according to the indicators of gastric acid secretion in the stomach. With doses above 80 mg daily, the dose should be divided and given twice a day. A temporary increase of the dose above 160 mg of pantoprazole is possible but should not be applied longer than required for adequate acid control.

Treatment duration of Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.

A daily dose of 20 mg should not be exceeded in patients with liver impairment. Panocid 40 must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe liver dysfunction since no data on the efficacy and safety of Panocid 40 in combination treatment of these patients are currently available.

No dose adjustment is necessary in patients with impaired renal function. Panocid 40 must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data on the efficacy and safety of Panocid 40 in combination treatment for these patients are available.

No dose adjustment is necessary in elderly patients.

General recommendations.

Panocid 40, coated and gastro-resistant tablets, should be swallowed without chewing 1 hour before breakfast with some liquid. In combination therapy, which is aimed at eradication of Helicobacter pylori, the second tablet of the drug should be taken before dinner. The duration of combination therapy usually makes 7 days, but it can be extended to a maximum of 2 weeks. If for the ulcers’ treatment the further pantoprazole therapy is indicated, the dosage recommendations for gastric and duodenum ulcers should be considered.

A duodenal ulcer generally usually heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within further 2 weeks.

A gastric ulcer and reflux esophagitis generally heal within 4 weeks. If a 4-week period of treatment is not sufficient, healing will be achieved in almost all cases within further 4 weeks.

Children.

Panocide 40 is prescribed for treatment of reflux esophagitis in children over 12 years. The preparation is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group.

Overdose.

There are no known symptoms of overdose. Systemic exposure of up to 240 mg of the drug administered intravenously during 2 minutes was well tolerated. As pantoprazole is extensively protein bound, it is not easily dialyzable. In case of an overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Adverse reactions.

General disorders: fever, facial oedema, peripheral oedema, generalized oedema, malaise, asthenia, abscess, heat stroke, chill, cyst, hernia, changes of laboratory indicators, candidiasis, neoplasms, non-specific reactions of the drug, photosensitivity reactions, allergic reactions, and increased fatigability.

Cardiovascular disorders: changes in ECG, stenocardia, arrhythmia, atrial fibrillation/atrial flutter, chest pain, retrosternal pain, congestive heart failure, haemorrhage, hypertension, hypotension, myocardial infarction, myocardial ischemia, palpitation sensation, vascular disorders of retina, syncope , tachycardia, thrombophlebitis, thrombosis, and vasodilatation.

Gastrointestinal disorders: epigastric pain, abdominal pain and discomfort, diarrhoea, constipation or meteorism, nausea, vomiting, dry mouth, pancreatitis, anorexia, aphthous stomatitis, kardiospazm, colitis, duodenitis, dysphagia, enteritis, esophageal heamorrhage ,esophagitis, gastrointestinal carcinoma, gastrointestinal haemorrhage, rectal haemorrhage, gastrointestinal candidiasis, gingivitis, glossitis, bad breath, bloody vomiting, increased appetite, melena, ulcers of tunica mucosa of mouth, stomatitis, disorders of stool, ulcerative colitis, periodontitis, periodontal abscess, gastric ulcer, rectal hemorrhage and oral candidiasis.

Endocrine disorders: hyperlipoproteinemia, hyperglycemia, painful breast tension, diabetes, glycosuria, goiter.

Hepatobiliary disorders: damage liver cells, increased liver enzymes levels (transaminases, γ-GT), triglycerides, hepatocellular disturbances that lead to the development of jaundice with / without liver impairment, biliary pain, hyperbilirubinemia, cholecystitis, cholelithiasis, cholestatic jaundice, hepatitis, increased alkaline phosphatase, SGOT.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, hypercholesterolemia, eosinophilia, hyperlipoproteinemia, anaemia, ecchymosis, hypochromic anaemia, iron deficiency anaemia, leukocytosis, agranulocytosis and pancytopenia.

Metabolic disorders: dehydration, gout, thirst, hyperlipidemia and increased levels of lipids (triglycerides, cholesterol), loss or increase of weight, hyponatremia, hypomagnesemia, hypocalcemia¹, hypokalemia.

Immune system disorders: anaphylactic reactions, including anaphylactic shock and angioneurotic oedema.

Musculoskeletal and connective tissue disorders: in rare cases arthralgia was observed, myalgia which disappeared when treatment discontinued, muscular spasm, arthritis, arthrosis, bone tissue disturbance, bone pain, bursitis, joint dysfunction, seizures, rigid neck, tenosynovitis, fractures of femoral bone, wrist, spine (see. section "Precautions for use").

Neurological disorders: headaches, dizziness, tremor, paresthesia, phobia, sleep disturbances, bad dreams, confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence), parageusia, seizures, dysarthria, emotional lability, hyperkinesia, hypoesthesia, decrease of libido, nervousness, neuralgia, neuritis, neuropathy, reduced reflexes and somnolence.

Psychiatric disorders: depression, which disappeared after treatment was discontinued, hallucinations, disorientation, embarrassment, and derangement.

Respiratory system disorders: asthma, epistaxis, hiccup, laryngitis, lung disease, pneumonia, voice alteration.

Skin and sub- cutaneous tissue disorders: allergic reactions such as itching and skin rash. In rare cases urticaria was observed, erythema multiforme, Lyell syndrome, Stevens-Johnson syndrome, photosensitivity, alopecia, exfoliative dermatitis, acne, contact dermatitis, dry skin, eczema, fungal dermatitis, hemorrhage, herpes simplex, herpes zoster, lichenoid dermatitis, maculopapular rash, skin disorders, ulcers of the skin, increased sweating, exanthema and anhioedema.

Sense organs: visual disturbances, lazy eyes, amblyopia, cataracts, deafness, diplopia, ear pain, extraocular palsy, glaucoma, otitis externa, parageusia and tinnitus.

Renal and urinary disorders: Interstitial Nephritis (with possible progression to renal failure), hematuria, albuminuria, balanitis, cystitis, dysmenorrhea, dysuria, epididymitis, kidney stones, kidney pain, nocturia, prostate dysfunction, pyelonephritis, swollen scrotum, urethral pain, urethritis, urinary tract disorders, urination disorders and vaginitis.

Reproductive system and breast disorders: impotence and gynaecomastia.

1. Hypocalcemia along with hypomagnesemia.
2. Muscle spasms as a result of an imbalance of electrolytes.

Storage life. 3 years.

Storage conditions.

Keep out of reach of children.

Store in the original package at temperature not exceeding 30 °С.

Package. 10 tablets in a blister. 1 or 3 blisters in a box.                                     

Terms of dispensing. On prescription.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer’s registered address

Е-28, Opp. Fire Brigade, M.I.D.C., Taloja, Dist. Raigad, Maharashtra, IN-410 208, India

Applicant. 

Flamingo Pharmaceuticals Ltd.

Applicant’s and/or declarant’s representative registered address.

7/1, Corporate Park, Sion-Trombay Road, Chembur, Mumbai - 400 071, India.