Instructions for Normatens film-coated tablets No. 20
Composition
active ingredients: clopamide (clopamide), dihydroergocristine (as dihydroergocristine mesylate), reserpine (reserpine);
1 tablet contains clopamide 5 mg, dihydroergocristine 0.5 mg (in the form of dihydroergocristine mesylate – 0.58 mg), reserpine 0.1 mg;
Excipients: lactose monohydrate; potato starch; povidone; talc; magnesium stearate; sucrose; gum arabic; a mixture of carnauba wax and white wax.
Dosage form
Film-coated tablets.
Main physicochemical properties: white or almost white, coated tablets, without spots, scratches or cracks, white when broken. The tablets are round, biconvex in shape.
Pharmacotherapeutic group
Combinations of antihypertensive and diuretic agents. ATX code C02L A51.
Pharmacological properties
Pharmacodynamics
The drug contains 3 active ingredients with antihypertensive properties: reserpine, clopamide and dihydroergocristine. The combination of the positive effects of reserpine, clopamide and dihydroergocristine enhances the hypotensive effect of the drug and makes it possible to use lower doses of each component, which reduces the risk of side effects.
Reserpine is a rauwolfia alkaloid with neuroleptic and hypotensive effects. It belongs to the group of drugs that block adrenergic neurons. The mechanism of action is the release of neurotransmitters from adrenergic synaptic granular depots of presynaptic structures. Reserpine prevents the capture and accumulation of catecholamines and serotonin in the central and peripheral nervous system, causes reflex vagotonia. It dilates blood vessels, slows heart rate and causes a long-term decrease in blood pressure.
Clopamide is a substance with a moderate diuretic effect, which is inherent in the group of thiazide diuretics. It inhibits the reabsorption of sodium ions in the cortical part of the ascending loop of Henle, as well as in the distal convoluted tubules, which causes increased diuresis and natriuresis and a decrease in blood pressure. Inhibition of the reabsorption of sodium ions increases kaliuresis and can lead to hypokalemia.
Dihydroergocristine belongs to the group of hydrogenated ergot alkaloids. It is an agonist of dopaminergic and serotoninergic receptors and an antagonist of alpha-adrenoreceptors. Due to its action on the central nervous system, it reduces the tone of the walls of blood vessels, reduces pressure. In addition, dihydroergocristine inhibits baroreceptor reflexes and reduces reactive tachycardia.
Pharmacokinetics
Absorption and distribution. The individual components of Normatens are absorbed from the gastrointestinal tract in the following quantities: reserpine - approximately 40%, clopamide - more than 90%, dihydroergocristine - approximately 25%. They reach maximum blood concentrations after oral administration in 1-3 hours, 1-2 hours and 0.6 hours, respectively.
Reserpine is not bound to plasma proteins, while clopamide and dihydroergocristine are bound to plasma proteins by 46% and 68%, respectively. The volume of distribution of clopamide is 1.5 l/kg, while that of dihydroergocristine is 16 l/kg.
Reserpine and dihydroergocristine penetrate the blood-brain barrier and the placenta.
Metabolism and excretion. All components of the drug are metabolized in the liver to inactive metabolites (clopamide to a lesser extent than reserpine and dihydroergocristine).
Reserpine is mainly excreted as metabolites in the feces and urine (less than 1% is excreted in the urine). The half-life is approximately 4.5 hours in the alpha phase and approximately 271 hours in the beta phase.
Dihydroergocristine is excreted from the body mainly in the feces; less than 1% is excreted in the urine. The half-life is approximately 2 hours in the alpha phase and approximately 14 hours in the beta phase.
Clopamide is excreted mainly by the kidneys (more than 30% of the administered dose). The half-life is approximately 6 hours.
Indication
Essential arterial hypertension and all forms of symptomatic arterial hypertension, monotherapy of which is ineffective.
Contraindication
Hypersensitivity to sulfonamides, reserpine and ergot alkaloids and other components of the drug. Hypokalemia.
Pregnancy and breastfeeding.
Reserpine.
Depression (current or history), Parkinson's disease, epilepsy, electroconvulsive therapy. Gastric and duodenal ulcer in the acute phase, ulcerative colitis; pheochromocytoma, concomitant or recent treatment with monoamine oxidase inhibitors.
Thiazide diuretics.
Severe renal failure (creatinine clearance less than 30 ml/min); hepatic failure; hyponatremia; hyperuricemia.
Dihydroergocristine.
