Omeprazole Healthkern 20 Mg 14 Gastro-resistant Capsules (blister)

Omeprazole Healthkern (20 Mg 14 Gastro-resistant Capsules (Blister))

ACTION AND MECHANISM

- Peptic ulcer inhibitor, H+/K+ pump inhibitor. Omeprazole 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 said proton pump prevents the production of gastric acid, both basal and before a stimulus, regardless of what it is (acetylcholine, gastrin or histamine).

Omeprazole is a racemic mixture of two stereoisomers, S-omeprazole (esomeprazole, pharmacologically active) and R-omeprazole (inactive on acid production).

Omeprazole is a prodrug with a weak base nature, which after its absorption is distributed throughout the body, and 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 sulfonamido derivative, which tends to accumulate in the canaliculi and bind to the proton pump via disulfide bonds with 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 last up to 4 days after administration of a single dose, and despite its low t1/2.

Administration of a 20 mg dose of omeprazole resulted in a 70% reduction in pentagastrin-induced acid secretion 24 hours after administration.

Effects on acid production begin to appear within 2 hours, although it may take up to 5 days for maximum antiulcer activity to be achieved. Its effects can be prolonged, and in some studies an inhibition of acid secretion of 26% (20 mg) and 48% (mg) has been observed 24 hours after administration.

PHARMACOKINETICS

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

- Absorption: it is rapidly and almost completely absorbed in the small intestine, normally in 3-6 hours, with a tmax of 1-2 hours. However, it undergoes significant first-pass hepatic metabolism, which reduces its bioavailability to 40%. This metabolism seems to be saturable, since after repeated doses the bioavailability increases to 60%.

Effect of food : they do not seem to significantly affect the absorption of omeprazole when administered in the form of modified release (gastro-resistant capsules). However, food could reduce and delay absorption, so as a general rule it is advisable to take it on an empty stomach.

- Distribution: strong binding to plasma proteins (95-97%), especially albumin and alpha-1 acid glycoprotein. Its Vd is 0.3 l/kg.

- Metabolism: extensive in the liver by CYP2C19, giving rise to the main metabolite, hydroxy-omeprazole. To a lesser extent, it also undergoes metabolism by CYP3A4, generating the sulfone and omeprazole sulfide. None of these metabolites exhibit appreciable activity.

Enzyme inducing/inhibiting capacity : it presents competitive inhibitory activity against CYP2C19 due to its high affinity for the enzyme. No inductive or inhibitory effects on other enzyme systems have been reported.

- Excretion: in urine (77%) and feces (20%), mainly in the form of metabolites. The t1/2 is 0.5-1 h and the CLt is 500-600 ml/min.

Pharmacokinetics in special situations :

- Children: no significant differences have been observed in the pharmacokinetic parameters of children from 1 year of age, compared to adults. In children < 6 months, a lower CLt could occur due to liver immaturity.

- Elderly: patients > 75 years of age could present greater bioavailability and less elimination of omeprazole, as a consequence of lower hepatic metabolism. When administering a 40 mg dose, a bioavailability of 76% and a CLt of 250 ml/min were recorded. However, dosage adjustments are not usually necessary.

- Renal failure: no specific pharmacokinetic alterations have been reported. In patients with moderate renal insufficiency (CLcr 30-60 ml/min), an accumulation of metabolites may occur, although these are not active. Omeprazole is not removed by hemodialysis.

- Hepatic insufficiency: an increase in bioavailability could occur due to the inhibition of the hepatic first pass, as well as an increase in t1/2 up to 3 h, while the CLt could be reduced to 70 ml/min. Despite this, omeprazole does not seem to accumulate after its administration in single daily doses in these patients.

- Pharmacogenetics: around 1-3% of the Caucasian population and 20% of the Asian population lack functional CYP2C19, being considered poor metabolizers, compared to patients who have the isoenzyme and are considered rapid metabolizers. In poor metabolisers, hepatic metabolism of omeprazole occurs by CYP3A4. Cmax has been observed to increase 3-5 fold and AUC 5-10 fold in these patients, although no significant clinical repercussions have been reported and no specific dosage adjustments have been recommended.

