PROXIUM

APPROVED

by Order of the Ministry of Health

of Ukraine

as of __________ No. ______

Registration Certificate

No. ________________

INSTRUCTION

For medical application of drug

PROXIUMTM

 

Drug Formulation:

active substance: pantoprazole;

1 tablet contains sodium pantoprazole in terms of water-free substance 40 mg;

adjuvants: water-free lactose, corn starch, povidone, magnesium stearate, water-free colloid silicon dioxide;

membrane: methacrylate copolymer dispersion, polyethylene oxide, talc, titanium dioxide (E 171), sunset yellow FCF (E 110).

Dosage Form. Tablets coated with membrane, intestine-soluble.

Pharmacotherapeutic Group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors.

ATC Code A02B C02.

Clinical Characteristics.

Indications.

  • Moderate and severe reflux-esophagitis;
  • Helicobacter pylori eradication in patients with peptic ulcers caused by this microorganism, in combination with certain antibiotics (See Section “Method of Application and Dosage”).
  • Duodenal ulcer.
  • Gastric ulcer.
  • Zollinger-Ellison syndrome and other pathologic hypersecretory conditions.

 

Contraindications.

Hypersensitivity to pantoprazole or any other component of the drug.

ProxiumTM should not be used for combined therapy aimed at H. pylori eradication in patients with liver or renal impairment of moderate or severe degree.

Similarly to other proton pump inhibitors, pantoprazole is contraindicated for use with atazanavir (See Section “Interaction with Other Drugs and Other Types of Interaction”).

Pregnancy and breast-feeding period.

Children’s age under 14.

Method of Application and Dosage.

Treatment of moderate and severe reflux-esophagitis.

For children above 14 and adults the recommended dose is 1 tablet of ProxiumTM 40 mg per day. In some cases the dose may be doubled (2 tablets of ProxiumTM 40 mg per day), especially when there is no effect from use of other drugs.

In adult patients with gastric and duodenal ulcer and positive result for H. pylori the microorganism eradication shall be achieved by means of combined therapy. Depending on the microorganisms susceptibility, the following therapeutic combinations may be used in adults with the purpose of H. pylori eradication:

a)   1 tablet of ProxiumTM 40 mg twice a day

+ 1000 mg of amoxicillin twice a day

+ 500 mg of clarithromycin twice a day;

b)   1 tablet of ProxiumTM 40 mg twice a day

+ 500 mg of metronidazole twice a day

+ 500 mg of clarithromycin twice a day;

c)   1 tablet of ProxiumTM 40 mg twice a day

+ 1000 mg of amoxicillin twice a day

+ 500 mg of metronidazole twice a day.

 

If there are no indications for combined treatment, for example in case of patients with negative result for H. pylori, the recommended dose of ProxiumTM 40 mg for monotherapy of gastric and duodenal ulcer is 1 tablet of ProxiumTM 40 mg once a day. In some cases the dose may be doubled (2 tablets of ProxiumTM 40 mg per day), especially if other drugs do not give any effect.

 

The daily dose for long-term treatment of Zollinger-Ellison syndrome and other pathologic hypersecretory conditions is 80 mg (2 tablets of ProxiumTM 40 mg). If necessary the dose may be titrated afterwards, increased or decreased depending on gastric acid secretion indices. In case of dosage that exceeds 80 mg per day, the dose should be divided into two takings. Temporary increase in dose over 160 mg of pantoprazole is possible, but the duration of application must be limited to the period required for adequate control of acid secretion.

 

Duration of treatment of Zollinger-Ellison syndrome and other pathologic conditions is unlimited and depends on the clinical need.

 

In patients with severely impaired liver function the dose may be reduced to 1 tablet of ProxiumTM 40 mg once per two days. Moreover, in case of such patients it is necessary to monitor the level of liver enzymes. In case of increase in their levels the treatment with ProxiumTM shall be stopped.

 

Elderly patients and patients with impaired renal function should not exceed the pantoprazole daily dose of 40 mg. The exception is made for combined therapy aimed at eradication of H. pylori in course of which elderly patients should receive ordinary daily dose of pantoprazole (1 tablet of ProxiumTM 40 mg twice a day) during 1 week.

 

General Instructions.

ProxiumTM tablets resistant to gastric juice should be taken 1 hour before breakfast with water, without chewing or grinding them. In case of combined therapy aimed at eradication of H. pylori, the second tablet of ProxiumTM should be taken before supper. As a rule the combined therapy lasts for 7 days, but it may be prolonged up to 2 weeks maximum. If the ulcer treatment requires further treatment with pantoprazole, it is necessary to consider recommendations concerning dosage for gastric and duodenal ulcer.

