Structure and form of release

Structure

active ingredient: pantoprazol;

1 tablet contains 45.1 mg of a pantoprazol of sexivihydrat of sodium (that is equivalent to 40.0 mg of a pantoprazol);

other components: attracts (E 421); sodium carbonate anhydrous; krospovidon; K 90 povidone; calcium stearate;

cover: gipromelloza of 2910; K 25 povidone; titan dioxide (E 171); ferrous oxide yellow (E 172); propylene glycol; methacrylate copolymer (type A); sodium lauryl sulfate; polysorbate 80; triethyl citrate; ink brown (S-1-16350).

release Form

Gastrorezistentny tablets.

Pharmacological properties

Pharmacodynamics. action mechanism. pantoprazol — the substituted benzimidazole which inhibits secretion of hydrochloric acid in a stomach by specific blockade of a proton pomp of covering cells. pantoprazol it is transformed to an active form in acidic environment in covering cells where inhibits enzyme of N + - to +-atfazu, that is blocks a final stage of production of hydrochloric acid in a stomach. the inhibition depends on a dose and suppresses both basal, and stimulated secretion of acid. at most of patients the symptoms disappear during 2 weeks use of a pantoprazol, as well as other inhibitors of a proton pomp (ipp) and inhibitors of n2-receptors, reduces acidity in a stomach and thus increases secretion of gastrin in proportion to decrease in acidity. increase in secretion of gastrin is reversible. as pantoprazol connects enzyme distally in relation to a cellular receptor, it can inhibit secretion of hydrochloric acid irrespective of stimulation by other substances (acetylcholine, a histamine, gastrin). the effect at peroral and in in use of medicament is identical.

At use of a pantoprazol the gastrin level on an empty stomach increases. At short-term use the gastrin level in most cases does not exceed the upper bound of norm. At long-term treatment the level of gastrin is in most cases doubled. Its excessive increase, however, arises only in rare instances. As a result, sometimes at long-term treatment note weak or moderate increase in specific endocrine (ECL) cells in a stomach (like an adenomatoid hyperplasia). However, according to the researches conducted at the moment, formation of progenitors of neuroendocrinal tumors (atypical hyperplasia) or the neuroendocrinal tumors of a stomach revealed in researches on animals at people are noted.

Proceeding from results of researches on animals, it is impossible to exclude completely influences long (more than one year) treatments pantoprazoly on endocrine parameters of a thyroid gland.

Against the background of treatment by anti-secretory medicines gastrin level in blood serum increases in response to decrease in secretion of acid. Besides, because of decrease in acidity of a stomach the level of chromogranin A (CgA) increases. The increased CgA level can affect results of researches at diagnosis of neuroendocrinal tumors. The available published data demonstrate that treatment of IPP should be stopped during the period of 5 days to 2 weeks before measurements of the CgA level. It allows the CgA level to return to the range of normal values which can be IPP which are mistakenly raised after treatment.

Pharmacokinetics. Absorption. Pantoprazol is quickly soaked up, and the C _max in blood plasma is reached after single oral administration of a dose of 20 mg. On average in 2-2.5 h after reception the C _max in serum at the level of about 1-1.5 mkg/ml is reached; concentration remains constant after multiple dose. Pharmacokinetic properties do not change after single or repeated dose. In the range of doses of 10-80 mg the pharmacokinetics of a pantoprazol in blood plasma remains linear both at oral administration, and at in in introduction. It is established that the absolute bioavailability of tablets is about 77%. The concomitant use of food does not influence AUC (the area under a curve "concentration time") or the C _max in serum and, respectively, bioavailability. At a concomitant use of food only the variability of stage of latency increases.

Distribution. Linking of a pantoprazol with proteins of serum makes about 98%. Distribution volume — about 0.15 l/kg.

Removal. Substance is metabolized almost only in a liver. The main metabolic way is demethylation by means of CYP2C19 with the subsequent sulphatic conjugation; oxidation by means of CYP3A4 belongs to other metabolic ways. Final the T _½ makes about 1 h, and clearance — 0.1 l/h/kg. Several cases of a delay of removal are noted. Thanks to specific linking of a pantoprazol with proton pompa of covering cells T _½ does not correspond to the much bigger duration of action (acid secretion oppression).

Main part of metabolites of a pantoprazol is removed by

with urine (about 80%), the rest — with a stake. The main metabolite both in serum, and in urine is desmetilpantoprazol, conjugated with sulfate. The t _½ main metabolite (about 1.5 h) not much more exceeds T _½ a pantoprazola.

Special groups of patients.

