Normatens

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMATENS (NORMATENS)

Composition:

Active substances: clopamidum (clopamide), dihydroergocristinum (as dihydroergocristine mesylate), reserpinum (reserpine);

1 tablet contains clopamide 5 mg, dihydroergocristine 0.5 mg (as dihydroergocristine mesylate – 0.58 mg), reserpine 0.1 mg;

Excipients: lactose monohydrate; potato starch; povidone; talc; magnesium stearate; sucrose; gum arabic; mixture of carnauba wax and white wax.

Pharmaceutical form. Coated tablets.

Main physicochemical properties: white or almost white coated tablets, free from spots, scratches, and cracks, white in cross-section. Tablets are round and biconvex in shape.

Pharmacotherapeutic group. Combinations of antihypertensive and diuretic agents.

ATC code C02L A51.

Pharmacological Properties

Pharmacodynamics

The medicinal product contains three active substances with antihypertensive properties: reserpine, clopamide, and dihydroergocristine. The combination of the positive effects of reserpine, clopamide, and dihydroergocristine enhances the antihypertensive action of the drug and allows for the use of lower doses of each component, thereby reducing the risk of adverse effects.

Reserpine is an alkaloid of Rauwolfia with neuroleptic and antihypertensive effects. It belongs to the group of drugs that block adrenergic neurons. Its mechanism of action involves the release of neurotransmitters from adrenergic synaptic granular storage sites in presynaptic structures. Reserpine interferes with the uptake and accumulation of catecholamines and serotonin in the central and peripheral nervous systems and causes reflex vagotonia. It dilates blood vessels, slows heart rate, and produces a prolonged reduction in arterial pressure.

Clopamide is a substance with moderate diuretic activity typical of thiazide diuretics. It inhibits sodium ion reabsorption in the cortical portion of the ascending limb of Henle's loop and in the distal convoluted tubules, resulting in enhanced diuresis and natriuresis and a reduction in arterial pressure. Inhibition of sodium reabsorption also increases potassium excretion and may lead to hypokalemia.

Dihydroergocristine belongs to the group of hydrogenated alkaloids of ergot. It acts as an agonist at dopaminergic and serotonergic receptors and as an antagonist at alpha-adrenergic receptors. Through its action on the central nervous system, it reduces vascular wall tone and lowers blood pressure. In addition, dihydroergocristine suppresses baroreceptor reflexes and reduces reflex tachycardias.

Pharmacokinetics

Absorption and distribution. The individual components of Normatens are absorbed from the gastrointestinal tract in the following amounts: reserpine—approximately 40%, clopamide—more than 90%, dihydroergocristine—approximately 25%. After oral administration, they reach maximum blood concentrations within 1–3 hours, 1–2 hours, and 0.6 hours, respectively.

Reserpine does not bind to plasma proteins, whereas clopamide and dihydroergocristine bind 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 cross the blood-brain barrier and placenta.

Metabolism and elimination. All components of the drug are metabolized in the liver to inactive metabolites (with clopamide undergoing less metabolism than reserpine and dihydroergocristine).

Reserpine is primarily excreted in feces and urine in the form of metabolites (less than 1% is excreted in urine). Its half-life is approximately 4.5 hours in the alpha phase and about 271 hours in the beta phase.

Dihydroergocristine is mainly eliminated via feces; less than 1% is excreted in urine. Its half-life is approximately 2 hours in the alpha phase and about 14 hours in the beta phase.

Clopamide is primarily excreted by the kidneys (more than 30% of the administered dose). Its half-life is approximately 6 hours.

Clinical characteristics.

Indications.

Essential arterial hypertension and all forms of symptomatic arterial hypertension, when monotherapy is ineffective.

Contraindications.

Hypersensitivity to sulfonamides, reserpine and ergot alkaloids, or other components of the medicinal product. Hypokalemia.

Pregnancy and breastfeeding.

Reserpine.

Depression (current or in history), Parkinson's disease, epilepsy, electroconvulsive therapy. Peptic ulcer of the stomach and duodenum in the phase of exacerbation, ulcerative colitis; pheochromocytoma, concomitant or recent treatment with monoamine oxidase inhibitors.

Thiazide diuretics.

Severe renal insufficiency (creatinine clearance less than 30 ml/min); hepatic insufficiency; hyponatremia; hyperuricemia.

Dihydroergocristine.