As a rule, duodenal ulcer is treated during 2 weeks. If this period of two weeks turns out to be insufficient, the recovery should be expected within the following 2 weeks.

Treatment of gastric ulcer and reflux-esophagitis usually takes 4 weeks. If this period is not enough, the recovery should be expected within the following 4 weeks.

 

Side effects.

According to the frequency of occurrence the side effects are classified into the following categories:

often (> 1/100 and < 1/10),

not often (> 1/1000 and < 1/100),

rarely (> 1/10000 and < 1/1000),

very rarely (< 1/10000), including isolated cases.

 

On blood system and lymphatic system

Very rarely: leukopenia, thrombocytopenia.

 

On immune system

Very rarely: anaphylactic reactions including anaphylactic shock.

 

General disorders

Very rarely: peripheral oedema.

Rarely: depression, hallucinations, disorientation, agitation, excitement, especially in patients with such predisposition, as well as exacerbation of such symptoms if they are present.

On nervous system

Very often: headache.

Not often: dizziness, vision disorders in the form of visual hallucinations.

 

On gastrointestinal tract

Often: pain in epigastric area, diarrhoea, constipation, meteorism.

Not often: nausea/vomiting.

Rarely: dry mouth.

 

On liver:

Very rarely: increase in level of liver enzymes (transaminases, GGT), triglycerides, increased body temperature, severe hepatocellular disorder which leads to jaundice with/without liver impairment.

 

On skin and subcutaneous tissues

Not often: allergic reactions (itching, rash).

Very rarely: urticaria, Quincke’s oedema, Stevens-Johnson syndrome, erythema multiforme, Lyell’s syndrome, photosensitization.

 

On musculoskeletal system and connective tissues

Rarely: arthralgia, myalgia.

 

On urinary system

Very rarely: interstitial nephritis.

 

On reproductive system and mammary glands

Very rarely: gynecomastia.

 

Other

Very rarely: peripheral oedemas, increased body temperature, hypernatremia in elderly patients.

 

Overdosage.

Symptoms of overdosage are unknown.

In case of overdosage with symptoms of intoxication it is necessary to take general disintoxication measures.

Application during Pregnancy and Breast-Feeding Periods.

The drug is not applied during pregnancy period.

Breast-feeding shall be stopped during the period of treatment with ProxiumTM.

Children.

ProxiumTM shall not be applied in children under 14.

Peculiarities of Application.

Before starting the treatment it is necessary to exclude malignant neoplasms in oesophagus or stomach, since application of the drug may mask the symptoms and delay the correct diagnostics.

In case of any alarming symptoms (e.g., significant and sharp loss of body weight, periodic vomiting, dysphagia, hematemesis, anaemia or melena) or suspicion/presence of gastric ulcer disease, it is necessary to exclude possibility of malignization.

If the symptoms of disease remain even after adequate treatment the further tests are required.

It is necessary to limit application of drug with the purpose of gastric and duodenal ulcer prevention in patients that have been applying NSAD for a long period of time or are in high-risk group.

The level of risk is evaluated with account to individual risk factors including age (over 65), history of development of gastric or duodenal ulcer, as well as gastrointestinal bleedings.

Pantoprazole may decrease absorption of vitamin B12 (cyanocobalamin) which may result in hypo- or achlorhydria. This should be taken into account in case of long-term application of the drug, as well as in case of patients with low body weight.

In case of long-term treatment, especially over 1 year, the patients should remain under constant observation.

Application in case of liver diseases. In patients with severe liver impairment it is required to adjust the dose of ProxiumTM in accordance with liver function indices. In course of drug application, especially in case of long-term treatment, it is necessary to systematically control the level of liver enzymes. In case of increase in level of liver enzymes, the drug application shall be stopped. Such patients need regular medical control.

Application in case of renal diseases. Patients with severe renal impairment shall reduce the dose. In course of treatment it is necessary to monitor the level of renal function indices.

The drug contains lactose, therefore the patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take the drug.

Ability to Affect Rate of Reactions when Driving or Operating Other
Mechanisms

Taking into consideration the fact that sensitive patients taking the drug may demonstrate some side reactions (dizziness, visual impairment in form of visual hallucinations), such patients shall avoid driving transport vehicles or performing other tasks requiring attention focusing during the course of treatment.

 

Interaction with Other Drugs and Other Types of Interaction.

ProxiumTM may inhibit absorption of drugs bioavailability of which depends on gastric acidity (e.g., ketoconazole, or itroconazole).