Slow metabolizator. About 3% of Europeans have a need for functionally active CYP2C19 enzyme; they are called slow metabolizator. In an organism of such persons the metabolism of a pantoprazol is probably mainly catalyzed by CYP3A4 enzyme. After reception of one dose of 40 mg of a pantoprazol, slow metabolizator had an average area limited to a pharmacokinetic curve "concentration in plasma time" approximately in 6 times more, than at the persons having functionally active CYP2C19 enzyme (fast metabolizator). The C _max in plasma increased approximately by 60%. These results do not influence a dosage of a pantoprazol.

Renal failure. Patients do not have recommendations about a dose decline when assigning a pantoprazol with a renal failure (including to patients on dialysis). As well as at healthy people, T _½ a pantoprazola at them short. Only very small amount of a pantoprazol is dialyzed. In spite of the fact that at the main metabolite moderately long T _½ (2–3 h), removal all the same is fast therefore cumulation does not happen.

Abnormal liver function. Though at patients with cirrhosis (classes A and B on a scale of Chayld-Pyyu) the T _½ increases to 3–6 h, and AUC increases by 3–5 times, the C _max in serum increases only slightly — by 1.5 times (by 1.3 times for Controlok, tablets gastrorezistenty 20 mg) in comparison with healthy volunteers.

Patients of advanced age. Insignificant increase in AUC and C _max at volunteers of advanced age in comparison with the corresponding indicators at younger volunteers has also no clinical value.

Children. After single dose of a dose of 20 or 40 mg of a pantoprazol orally AUC and C _max at children at the age of 5–16 years were in limits of the corresponding values at adults. After single in/in introductions of a pantoprazol in a dose of 0.8 or 1.6 mg/kg to children at the age of 2–16 years the significant communication between clearance of a pantoprazol and age or body weight of the patient is noted. AUC and volume of distribution corresponded to the data obtained during the researches with participation of adults.

Indication

Adults and children are aged more senior than 12 years

• Reflux esophagitis

Adult

• Eradikation Helicobacter pylori (H. pylori) at patients with H. rylori-associated ulcers of stomach and duodenum in combination with the corresponding antibiotics.
• duodenum Ulcer.
• Stomach ulcer.
• Zollinger's Syndrome — Ellisona and other hyper secretory morbid conditions.

Contraindication

Hypersensitivity to active agent, derivatives of benzimidazole or any component of drug.

Use

Adults and children aged from 12 years

Treatment a reflux esophagitis. The recommended dose for children aged from 12 years and adults makes 1 tablet Controloka of 40 mg of 1 times a day. In some cases a dose it is possible to double (2 tablets Controloka of 40 mg/days), especially in the absence of effect of use of other medicaments for treatment a reflux esophagitis.

reflux esophagitis, as a rule, is required to

For treatment 4 weeks. If it is not enough, treatment can be expected during the following 4 weeks

Adult

Eradikation H. rylori's

in a combination with two antibiotics. At adult patients with ulcer of stomach and duodenum and with positive take on H. pylori the eradikation of a microorganism needs to reach by means of combination therapy. It is necessary to take into account local data concerning bacterial resistance and national recommendations concerning use and prescribing of the appropriate antibacterial agents. Depending on sensitivity for Helicobacter pylori eradikation at adults such therapeutic combinations can be appointed:

• a) 1 tablet of the medicament Controlok of 40 mg 2 times a day + 1000 mg of amoxicillin 2 times a day + 500 mg of a klaritromitsin 2 times a day;
• b) 1 tablet of the medicament Controlok of 40 mg 2 times a day + 400–500 mg of metronidazole (or 500 mg of Tinidazolum) 2 times a day + 250–500 mg of a klaritromitsin 2 times a day;
• c) 1 tablet of the medicament Controlok of 40 mg 2 times a day + 1000 mg of amoxicillin 2 times a day + 400–500 mg of metronidazole (or 500 mg of Tinidazolum) 2 times a day.

At use of combination therapy for an eradikation of H. pylori the second tablet of the medicament Controlok of 40 mg should be taken in the evening for 1 h to food. Duration of treatment is 7 days and can be prolonged for 7 days with lasting treatments no more than 2 weeks

If for ensuring healing of an ulcer the further treatment pantoprazoly is shown, it is necessary to consider recommendations concerning dosing in ulcer of stomach and duodenum. If combination therapy is not shown, for example, to patients with negative take on H. pylori, for monotherapy the medicament Controlok of 40 mg is used in the following dose.

Treatment of stomach ulcer. 1 tablet of the medicament Controlok of 40 mg a day. In some cases it is possible to double a dose (2 tablets of the medicament Controlok of 40 mg a day), especially in the absence of effect of use of other drugs.

