Normogastrol Efg 20 Mg 14 Gastro-resistant tablets

Normogastrol Efg (20 Mg 14 Gastro-resistant Tablets)

Pantoprazole 20Mg

ACTION AND MECHANISM

- Peptic ulcer, H + / K + pump inhibitor. Pantoprazole is a benzimidazole that acts as a specific, non-competitive and irreversible inhibitor of the proton pump (PPI) or H + / K + ATPase, located on the surface of the gastric parietal cell. The blockade of this proton pump prevents the production of gastric acid, both basal and in the event of a stimulus, regardless of which is (acetylcholine, gastrin or histamine).

Pantoprazole is a prodrug with a weak base nature, which after absorption is distributed throughout the body, especially in the lumen of the secretory canaliculi of the parietal cell. Here, and in the presence of an acid medium, it undergoes a non-enzymatic chemical reaction giving rise to the active form, a totally hydrophilic sulfonamide derivative, which tends to accumulate in the canaliculi and bind to the proton pump through disulfide bonds with the cysteine ​​residues of the alpha-luminal chain.

Due to the formation of covalent bonds, the only way for the parietal cell to recover its secretory activity is the synthesis of new pumps, which takes a long period of time and explains the long duration of the effects of PPIs, which can it can last up to 4 days after the administration of a single dose, despite its low t1 / 2.

The effects on acid production begin to appear after 15-30 min (iv) or 2.5 h, and can last for 24 h. Some studies have shown that basal hydrochloric acid secretion does not normalize until 7 days after discontinuation of pantoprazole.

PHARMACOKINETICS

Oral, parenteral route:

Pantoprazole is a prodrug, and after its absorption and distribution to the parietal cell, it is transformed by an acid-catalyzed chemical reaction into the active sulfonamido derivative.

It has linear pharmacokinetics at doses between 10-80 mg.

- Absorption: rapid digestive absorption, obtaining a cmax of 1-1.5 mcg / ml (20 mg) and 1.91-2.2 mcg / ml (40 mg) after 2-2.5 h. It has a small hepatic first pass effect and its bioavailability is 77%.

Effect of food : they do not significantly affect the amount absorbed (cmax, bioavailability), although they can delay absorption for up to 2 hours.

- Distribution: high binding to plasma proteins (98%), mainly albumin. Your Vd is 0.15-0.43 l / kg.

- Metabolism: extensive hepatic metabolism by demethylation (CYP2C19) giving rise to desmethyl-pantoprazole, the main metabolite that subsequently undergoes sulphation. It is also metabolized to a lesser extent by CYP3A4, while CYP2C9 and 2D6 are minimally involved. Active metabolites have not been described.

Enzyme inducing / inhibiting capacity : pantoprazole does not show activity on cytochrome P450 isoenzymes (such as CYP1A2, 2C9, 2D6 or 2E1), nor on P-gp. It also does not appear to have significant CYP2C19 inhibitory activity, unlike omeprazole or esomeprazole.

- Excretion: in urine (71%) and feces (18%), as metabolites. The t1 / 2 is 1 h and its CLt 0.1 l / h / kg.

Pharmacokinetics in special situations :

- Children: in the trials carried out with pantoprazole in children and adolescents (5-16 years po; 2-16 years iv) no differences were found in pharmacokinetics compared to adults.

- Elderly: patients> 65 years of age present an increase in AUC and cmax, although it does not seem to be of clinical importance.

- Renal impairment: no significant pharmacokinetic differences have been observed. Pantoprazole is not significantly removed by hemodialysis.

- Hepatic impairment: cirrhotic patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) have a 3-5-fold increase in AUC and 1.3-fold increase in cmax, while t1 / 2 is increases 3-6 h.

- Pharmacogenetics: about 1-3% of the Caucasian population and 20% of the Asian population lack functional CYP2C19, which are considered poor metabolizers, compared to patients who have the isoenzyme and are considered rapid metabolizers. In poor metabolisers, hepatic metabolism of pantoprazole is by CYP3A4. Cmax has been found to increase 60% and AUC 6-fold in these patients, although no significant clinical impact has been reported, and no specific dosage adjustments have been recommended.