In course of simultaneous application of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once a day) or atazanavir 400 mg with lansoprazole (60 mg once), the significant decrease in atazanavir bioavailability in healthy volunteers took place. Atazanavir absorption depends on acidity of gastric juice. Thus, inhibitors of proton pump, including pantoprazole, should not be used along with atazanavir.

There is a possibility of interaction with drugs that are metabolized in liver with the help of CYP3A and CYP 2C19 enzymes. Special-purpose research has not been detected any clinically significant interaction of pantoprazole with carbamazepine, caffeine, diazepam, diclofenac, ethanol, glibenclamid, naproxen, digoxin, glibenclamid, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, teofilin, and oral contraceptives.

In case of patients that take indirect anticoagulants, phenprocoumon, warfarin, it is recommended to do laboratory tests for blood coagulability at the beginning and at the end, as well as in case of irregular treatment with pantoprazole.

Application with antacids. No clinically significant interaction was observed in case of simultaneous application with antacids.

Application with antibiotics. No clinically significant interaction was observed in course of study of pantoprazole interaction with relevant antibiotics (clarithromycin, amoxicillin).

Pharmacological Properties.

Pharmacodynamics. Pantoprazole – an active substance of ProxiumTM – inhibits secretion of hydrochloric acid in stomach by influencing the proton pump of parietal cells.

Pantoprazole is transformed into its active form in acid environment, namely: in stomach parietal cells where it inhibits H+/K+-ATP, i.e. the final stage of hydrochloric acid formation irrespective of the nature of irritant that stimulates its formation. Inhibition is dose-dependent and influences the basal and stimulated secretion of gastric juice. Treatment with pantoprazole reduces the level of gastric acidity which leads to proportional increase in gastrin secretion. Increase in gastrin level is reversible.

In most cases of short-term treatment the gastrin levels do not exceed the upper limit of norm. In most cases of long-term treatment the gastrin levels are doubled. Excessive increase of them was rarely observed. In some cases it resulted in slight or moderate increase in number of various stomach endocrine cells (adenomatoid hyperplasia).

Pharmacokinetics. Pantoprazole is rapidly absorbed, maximum concentration (Cmax) in plasma is reached even after the one dose of 40 mg. In average, Cmax of 2-3 mcg/ml is reached in 2.5 hours after taking; these levels remain the same after repeated application of the drug. Distribution volume is 0.15 l/kg, its clearance is about 0.1 l/hour/kg.  Period of half-excretion is 1 hour. Due to specific activation of pantoprazole in parietal cells the period of half-excretion does not correlate with the duration of action (inhibition of acid secretion).

Pharmacokinetics does not change after single-time or repeated taking. Within the dose range between 10 mg and 80 mg the pantoprazole pharmacokinetics remains linear both when introduced orally and intravenously.

Binding with plasma proteins is 98%. The drug is metabolized in liver. Metabolites are mainly excreted by kidneys (almost 80%), 20% are excreted with faeces. The main metabolite in plasma and urine is desmethyl pantoprazole bound with sulphate. Period of half-excretion of the main metabolite (1.5 hour) is not much longer than that of pantoprazole.

Bioavailability. Pantoprazole is completely absorbed after having been taken orally. The absolute bioavailability of tablets is 77%. Food intake does not influence the AUC (area under “concentration-time” curve), Cmax, and bioavailability.

Characteristics for specific groups of patients. Patients with impaired renal function (including patients on haemodialysis) do not need reduction of pantoprazole dose. Similar to healthy volunteers, the period of half-excretion is short in such patients. Small part of pantoprazole is dialysed. Notwithstanding the fact that the period of half-excretion of the main metabolite is slightly increased (2-3 hours), it is rapidly excreted and therefore is not accumulated.

Although in patients with liver cirrhosis (A and B type) the period of half-excretion of active substance is increased up to 7-9 hours and respective increase in AUC takes place, Cmax of pantoprazole in plasma is increased by 1.3 times as compared to healthy volunteers.

Slight increase in AUC and Cmax in elderly patients as compared to younger patients is not clinically significant.

 

Pharmaceutical Characteristics.

Main Physicochemical Properties: round-shaped, biconvex tablets coated with intestine-soluble membrane, of orange colour, with smooth surface. At cross fracture one may see the nucleus coated with the membrane.

 

Effective Period.

3 years.

Storage Conditions.

Store in original packaging under the temperature below 25°C.

Store in place out of reach of children.

 

Packaging.

10 tablets in blister, 1 or 3 blisters in a pack.

Category of Selling.

On prescription.

Manufacturer.

OJSC “Lubnypharm”.

Location

16 Petrovskogo St., Lubny, Poltava Region, 37500 Ukraine.

Date of Last Revision.

Stamp: agreed with the materials of registration file and reliable data concerning application of the drug.