INDICATIONS

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

POSOLOGY

"ORAL ADMINISTRATION"

- Adults:

* Gastric reflux: 20 mg/24 h. Normally 2-3 days of treatment are required to eliminate the symptoms. Discontinue treatment when symptoms disappear, generally in about 7 days. Maximum duration of treatment 14 days.

- Children and adolescents <18 years: safety and efficacy have not been evaluated.

- Elderly: does not require dose readjustment.

Forgotten dose : take as soon as possible, unless there is a short time left for the next dose. In this case, skip the dose. Do not double the dose in the next administration.

DOSAGE IN RENAL FAILURE

It does not require dosage readjustment.

DOSAGE IN LIVER FAILURE

Normally a dose of 10-20 mg/24 h is sufficient.

RULES FOR CORRECT ADMINISTRATION

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

If the patient experiences difficulty in swallowing the capsules, they can be opened and sucked or suspended in half a glass of still water, fruit juice or soft food such as applesauce. The suspension with the granules should be drunk immediately or within 30 min. Next, fill the glass halfway with water and drain the contents. The granules should not be chewed or crushed.

Suspension of the granules in milk or sparkling water is not recommended.

Administration with food: administer preferably on an empty stomach, first thing in the morning.

CONTRAINDICATIONS

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

- Concomitant treatment with nelfinavir (see Interactions – Protease inhibitors).

PRECAUTIONS

- [LIVER FAILURE]. Hepatic impairment could increase exposure, by reducing the hepatic first-pass effect, and decrease elimination by reduced metabolism. However, it has been found that omeprazole does not tend to accumulate in these patients when administered once daily. It is advised to use with caution. Patients with hepatic impairment may require a lower maintenance dose.

- [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 agent in whom severe diarrhea appears.

- [CYANOCOBALAMIN DEFICIENCY]. 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 stores of this vitamin, such as in patients with [MALNUTRITION] or strict vegetarian diets without supplementation with this vitamin. , or situations in which its absorption could be reduced, such as [CHRONIC ALCOHOLISM], [INTESTINAL MALABSORPTION] or situations that could give rise to malabsorption, such as [INFLAMMATORY INTESTINAL DISEASE] or major surgical processes of the digestive system.

- [HYPOMAGNESEMIA]. PPI treatment has been related to the appearance of severe cases of hypomagnesemia, which could be associated with [HYPOCALCEMIA]. Its frequency has not been estimated, but it is considered rare. However, the wide use of these drugs must be taken into account, so their clinical impact could be important. 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.

If symptoms of hypomagnesemia appear, such as fatigue, dizziness, tetany, delirium, seizures or cardiac arrhythmia, magnesium levels will be determined. Hypomagnesemia responds to PPI withdrawal 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 fractures, especially in elderly people with risk factors. It is therefore recommended that women with osteoporosis receive treatment and an adequate intake of calcium and vitamin D.

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

- [SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS] (LECS). PPIs have been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions appear, especially in areas exposed to the sun, accompanied by arthralgia, consider discontinuing treatment. Patients with LECS due to a PPI may experience this picture again 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 baseline 4 weeks after stopping treatment) and chromogranin A (CgA).

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

- Long-term treatment. Anti-ulcer 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 receiving prolonged treatment, greater than one year, be subject 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 blood or feces. In case of suspicion of a serious digestive process, a differential diagnosis is recommended.

Patients using non-prescription omeprazole should tell their doctor and/or pharmacist if they have recurring symptoms of indigestion or heartburn, are on continuous treatment for more than 4 weeks without relief of symptoms, or if their symptoms have changed or new symptoms have appeared, especially in > 55 years.

PRECAUTIONS RELATED TO EXCIPIENTS

- This medicine contains sucrose. Patients with hereditary [FRUCTOSE INTOLERANCE], glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.

ADVICE TO THE PATIENT

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

- Tell your doctor about the medicines 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 feces.

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

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

* Symptoms of indigestion or heartburn frequently, despite treatment, especially if they are older than 55 years.