Concomitant use with potent inhibitors of CYP3A4 isoenzymes, such as protease inhibitors, macrolide antibiotics, and azole antifungal agents (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 reduce the antihypertensive effect of the drug.

When used concomitantly with agents that lower blood pressure, an enhanced hypotensive effect of Normatens may occur.

The drug reduces renal clearance of lithium, leading to increased blood levels. When used concomitantly, lithium blood levels should be monitored and doses adjusted if necessary.

Clopamide, a component of the drug, reduces the effect of oral anticoagulants.

Effects of medicinal products that have a depressant action on the central nervous system (alcohol and antidepressants) may be enhanced when combined with Normatens. Therefore, patients should not consume alcohol and should use antidepressants cautiously during Normatens therapy.

Reserpine enhances the central nervous system depressant effects of anesthetics, certain antihistamines, and barbiturates. Reserpine may also enhance the effects of epinephrine or other sympathomimetic agents.

Combining the drug with monoamine oxidase inhibitors is not recommended due to central nervous system depression, increased arterial blood pressure, and significant decrease in body temperature. In addition, the interval between administration of these drugs should be at least 2 weeks.

The drug reduces the effectiveness of levodopa.

Combining reserpine with diuretics increases the risk of hypotension. Combining with other antihypertensive agents leads to enhanced hypotensive action.

Concomitant use of ergot-containing agents with inhibitors of CYP3A4 isoenzymes, such as macrolide antibiotics, protease inhibitors, or azole antifungal agents, is contraindicated (see section "Contraindications"), as in such cases acute toxic effects of ergot alkaloids (ergotism) may occur, characterized by vasospasm and ischemia of the limbs, which sometimes leads to the need for amputation. Examples of potent CYP3A4 isoenzyme inhibitors include antifungal agents ketoconazole and itraconazole, protease inhibitors ritonavir, nelfinavir, and indinavir, as well as macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent inhibitors of CYP3A4 isoenzymes should be used with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole.

Special precautions for use.

• During treatment, alcoholic beverages should not be consumed.
• It should be borne in mind that the clinical effect of Normatens occurs after several days, and sometimes only after 4 weeks of starting therapy. Therefore, the dose should not be increased if no reduction in arterial pressure is observed at the beginning of treatment.
• Due to the possible increase in blood glucose concentration, patients with diabetes mellitus or impaired glucose metabolism should periodically monitor blood glucose levels and, if necessary, adjust the dose of hypoglycemic agents.
• The drug should be used with caution in patients with gout, as it may increase serum uric acid levels.
• Since Normatens may cause hypokalemia, patients should be advised to consume foods rich in potassium (fruits, vegetables, fish) during treatment and to periodically monitor serum potassium levels.
• The medicinal product should be used with particular caution in patients with renal impairment, as it may exacerbate renal insufficiency on one hand, and on the other hand, its efficacy may be reduced. The drug should not be administered to patients with severe hepatic or renal insufficiency.
• Due to the presence of sucrose in the formulation, this product should not be administered to patients with congenital fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.
• The product contains lactose; therefore, it should not be administered to patients with congenital galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.
• Since the drug contains dihydroergocristine, its use in higher than recommended doses or for longer than recommended should be avoided. Prolonged use of high doses may lead to fibrotic changes, particularly in the pleura and retroperitoneal tissues. There have also been rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves associated with long-term continuous use of medicinal products containing ergot alkaloids.

Caution should also be exercised in patients with sinus bradycardia.

Reserpine: Reserpine should be discontinued at least 7–14 days prior to electroconvulsive therapy.

Reserpine: Reserpine should be discontinued several days before planned surgery to avoid excessive reduction in arterial pressure during anesthesia.

Reserpine: Reserpine should be administered with caution in elderly patients. Caution should also be exercised in patients with bronchial asthma.

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 any potential benefit to the mother.

Breastfeeding. The medicinal product Normatens should not be used during breastfeeding, since reserpine and dihydroergocristine contained in the product are excreted in breast milk and may have a negative effect on breastfed infants.

Ability to affect reaction speed when driving or operating machinery.

Normatens affects the ability to drive vehicles and operate machinery.

In particular, at the beginning of treatment and after dose increases, asthenia and orthostatic hypotension may occur, which may impair the ability to drive vehicles or operate machinery.

Method of administration and dosage.

The drug may be used in combination with other antihypertensive agents such as beta-blockers and vasodilators.

Dosage is determined individually by a physician for each patient.