INDICATIONS

- Short-term treatment of the symptoms of [GASTROESOPHAGIC REFLUX], such as [GASTRIC HYPERACIDEZ] or acid regurgitation in adults.

POSOLOGY

"ORAL ADMINISTRATION"

- Adults:

* Gastric reflux: 20 mg / 24 h. Typically 2-3 days of treatment are required to eliminate symptoms. If symptoms continue or worsen after 2 weeks of treatment, consult your doctor.

Avoid treatments longer than 4 weeks without medical recommendation.

- Children and adolescents <18 years:

Safety and efficacy have not been evaluated.

- Elderly: does not require dosage adjustment.

Missed dose : take the next dose at the usual time. Do not double the dose in the next administration.

DOSAGE IN KIDNEY INSUFFICIENCY

It does not require dosage adjustment.

DOSAGE IN LIVER INSUFFICIENCY

- Mild to moderate hepatic impairment (Child-Pugh classes A and B): does not require dosage adjustment.

- Severe hepatic impairment (Child-Pugh class C): maximum dose 20 mg / 24 h.

RULES FOR CORRECT ADMINISTRATION

- Gastro-resistant tablets: swallow whole with the help of a glass of liquid. They should not be chewed, crushed or split.

Administration with food : administer 1 h before one of the main meals.

CONTRAINDICATIONS

- Hypersensitivity to pantoprazole, any other PPI, or any other component of the drug.

PRECAUTIONS

- [DIGESTIVE INFECTIONS]. The increase in gastric pH produced by antiulcer drugs could favor the colonization of the digestive system by certain pathogenic microorganisms, such as Salmonella, Campylobacter and even Clostridium difficile in hospitalized patients. A differential diagnosis of [PSEUDOMEMBRANOUS COLITIS] is recommended in patients treated with an antiulcer in whom severe diarrhea occurs.

- Long-term treatment. Antiulcer drugs eliminate the symptoms related to acid diseases, which are common to those of malignant processes such as [STOMACH CANCER] or [ESOPHAGUS CANCER]. Therefore, there is a risk of delaying the diagnosis of these processes.

It is recommended that patients who receive prolonged treatment, greater than a year, are subjected to regular surveillance, and that they be warned to report the presence of other symptoms associated with these neoplasms, such as significant and unjustified weight loss, recurrent vomiting , dysphagia or vomiting in blood or stool. In case of suspicion of a serious digestive process, a differential diagnosis is recommended.

- [CYANOCOBALAMINE DEFICIT]. The increase in pH produced by antiulcer drugs could decrease the absorption of cyanocobalamin, so it is recommended to take it into account in people with low deposits of this vitamin, such as in patients with [MALNUTRITION] or strict vegetarian diets without supplementation is this vitamin , or situations in which its absorption could be reduced, such as in [CHRONIC ALCOHOLISM], [INTESTINAL MALABSORPTION] or situations that could lead to malabsorption, such as [INFLAMMATORY INTESTINAL DISEASE] or major surgical processes of the digestive system.

- [HYPOMAGNESEMIA]. Treatment with PPIs has been associated with the development of severe cases of hypomagnesemia, which could be associated with [HYPOCALCEMIA]. Its frequency has not been estimated, but it is considered rare. However, the great use of these drugs must be taken into account, so their clinical impact could be significant. Most of the patients who presented hypomagnesemia were on long-term treatment (at least 3 months and mainly 1 year).

It is recommended to monitor magnesium levels at the beginning of treatment and periodically throughout it in patients on long-term treatment with PPIs, on treatment with digoxin or with drugs that could lead to hypomagnesemia, such as diuretics.

In the event of symptoms of hypomagnesemia, such as tiredness, dizziness, tetany, delirium, seizures or cardiac arrhythmia, magnesium levels should be determined. Hypomagnesemia responds to removal of PPI and magnesium supplementation.

- [OSTEOPOROSIS]. The administration of PPIs at high doses and for prolonged periods of time (> 1 year) has been associated with an increased risk of hip, wrist and vertebral fracture, especially in the elderly and with risk factors. It is therefore advised that women with osteoporosis receive treatment and an adequate intake of calcium and vitamin D.