SPECIAL WARNINGS

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

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

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

- Treatment with PPIs for a prolonged period has rarely given rise to severe hypomagnesaemia, which could be associated with hypocalcaemia. If the patient experiences symptoms such as fatigue, dizziness, tetany, seizures or cardiac arrhythmia, magnesium levels will be determined, and in case of hypomagnesemia, treatment will be suspended and a magnesium supplement will be administered.

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

- Monitoring:

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

INTERACTIONS

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

- Clopidogrel. Omeprazole at high doses could decrease the effect of clopidogrel, by inhibiting the transformation to its active metabolite, mediated by CYP2C19 (although there could be some other mechanism since clopidogrel has several metabolic pathways). It is recommended to avoid the association between omeprazole and clopidogrel. Pantoprazole, and to a lesser extent lansoprazole and rabeprazole, could be safer alternatives.

- Disulfiram. A case of catatonic reaction has been described when combined with omeprazole.

- Drugs with absorption dependent on pH. The increase in pH produced by antiulcer drugs could modify the absorption of certain medications, by favoring or reducing their dissolution in the aqueous medium of gastric contents. 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).

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

- Enzyme inducers/inhibitors. Omeprazole is metabolized by CYP2C19 and to a lesser extent by CYP3A4, so its plasma levels could be modified by strong 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. A dose adjustment is not considered necessary, since the effect would be as observed in poor metabolisers, but it could be more important in case of severe hepatic insufficiency 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. Co-administration with nelfinavir is contraindicated, and combination with atazanavir is not advised. If it is not possible to avoid this association, it is recommended to increase the dose of atazanavir from 300 to 400 mg, although this dose increase did not completely counteract the effect on plasmatic levels of atazanavir, so the response in the patient must be evaluated.

An increase in saquinavir levels of up to twofold has been described.

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

- Methotrexate. PPIs could increase serum methotrexate levels.

- CYP2C19 substrates. Omeprazole is a moderate inhibitor of CYP2C19, so it could increase the plasma levels of drugs that are metabolized by this system, such as certain tricyclic antidepressants (clomipramine, imipramine), cilostazol, citalopram, diazepam, phenytoin, voriconazole, or warfarin. It may be necessary to reduce the doses of these drugs, especially in the case of on-demand treatments with PPIs.

In the case of phenytoin and warfarin, it would also be advisable to monitor their plasma levels when starting and ending treatment with omeprazole.

- Tacrolimus. Increased tacrolimus serum levels have been reported when administered with omeprazole.

No drug interactions have been found when associated with antacids, beta-blockers (metoprolol, propranolol), domperidone, fluoroquinolones, or theophylline.

PREGNANCY

Animal Safety : Omeprazole was not teratogenic when administered to pregnant rats or rabbits at doses 345 and 172 MRHD, although increased fetal mortality was reported.

Safety in humans : The gestational safety of PPIs (including lansoprazole, omeprazole, and pantoprazole) has been evaluated in several clinical trials and meta-analyses, and no teratogenic or embryotoxic effects have been found, although they cannot be completely ruled out, 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.

Omeprazole crosses the placenta. It is recommended to use it 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 : No specific studies have been performed on its effects on fertility.

LACTATION

Animal Safety : Administration to lactating rats (35-345 MDRH) was associated with reduced pup weight gain.

Safety in humans : Omeprazole is excreted in breast milk, reaching levels of 7% of the maternal cp. The consequences it could have for the infant are unknown, although it must be taken into account that PPIs are labile drugs at acidic pH, which is why they are administered orally as gastro-resistant forms. Is recomended to suspend the lactancy or evy the administration.

SENIORS

No specific problems have been described in the elderly that require a dose readjustment.

EFFECTS ON DRIVING

It does not seem to have significant effects. It is rare that dizziness appears, and on rare occasions blurred vision and vertigo.

ADVERSE REACTIONS

The adverse reactions of omeprazole appear to be dose-independent. The most frequent are of a digestive nature, as well as headache.

In the trials performed, the safety profile in children was similar to that recorded in adult patients. There are no long-term safety data in children, nor on the effects on growth.