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For treatment of stomach ulcer, as a rule, needs 4 weeks. If it is not enough, healing of an ulcer can be expected during the following 4 weeks

Treatment of an ulcer of a duodenum. 1 tablet of the medicament Controlok of 40 mg a day. In some cases it is possible to double a dose (2 tablets of the medicament Controlok of 40 mg a day), especially in the absence of effect of use of other drugs.

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For treatment of an ulcer of a duodenum, as a rule, needs 2 weeks. If it is not enough, healing of an ulcer can be expected during the following 2 weeks

Treatment of a syndrome of Zollinger — Ellison and other hyper secretory morbid conditions. For long-term treatment of a syndrome of Zollinger — Ellison and other morbid hyper secretory conditions the initial daily dose makes 80 mg (2 tablets of the medicament Controlok on 40 mg). If necessary after that the dose can be titrated, raising or reducing depending on indicators of acidity of gastric juice. The dose exceeding 80 mg/days needs to be divided into 2 receptions. Perhaps temporary increase in a dose to more than 160 mg of a pantoprazol, but duration of use has to be limited only to the period necessary for adequate control of acidity.

Duration of treatment of a syndrome of Zollinger — Ellison and other morbid conditions is not limited to

and depends on clinical need.

Patients with an abnormal liver function. Patients with heavy abnormal liver functions should not exceed a daily dose of 20 mg (1 tablet of the medicament Controlok of 20 mg). It is not necessary to use the medicament Controlok for an eradikation of H. pylori of combination therapy to patients from the liver of average and heavy degree broken by function as there are no data on efficiency and safety of such use for this category of patients for today. it is not required by

For patients with a renal failure of dose adjustment to p. Patients with a renal failure should not use the medicament Controlok for an eradikation of H. pylori in combination therapy as there are no data on efficiency and safety of such use for this category of patients now. it is not required by

For patients of advanced age of dose adjustment to p.

Special instructions

Abnormal liver function. patients with heavy abnormal liver functions need to control regularly the level of liver enzymes, especially at long-term treatment. in case of increase in level of liver enzymes the medicament treatment needs to be stopped (see use).

Combined use with NPVP. Use of the medicament Controlok, a tablet on 20 mg, for the prevention of stomach ulcer and a duodenum caused by long reception of NPVP it is necessary to limit at the patients inclined to frequent exacerbations of stomach ulcer and a duodenum.

Assessment of risk level is carried out by

taking into account individual risk factors, including age (65 years), the anamnesis of development of stomach ulcer or a duodenum and also gastrointestinal bleedings.

Malignant new growths of a stomach. The symptomatic response to use of a pantoprazol can mask symptoms of malignant new growths of a stomach and postpone their diagnostics in time. In the presence of disturbing symptoms (for example in case of significant degrowth of a body, periodic vomiting, a dysphagy, vomiting with blood, anemias, melenas) and also at suspicion or presence of stomach ulcer it is necessary to exclude existence of malignant process.

If symptoms remain at adequate treatment, it is necessary to perform additional examination.

HIV protease Inhibitors. Simultaneous use of a pantoprazol with HIV protease inhibitors (such as atazanavir) which absorption depends on an intragastric rn, because of significant decrease in their bioavailability is not recommended (see INTERACTIONS).

Absorption of _{12 vitamin B} . At patients with Zollinger's syndrome — Ellisona and other hyper secretory morbid conditions which need long-term treatment pantoprazol, as well as all medicaments blocking products of hydrochloric acid can reduce absorption of _{12 vitamin B} (cyanocobalamine) in connection with emergence hypo - and achlorhydrias. It should be considered at degrowth of a body at patients or presence of risk factors of decrease in absorption of _{12 vitamin B} at long-term treatment or existence of the corresponding clinical symptoms.

Long treatment. At long treatment, especially more than 1 year, patients have to be under regular observation of the doctor.

Infection of a GIT, caused by bacteria. The Controlok medicament treatment can increase several risk developing of the gastrointestinal infections caused by such bacteria as Salmonella and Campylobacter or C. difficile.

Hypomagnesiemia. Cases of a heavy hypomagnesiemia at the patients receiving IPP, such as pantoprazol, within not less than 3 months and in most cases during 1 year were observed. Can arise and at first imperceptibly develop the following serious clinical manifestations of a hypomagnesiemia: fatigue, tetany, delirium, spasms, dizziness and ventricular arrhythmia. At a hypomagnesiemia in most cases the condition of patients improved after the replacement adjusting therapy by medicaments of magnesium and the termination of reception of IPP.

to the Patients demanding long therapy or patients who accept IPP along with digoxin or medicaments which can cause a hypomagnesiemia (for example diuretics) should determine by

magnesium level before an initiation of treatment of IPP and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 year) high doses of IPP can moderately increase risk of a fracture of hip, wrist and backbone, mainly at elderly people or with other risk factors. Observation researches indicate that use of IPP can increase the general risk of changes by 10–40%. Some of them can be caused by other risk factors. Patients with risk of developing osteoporosis have to receive treatment according to the existing clinical recommendations and use enough vitamin D and calcium.