- [PNEUMONIA]. Treatment with PPIs has been associated with cases of pneumonia, including community-acquired pneumonia (CAP), interstitial pneumonia, or nosocomial pneumonia. The risk seems to be higher in patients who have just started a treatment (especially <2 days), rather than in long-term treatments.

- [LUPUS ERYTHEMATOSUS CUTANEO SUBACUDO] (LECS). PPIs have been associated with very rare cases of subacute cutaneous lupus erythematosus. In the event of skin lesions, especially in areas exposed to the sun, accompanied by arthralgia, consider interrupting treatment. Patients with LECS from a PPI may re-experience this condition if they receive a different PPI.

- Analytical interferences. The increase in gastric pH induced by antiulcer drugs can increase plasma levels of gastrin (which usually return to basal levels 4 weeks after stopping treatment) and chromogranin A (CgA).

CgA is a specific marker for neuroendocrine tumors, so antiulcer drugs could lead to false positives when this marker is used in diagnostic tests. Therefore, any antiulcer must be discontinued at least 5 days before the determination of CgA. If the CgA levels have not normalized in this period, the test should be repeated 14 days after the suspension of the antiulcer.

- [LIVER FAILURE]. Pantoprazole is eliminated primarily by hepatic metabolism, which could lead to accumulation of the drug. However, after daily administration no accumulation has been observed, and in fact it does not seem necessary to readjust the dosage. It is advised to use with caution, especially in patients with severe hepatic impairment (Child-Pugh class C), in whom liver function (transaminase levels) should be monitored. In the event of a significant increase, discontinue pantoprazole.

ADVICE TO THE PATIENT

- Do not stop treatment until your doctor tells you to, even if the symptoms have disappeared. A premature suspension could cause symptoms to reappear.

- If you are undergoing treatment "on demand" (administered when symptoms appear), notify your doctor and / or pharmacist of any change in your usual symptoms.

- Advise your doctor about the medications you are taking.

- Tell your doctor and / or pharmacist if you have any of these symptoms:

* Intense and / or persistent diarrhea.

* Significant and unjustified weight loss, frequent vomiting, difficulty swallowing or presence of blood in vomit or stool.

* Unexcused tiredness, dizziness, muscle stiffness, seizures or cardiac arrhythmias.

* Appearance of skin lesions, especially in areas exposed to the sun, accompanied by joint pain.

- If you are undergoing treatment "on demand" (administered when symptoms appear), notify your doctor and / or pharmacist of any change in your usual symptoms.

- Consult your doctor or pharmacist if you are over 55 years old and you are starting treatment with pantoprazole for the first time.

SPECIAL WARNINGS

- It is recommended to confirm the healing of ulcerations by endoscopy before stopping treatment.

- PPIs may mask the symptoms of digestive tumors of the esophagus or stomach. It is recommended to closely monitor patients treated with a PPI for prolonged periods of more than 1 year. If the patient experiences symptoms such as significant and unwarranted weight loss, frequent vomiting, dysphagia, hematemesis, or melena, a differential diagnosis is recommended.

- In the event of severe and prolonged diarrhea, a possible infection by Clostridium difficile will be investigated.

- Treatment with PPIs for a prolonged period (> 3 months) can rarely lead to severe hypomagnesemia, which could be associated with hypocalcaemia and / or hypokalaemia. If the patient experiences symptoms such as asthenia, dizziness, tetany, seizures or cardiac arrhythmia, the magnesium levels will be determined, in case of hypomagnesemia, he must notify the doctor immediately, the treatment will be suspended and a magnesium supplement will be administered. The doctor should consider performing regular blood tests to monitor blood levels of magnesium.

- Antiulcer drugs could interfere in the diagnosis of neuroendocrine tumors, by increasing the levels of the specific marker chromogranin A (CgA), leading to false negatives. Suspend the antiulcer at least 5 days before the test, and if its levels have not normalized, repeat the test 14 days after suspension.

- Monitoring:

* Liver function tests (transaminases, bilirubin) in patients with severe liver function (Child-Pugh class C).

* Magnesium levels at baseline and periodically in patients treated for long periods with pantoprazole, treated with digoxin or with drugs that could lead to hypomagnesemia, such as diuretics.