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

- Digestive: frequent [NAUSEA] and [VOMITING], [ABDOMINAL PAIN], [CONSTIPATION], [DIARRHEA], [FLATULENCE]; rare [DRY MOUTH], [STOMATITIS], [CANDIDIASIS]; unknown frequency [PANCREATITIS].

- Hepatic: infrequent [INCREASED TRANSAMINASES]; rare [HEPATITIS] with or without [JAUNDICE]; very rare [HEPATIC FAILURE], [HEPATIC ENCEPHALOPATHY] in patients with previous liver disease; frequency unknown [CHOLESTASIS].

- Cardiovascular: unknown frequency [ARTERIAL HYPERTENSION], [PALPITATIONS], [ANGINA PECTOR], [RAYNAUD'S SYNDROME].

- Neurological/psychological: frequent [CEFALEA]; infrequent [DIZZINES], [PARESTHESIS], [SOMNOLENCE], [INSOMNIA]; rare [NERVOUSNESS], [CONFUSION], [DEPRESSION], [DYSGEUSIA]; very rare [HALLUCINATIONS], [AGGRESSION]; unknown frequency [ATAXIA].

- Respiratory: frequent [TOS], [RESPIRATORY INFECTION]; rare [BRONCHIAL SPASM]; frequency unknown [PNEUMONIA].

- Genitourinary: rare [INTERSTITIAL NEPHRITIS]; very rare [GYNECOMASTIA]; unknown frequency [GALACTORRHEA], [INCREASED SERUM CREATININE].

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

- Allergic: rare [HYPERSENSITIVITY REACTIONS], with [FEVER], [ANGIOEDEMA] or [ANAPHYLAXIS], and [LUPUS ERYTHEMATOSO].

- Osteomuscular: frequent [BACK PAIN]; uncommon [HIP FRACTURE], [VERTEBRAL FRACTURE] or wrist; rare [OSTEOMUSCULAR PAIN], [MYALGIA]; very rare [MYASTHENIA]; unknown frequency [RABDOMYOLYSIS].

- Ophthalmological: rare [BLURRY VISION]; unknown frequency [OPTIC NEURITIS], [OPTIC NEUROPATHY].

- Otic: rare [VERTIGO].

- Hematological: rare [LEUCOPENIA], [TROMBOCYTOPENIA]; very rare [AGRANULOCYTOSIS], [PANCITOPENIA]; unknown frequency [NEUTROPENIA], [HEMOLYTIC ANEMIA] or [MEGALOBLASTIC ANEMIA].

- Metabolic: rare [HYPONATREMIA]; unknown frequency [HYPOMAGNESEMIA], [HYPERCALCEMIA], [HYPOGLYCEMIA], [HYPOKOTASEMIA], [CYANOCOBALAMIN DEFICIENCY], [WEIGHT GAIN].

Hypomagnesemia can occur with [ASTENIA], [DIZZNESS], [TETANY], [DELIRIO], [SEIZURES] or [CARDIAC ARRHYTHMIA] among others. If symptoms appear, magnesium levels will be determined. Hypomagnesemia responds to PPI withdrawal and magnesium supplementation.

- General: frequent [ASTENIA], [FEVER]; uncommon [GENERAL DISCOMFORT], [MALEOLAR EDEMA]; rare [HYPERHIDROSIS].

OVERDOSE

Symptoms : Single doses up to 2,400 mg, equivalent to 120 DMRH, have been administered. No serious or irreversible adverse reactions have been described, and in most cases the patients presented symptoms such as nausea and vomiting, abdominal pain, diarrhoea, dizziness, headache, depression, apathy or confusion.

Measures to take :

- Antidote: there is no specific antidote.

- General elimination measures: administer activated carbon in case of very serious poisoning, although it is not usually necessary. It is not expected to be readily dialyzable due to its high plasma protein binding.

- Monitoring: clinical status of the patient.

- Treatment: symptomatic.

Leaflet Omeprazole Healthkern 20 Mg 14 Gastro-resistant Capsules