Concomitant use with potent inhibitors of CYP3A4 isoenzymes, such as protease inhibitors, macrolide antibiotics and azole antifungals (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Systemic corticosteroids and nonsteroidal anti-inflammatory drugs weaken the antihypertensive effect of the drug.
The drug reduces the renal clearance of lithium, which leads to increased levels in the blood. When used simultaneously, it is necessary to monitor the level of lithium in the blood and adjust the dose if necessary.
Clopamide, which is part of the drug, reduces the effect of oral anticoagulants.
The effects of drugs that depress the central nervous system (alcohol and antidepressants) may be enhanced when combined with Normatens. Therefore, patients should not drink alcohol and use antidepressants with caution during Normatens therapy.
Reserpine enhances the central nervous system depressant effects of anesthetics, some antihistamines and barbiturates. Reserpine may enhance the effects of adrenaline or other sympathomimetic substances.
It is not recommended to combine the use of the drug with monoamine oxidase inhibitors due to central nervous system depression, increased blood pressure and a significant decrease in body temperature. In addition, the interval between the use of these drugs should be at least 2 weeks.
The drug reduces the effectiveness of levodopa.
When combining reserpine with diuretics, the risk of hypotension increases. When combined with other antihypertensive agents, the hypotensive effect is enhanced.
The concomitant use of ergot derivatives with CYP3A4 inhibitors, such as macrolide antibiotics, protease inhibitors or azole antifungals, is contraindicated (see section "Contraindications"), as in such cases acute toxicity of ergot alkaloids (ergotism) is possible, characterized by vasospasm and ischemia of the extremities, sometimes leading to the need for amputation. Examples of potent CYP3A4 inhibitors are the antifungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir and indinavir, and the macrolide antibiotics erythromycin, clarithromycin and troleandomycin. Other less potent CYP3A4 inhibitors should be used with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole.
Application features
During treatment, you should not drink alcoholic beverages. It should be remembered that the clinical effect of Normatens occurs after a few days, and sometimes after 4 weeks after the start of treatment. Therefore, the dosage should not be increased if there is no decrease in blood pressure at the beginning of treatment. Due to the possible increase in blood glucose concentration, patients with diabetes mellitus or metabolic disorders should periodically monitor glycemia or, if necessary, select an adequate dose of a hypoglycemic agent. The drug should be used with caution in patients with gout, since the drug may increase the level of uric acid in the blood serum. Since Normatens may cause hypokalemia, patients are recommended to eat foods high in potassium (fruits, vegetables, fish) and periodically monitor the level of potassium in the blood during treatment. The drug should be used with special caution in patients with renal failure, since it may aggravate renal failure on the one hand, and on the other hand, its effectiveness may decrease. The drug should not be used in patients with severe hepatic and renal insufficiency. Due to the presence of sucrose in the drug, patients with congenital disorders associated with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency should not use this drug. The drug contains lactose, therefore it should not be used in patients with congenital disorders associated with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome. Since the drug contains dihydroergocristine, its use in higher doses and for longer than recommended should be avoided. Long-term use of high doses may cause fibrotic changes, particularly in the pleura and retroperitoneal tissues. There are also reports of rare cases of fibrous thickening of the aortic, mitral, tricuspid and/or pulmonary valves with long-term continuous use of medicines containing ergot alkaloids.
Caution should also be exercised in patients with sinus bradycardia.
Reserpine should be discontinued at least 7-14 days before starting electroconvulsive therapy.
Reserpine should be discontinued a few days before elective surgery to avoid excessive lowering of blood pressure during anesthesia.
Reserpine should be used with caution in elderly patients. Caution should be exercised in patients with bronchial asthma.
Ability to influence reaction speed when driving vehicles or other mechanisms
Normatens affects the ability to drive a car and other mechanisms.
In particular, at the beginning of treatment and after increasing the dose of the drug, asthenia and orthostatic hypotension may occur, which limits the ability to drive a car and other mechanisms.
Use during pregnancy or breastfeeding
Pregnancy. The drug is contraindicated during pregnancy, as animal studies and human observations indicate a high risk to the fetus, which significantly outweighs the potential benefit to the mother.
Breastfeeding. The drug Normatens should not be used during breastfeeding, since reserpine and dihydroergocristine contained in the drug are excreted in breast milk and may have a negative effect on breast-fed children.
Method of administration and doses
The drug can be used in combination with other antihypertensive agents, such as beta-blockers and vasodilators.
The dosage is determined by the doctor individually for each patient.