It is recommended to start treatment with 1 tablet once daily. Depending on the efficacy of treatment and severity of adverse reactions, the dose may be increased to 3 tablets once daily, administered in three divided doses. However, it should be remembered that, due to the mechanism of action and pharmacological properties of the individual active ingredients, treatment may be considered ineffective only if there is no positive effect within 14 days after initiation of therapy. Therefore, the dose should not be increased without a clear need.

The expected therapeutic effect occurs approximately within 1–4 weeks.

Dosage should be increased gradually.

The usual effective dose is 1 tablet once daily. However, in some patients, the effective dose is 1 tablet every other day. If an adequate antihypertensive effect is not achieved, the dose should be increased to 1 tablet twice daily, and in exceptional cases up to 1 tablet three times daily (higher doses should not be used).

The tablet should be taken during or immediately after a meal.

Dosing in elderly patients. There is no need for dose adjustment. However, caution is advised due to an increased risk of developing arterial hypotension and disturbances in blood electrolyte levels.

Dosing in patients with hepatic or renal impairment. The drug should not be administered to patients with severe hepatic or renal insufficiency (creatinine clearance below 30 mL/min).

Children. Not to be used.

Overdose.

Symptoms of overdose: nausea, vomiting, diarrhea, headache, sensation of warmth, thirst, hypokalemia, myasthenia, arterial hypotension, bradycardia, cardiac arrhythmias, depression, dizziness, coma, headache, confusion, muscle weakness.

In case of overdose, gastric lavage should be performed immediately, and activated charcoal should be administered. Cardiac function, arterial pressure, and fluid-electrolyte balance should be monitored. Symptomatic treatment should be provided if necessary.

Adverse reactions.

Criteria for assessing the frequency of adverse reactions during drug use:

Gastrointestinal disorders: Unknown – nausea and vomiting.

Metabolism and nutrition disorders: Unknown – hypokalemia.

Cardiovascular disorders: Unknown – orthostatic hypotension.

Nervous system disorders: Unknown – myasthenia.

Respiratory disorders: Unknown – rhinitis.

Laboratory findings: Unknown – hyperuricemia and hyperglycemia.

General disorders: Unknown – asthenia.

Blood and lymphatic system disorders: Unknown – thrombocytopenia.

Psychiatric disorders: Unknown – depression.

Adverse reactions characteristic of reserpine may also occur.

Gastrointestinal disorders: diarrhea, dry mouth, increased gastric juice secretion, increased salivation, increased appetite, peptic ulcer, gastrointestinal hemorrhage, abdominal pain.

Metabolism and nutrition disorders: hypocalcemia, metabolic alkalosis.

Cardiovascular disorders: sinus bradycardia, cardiac arrhythmia, angina symptoms, arterial hypotension, flushing, loss of consciousness, heart failure, cerebrovascular disorders.

Central nervous system disorders: dizziness, irritability, nightmares, increased fatigue, extrapyramidal disorders (including parkinsonism), headache, anxiety, impaired concentration, stupor, disorientation, cerebral edema, somnolence, insomnia.

Respiratory disorders: rhinitis, nasal mucosa edema, dyspnea, epistaxis.

General disorders: edema, weakness.

Blood and lymphatic system disorders: anemia.

Endocrine disorders: increased prolactin secretion, galactorrhea, gynecomastia, breast engorgement.

Metabolism and nutrition disorders: weight gain.

Sensory organ disorders: blurred vision, conjunctival hyperemia, lacrimation, hearing disturbances.

Skin and subcutaneous tissue disorders: eczema, pruritus, purpura, rash.

Renal and urinary disorders: dysuria, glomerulonephritis.

Reproductive system disorders: decreased libido, erectile and ejaculatory dysfunction.

Musculoskeletal and connective tissue disorders: postural disorders.

Fibrotic changes have been observed in some patients who regularly took alkaloids of rye ergot for several years, particularly in the pleura and retroperitoneal tissues; in some cases, fibrotic changes of heart valves have also been observed (see also section "Special precautions").

Shelf life. 5 years.

Storage conditions. Store in the original packaging, protected from light and moisture, at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 20 tablets per blister; 1 blister per pack.

Prescription status. Prescription only.

Manufacturer.

I.C.N. Polfa Rzeszów S.A.

Address of manufacturer and location of business activity.

35-959 Rzeszów, ul. Przemysłowa 2, Poland / 35-959 Rzeszów, ul. Przemysłowa, 2, Poland.