INTERACTIONS

- Oral anticoagulants. Cases of increases in INR have been described in patients treated with an anticoagulant and a PPI. It is recommended to use with caution, monitoring the INR.

- Clopidogrel. Reductions in the antiplatelet effect have been reported in patients receiving omeprazole. Pantoprazole does not seem to interact with clopidogrel, although it is recommended to use with caution, monitoring the effect of clopidogrel.

- Drugs with pH-dependent absorption. The increase in pH produced by antiulcer drugs could modify the absorption of certain drugs, by favoring or reducing their dissolution in the aqueous medium of the gastric content. Thus, an increase in the absorption of digoxin has been observed, as well as a reduction in that of azole antifungals (itraconazole, ketoconazole, posaconazole), mycophenolate mofetil, rilpivirine, vitamin B12 and tyrosine-kinase inhibitors (dasatinib, erlotinib, gefitinib, lapatinib, nilotinib, pazopanib).

Digoxin toxicity is rare, but given its serious effects, caution is advised in elderly patients treated with high doses. Monitoring of digoxin plasma levels is recommended.

- Enzyme inducers / inhibitors. Pantoprazole is metabolized by CYP2C19 and to a lesser extent by CYP3A4, so its plasma levels could be modified by potent inhibitors (fluconazole, fluvoxamine, ticlopidine) or inducers (rifampicin) of both isoenzymes. There are also certain risks with drugs that affect a single isoenzyme, especially CYP2C19, which is the majority. No dosage adjustment is considered necessary, as the effect would be like that seen in poor metabolisers, but could be more important in severe hepatic impairment and long-term treatment.

- Protease inhibitors (PI). PPIs could alter the plasma levels of certain PIs, either by increasing the pH or by inhibiting CYP2C19.

Significant reductions in plasma levels of nelfinavir and atazanavir have been reported. Combination with nelfinavir or atazanavir is not advised. If it is not possible to avoid this association, it is advisable to increase the dose of atazanavir from 300 to 400 mg and not to exceed the dose of pantoprazole 20 mg / 24 h. However, this increase in dose did not completely offset the effect on plasma levels of atazanavir, so it is advisable to evaluate the response in the patient.

An increase in saquinavir levels of up to double has been reported.

Finally, no significant pharmacokinetic alterations have been observed when combining with amprenavir, darunavir, fosamprenavir, lopinavir or tipranavir.

- Methotrexate. PPIs could increase serum levels of methotrexate. It may be advisable to temporarily suspend the antiulcer drug in patients treated with high doses of methotrexate.

No drug interactions have been found when combining antacids, metoprolol or theophylline.

PREGNANCY

Safety in animals : administration in rats and rabbits at doses higher than those recommended in humans was not related to teratogenic or embryotoxic effects.

Safety in humans : The gestational safety of PPIs (including lansoprazole, omeprazole and pantoprazole) has been evaluated in several clinical trials and meta-analyzes, and no teratogenic or embryotoxic effects have been found, although they cannot be completely ruled out either, especially in the case of rare or delayed onset fetal adverse reactions. However, and based on the information obtained in animal studies, the risk would not be very high.

It is unknown if pantoprazole could cross the placenta, but due to its low molecular weight this step is possible. Other PPIs such as omeprazole have the ability to cross this barrier. However, due to the high plasma protein binding and low t1 / 2, the amount that could access the fetus is not estimated to be very high.

It is recommended to use with caution, restricting its use to situations in which there are no safer therapeutic alternatives, and the benefits outweigh the possible risks.

Effects on Fertility : Pantoprazole did not adversely affect fertility in animals. There have been no specific studies on its effects on fertility.

LACTATION

Animal safety : no data available.

Safety in humans : Pantoprazole is excreted in milk in small amounts, ceasing to be detectable after 6 hours of administration. It is estimated that the dose an infant would receive would be around 0.14% of the dose administered to the mother. The consequences for the infant are unknown, although it must be taken into account that PPIs are acid-pH labile drugs, which is why they are administered orally as gastro-resistant forms. Is recomended to suspend the lactancy or evy the administration.

CHILDREN

Safety and efficacy have not been evaluated in children and adolescents <18 years of age, therefore its use is not recommended.