Subacute skin lupus erythematosus. Use of IPP is connected with very exceptional cases of development of a subacute skin lupus erythematosus. At defeat emergence, especially on the sites which are affected by the sunlight which is followed by an arthralgia, the patient needs to see a doctor who will consider need of medicament withdrawal immediately. Emergence of a subacute skin lupus erythematosus at patients during the previous therapy of IPP can increase risk of its development at use of other IPP.

Influence on results of laboratory researches.

Increased level of chromogranin A (CgA) can affect results of researches at diagnosis of neuroendocrinal tumors. To avoid such influence, the Controlok medicament treatment should be stopped temporarily at least in 5 days prior to evaluating the CgA level (see the Pharmacodynamics). If the CgA levels and gastrin did not return to the range of normal values after initial measurement, it is necessary to take repeated measurements in 14 days after cancellation of treatment of IPP.

Use during pregnancy and feeding by a breast

Pregnancy. The available data on use of the medicament Controlok for pregnant women (about 300-1000 messages about results of pregnancy) indicate absence embryonal or feto / neonatal toxicity of drug. During the researches on animals observed reproductive toxicity. As a measure of restraint it is necessary to avoid use of the medicament Controlok for pregnant women.

Feeding by a breast. Researches on animals showed excretion of a pantoprazol in breast milk. There are not enough data on excretion of a pantoprazol in breast milk of the person, however about that it was reported. It is impossible to exclude risk for newborns/babies. The decision on the feeding termination by a breast or termination/abstention from the Controlok medicament treatment should be accepted taking into account advantage of feeding by a breast for the child and advantage of the Controlok medicament treatment for the woman.

Fertility. Pantoprazol did not break fertility in researches on animals.

Children. Controlok do not recommend to apply at children aged up to 12 years as data on safety and efficiency of medicament for this age category are limited.

Controlok of 40 mg is shown by

to children aged 12 years for treatment a reflux esophagitis are more senior.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Pantoprazol does not influence or has very insignificant impact on ability to run vehicles or to work with other mechanisms. It is necessary to take possible development of side reactions, such as dizziness and disorder of vision into account (see. Side EFFECTS). In such cases it is not necessary to run vehicles or to work with other mechanisms.

Overdose to

Symptoms of overdose are unknown to

.

at in in introduction within 2 min. were well transferred by

Dose up to 240 mg.

As pantoprazol extensively contacts proteins, it does not belong to medicaments which are easily removed by means of dialysis.

in case of overdose with clinical signs of intoxication perform symptomatic and maintenance therapy. There are no recommendations of rather specific therapy.

Side effects

noted Emergence of side reactions at about 5% of patients. frequent side reactions — diarrhea and a headache (about 1%).

Undesirable effects on the frequency of emergence classify

by such categories: very often (≥1/10), it is frequent (≥1/100 and 1/10), infrequently (≥1/1000 and 1/100), is rare (≥1/10,000 and 1/1000), is very rare (1/10,000), it is unknown (frequency is not determined by the available data). For all side reactions about which it was reported during the post-marketing period it is impossible to determine frequency therefore they are designated by the term it "is unknown".

frequency of side reactions is noted by

within each category in decreasing order of gravity.

from blood and lymphatic system: seldom — an agranulocytosis; very seldom — a leukopenia, thrombocytopenia, a pancytopenia.

from the immune system: seldom — reactions of hypersensitivity (including anaphylactic reactions, an acute anaphylaxis).

Metabolism and disbolism: seldom — a lipidemia and increase in level of lipids (TG, XC), changes of body weight; it is unknown — a hyponatremia, a hypomagnesiemia (see. Special INSTRUCTIONS), hypocalcemia ¹ , hypopotassemia.