It is recommended to start treatment with 1 tablet once a day. Depending on the effectiveness of treatment and the severity of adverse reactions, the dose may be increased to 3 tablets once a day in 3 divided doses. However, it should be remembered that, given the mechanism of action and pharmacological properties of the individual active ingredients of the drug, treatment may be considered ineffective only due to the lack of a positive effect 14 days after the start of therapy. Thus, the dose cannot be increased without urgent need.
The expected therapeutic effect is observed after approximately 1–4 weeks.
The dosage should be increased gradually.
The total effective dose is 1 tablet once a day. However, in some patients the total effective dose is 1 tablet every other day. In the absence of a satisfactory hypotensive effect, the dose of the drug should be increased to 1 tablet twice a day, and in exceptional cases - to 1 tablet three times a day (higher doses should not be used).
The tablet should be taken during or immediately after a meal.
Dosage in elderly patients. No dosage adjustment is necessary. However, caution should be exercised due to the increased risk of hypotension and electrolyte disturbances in the blood.
Dosage for patients with hepatic and renal insufficiency. The drug should not be used in patients with severe hepatic and renal insufficiency (creatinine clearance below 30 ml/min).
Children
Do not apply.
Overdose
Symptoms of drug overdose: nausea, vomiting, diarrhea, headache, feeling of heat, thirst, hypokalemia, myasthenia gravis, arterial hypotension, bradycardia, heart rhythm disturbances, depression, dizziness, coma, headache, confusion, muscle weakness.
After overdose, gastric lavage and activated charcoal should be performed immediately. Cardiac function, blood pressure and water and electrolyte balance should be monitored. If necessary, symptomatic treatment should be applied.
Adverse reactions
Criteria for assessing the frequency of adverse reactions when using the drug:
Very common: ≥ 1/10
Common: ≥ 1/100 - < 1/10
Uncommon: ≥ 1/1000 - < 1/100
Rare: ≥ 1/10,000 – < 1/1,000
Very rare: < 1/10,000
Not known: frequency cannot be estimated from the available data
Gastrointestinal: unknown - nausea and vomiting.
Metabolic: unknown - hypokalemia.
Cardiovascular system: unknown - orthostatic hypotension.
Nervous system disorders: not known – myasthenia gravis.
Respiratory system: unknown - rhinitis.
Laboratory parameters: unknown – hyperuricemia and hyperglycemia.
General disorders: not known – asthenia.
From the hematopoietic system: unknown - thrombocytopenia.
On the part of the psyche: unknown - depression.
Adverse reactions characteristic of reserpine may also be observed.
Gastrointestinal: diarrhea, dry mouth, increased secretion of gastric juice, increased salivation, increased appetite, peptic ulcer, gastrointestinal bleeding, abdominal pain.
Metabolic: hypocalcemia, metabolic alkalosis.
Cardiovascular system: sinus bradycardia, cardiac arrhythmia, angina symptoms, hypotension, hot flashes, loss of consciousness, heart failure, cerebrovascular disorders.
From the side of the central nervous system: dizziness, irritability, nightmares, increased fatigue, extrapyramidal disorders (including parkinsonism), headache, anxiety, impaired concentration, stupor, disorientation, cerebral edema, drowsiness, insomnia.
On the part of the respiratory system: rhinitis, swelling of the nasal mucosa, shortness of breath, nosebleeds.
General disorders: edema, weakness.
Blood and lymphatic system disorders: anemia.
On the part of the endocrine system: increased secretion of prolactin, galactorrhea, gynecomastia, swelling of the mammary glands.
Metabolism and nutrition disorders: weight gain.
From the sensory organs: blurred vision, conjunctival hyperemia, lacrimation, hearing impairment.
Skin and subcutaneous tissue disorders: eczema, pruritus, purpura, rash.
Renal and urinary disorders: dysuria, glomerulonephritis.
From the reproductive system: decreased libido, impaired potency and ejaculation.
Fibrous changes have been observed in some patients who have regularly taken ergot alkaloid preparations for several years, particularly in the pleura and retroperitoneal tissues, and in some cases fibrotic changes in the heart valves have also been observed (see also the section "Special warnings and precautions for use").
Expiration date
5 years.
Storage conditions
Store in the original packaging in a place protected from light and moisture at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
20 tablets in a blister; 1 blister in a pack.
Vacation category
According to the recipe.
Producer
ICN Polfa Rzeszow SA
Location of the manufacturer and its business address
35-959 Rzeszow, ul. Przemyslowa, 2, Poland/35-959 Rzeszow ul. Przemyslowa, 2, Poland.