SENIORS

No specific problems have been described in the elderly that require a dosage adjustment. However, it must be taken into account that in patients> 65 years of age, a physiological reduction in liver function could occur.

EFFECTS ON DRIVING

It does not appear to present significant effects. Dizziness is rare, and blurred vision and vertigo are rare.

ADVERSE REACTIONS

Pantoprazole is generally well tolerated, and in clinical trials only 5% of patients experienced any adverse reactions, usually mild and transient. Pantoprazole adverse reactions appear to be dose-independent.

Adverse reactions are described according to each frequency range, being considered very common (> 10%), common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%) , very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

- Digestive: infrequent [NAUSEAS] and [VOMITING], [ABDOMINAL PAIN], [DIARRHEA], [CONSTIPATION], [FLATULENCE], [ABDOMINAL DISTENSION], [DRY MOUTH].

- Hepatic: infrequent [INCREASED TRANSAMINASES] (AST, ALT and GGT); rare [HYPERBILIRUBINEMIA]; frequency unknown [JAUNDICE], [HEPATIC INSUFFICIENCY], [HEPATITIS].

- Cardiovascular: infrequent [ELECTROCARDIOGRAM ALTERATIONS]; frequency unknown [THROMBOPHLEBITIS].

- Neurological / psychological: uncommon [HEADACHE], [DIZZINESS], [SOMNOLENCE], [INSOMNIA]; rare [DYSGEUSIA], [DEPRESSION]; very rare [DISORIENTATION]; frequency unknown [HALLUCINATIONS], [CONFUSION], [PARESTHESIA].

- Respiratory: frequency unknown [PNEUMONIA].

- Genitourinary: infrequent [ERECTILE DYSFUNCTION]; rare [GYNECOMASTIA]; frequency unknown [INTERSTICIAL NEFRITIS].

- Dermatological: infrequent [EXANTEMATIC ERUPTIONS], [PRURITO]; rare [ANGIOEDEMA], [URTICARIA]; frequency unknown [PHOTOSENSITIVITY REACTIONS], [ERYTHEMA MULTIFORME], [STEVENS-JOHNSON SYNDROME], [TOXIC EPIDERMAL NECROLYSIS], [SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS].

- Allergic: rare [HYPERSENSITIVITY REACTIONS], including [ANAPHYLAXIA].

- Osteomuscular: uncommon [HIP FRACTURE], [VERTEBRAL FRACTURE] or wrist; rare [ARTHALGIA], [MIALGIA]; frequency unknown [RABDOMYOLYSIS].

- Ophthalmological: rare [VISION DISORDERS], such as [BLURRED VISION].

- Hematological: infrequent [EOSINOPHILIA]; rare [AGRANULOCYTOSIS]; very rare [THROMBOCYTOPENIA], [LEUCOPENIA], [PANCITOPENIA]; frequency unknown [NEUTROPENIA].

- Metabolic: rare [HYPERCHOLESTEROLEMIA], [HYPERTRIGLYCERIDEMIA], [WEIGHT GAIN], [WEIGHT LOSS]; frequency unknown [HYPONATREMIA], [HYPOMAGNESEMIA], [HYPOCALCEMIA], [HYPOPOTASEMIA], [HYPERGLYCAEMIA]; [CYANOCOBALAMINE DEFICIT].

Hypomagnesemia can occur with [ASTENIA], [DIZZINESS], [TETANIA], [DELUSION], [SEIZURES] or [CARDIAC ARRHYTHMIA] among others. In the event of symptoms, magnesium levels will be determined. Hypomagnesemia responds to removal of PPI and magnesium supplementation.

- General: infrequent [GENERAL DISASTER], [ASTENIA], [FATIGUE]; rare [FEVER], [EDEMA MALEOLAR].

OVERDOSE

Symptoms : doses of up to 240 mg (iv) have been administered in a period of 2 min, without observing adverse reactions.

Measures to be taken :

- Antidote: there is no specific antidote.

- General elimination measures: it is not expected to be easily dialyzable due to its high binding to plasma proteins.

- Monitoring: clinical status of the patient.

- Treatment: symptomatic.

Normogastrol Efg 20 Mg 14 Gastro-resistant Tablets Leaflet