Mental disturbances: infrequently — a sleep disorder; seldom — a depression (including aggravation); very seldom — a disorientation (including aggravation); it is unknown — hallucinations, confusion of consciousness (especially at patients with tendency to these disorders and also aggravation of these symptoms in case of their existence).

from nervous system: infrequently — a headache, dizziness; seldom — disturbances of taste; it is unknown — paresthesia.

from an organ of sight: seldom — disturbance sight/misting.

from a digestive tract: often — polyps from fundal glands (benign); infrequently — diarrhea, nausea, vomiting, an abdominal distension, a constipation, dryness in a mouth, abdominal pain and discomfort.

from a gepatobiliarny system: infrequently — increase in level of liver enzymes (transaminases, gamma glutamiltransferazy); seldom — increase in level of bilirubin; it is unknown — damage of hepatocytes, jaundice, hepatocellular insufficiency.

from skin and hypodermic fabrics: infrequently — skin rash, a dieback, an itching; seldom — urticaria, a Quincke's disease; it is unknown — Stephens's syndrome — Johnson, a Lyell's disease, a multiformny erythema, a photosensitization, a subacute skin lupus erythematosus (see. Special INSTRUCTIONS).

from a musculoskeletal system and connective tissue: infrequently — a fracture of a hip, wrist or backbone (see. Special INSTRUCTIONS); seldom — an arthralgia, myalgia; it is unknown — a spasm of muscles ² .

from kidneys and an urinary system: it is unknown — interstitial nephrite (with possible development of a renal failure).

from a reproductive system and mammary glands: seldom — a gynecomastia.

General disturbances: infrequently — an asthenia, fatigue, an indisposition; seldom — fervescence, peripheral hypostases.

¹ Hypocalcemia along with a hypomagnesiemia.

² Spasm of muscles owing to disturbance of balance of electrolytes.

Interaction

Medicines which absorption depends from rn. as a result of complete and long inhibition of secretion of hydrochloric acid pantoprazol can influence absorption of medicaments for which the value rn gastric juice is an important factor of their bioavailability (for example some antifungal drugs, such as ketokonazol, itrakonazol, pozakonazol, or other drugs, such as erlotinib).

HIV protease Inhibitors. The combined use of a pantoprazol with HIV protease inhibitors is not recommended (such as atazanavir) which absorption depends on an intragastric rn, because of significant decrease in their bioavailability (see. Special INSTRUCTIONS).

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In case the combined use of inhibitors of HIV protease with IPP cannot be avoided, recommends careful clinical monitoring (for example viral load). It is not necessary to exceed a daily dose of a pantoprazol in 20 mg. There can be a need for dose adjustment of inhibitors of HIV protease.

Coumarinic anticoagulants (fenprokumon and warfarin). The combined use of a pantoprazol with warfarin or fenprokumony did not influence pharmacokinetics of warfarin, a fenprokumon or the international normalized index (INI). However it was reported about increase THINK also lengthening of a prothrombin time at the patients who were at the same time applying IPP and warfarin or fenprokumon. RUMPLE increase and lengthening of a prothrombin time can be led to development of pathological bleeding and even death. In case of such combined use it is necessary to carry out monitoring THINK also a prothrombin time.

Methotrexate. It was reported that simultaneous use of high doses of a methotrexate (for example 300 mg) and IPP increases methotrexate levels in blood at some patients. To patients, for example, the cancer patient accepting high doses of a methotrexate or psoriasis, it is recommended to stop temporarily treatment pantoprazoly.

Other interactions. Pantoprazol is substantially metabolized in a liver through the system of enzymes of P450 cytochrome. The main way of metabolism — demethylation by means of CYP2C19 and other metabolic ways, including oxidation by CYP3A4 enzyme. Researches with medicines which are also metabolized by means of these ways such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinylestradiol did not reveal clinically significant interactions.

Cannot exclude interaction of a pantoprazol with other medicaments which are metabolized through the same fermental system.

Results of a number of researches of possible interactions specify that pantoprazol does not influence metabolism of active agents which are metabolized by means of CYP1A2 (for example caffeine, theophylline), CYP2C9 (for example piroxicam, diclofenac, Naproxenum), CYP2D6 (for example metoprolol), CYP2E1 (for example ethanol), does not influence a r-glycoprotein which is associated with digoxin absorption.

by

did not reveal interaction with at the same time appointed antacids.

by

conducted researches on studying interaction of a pantoprazol with at the same time appointed certain antibiotics (klaritromitsin, metronidazole, amoxicillin). Clinically significant interactions between these medicaments are not revealed.

Medicines which inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoksamin, can increase system influence of a pantoprazol. It is necessary to consider need of a dose decline of medicament for patients who receive long therapy pantoprazoly in high doses, and for patients with abnormal liver functions. Inductors of the enzymes influencing CYP2C19 and CYP3A4, such as rifampicin and St. John's wort usual (Hyper_cum perforatum) can reduce plasma concentration of IPP which are metabolized through these fermental systems.

Storage conditions

does not demand special storage conditions.

UA/(PPIF)/1018/0045.