Normodipine, tablets 10 mg 30 pcs

Normodipine has antianginal, hypotensive effect.

A slow calcium channel blocker, a dihydropyridine derivative, has antianginal and hypotensive effects. Binding to segments S6 of III and IV domains of alpha1-subunit of L-type calcium channel, it blocks calcium channels, decreases transmembrane transition of calcium ions into cell (more in vascular smooth muscle cells than in cardiomyocytes).

Antianginal action is caused by the dilation of coronary and peripheral arteries and arterioles: in angina pectoris it reduces myocardial ischemia; dilation of peripheral arterioles reduces myocardial hypertension and decreases cardiac preload, reduces myocardial oxygen demand.

Dilates coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases the flow of oxygen to the myocardium (especially in vasospastic angina); prevents the development of coronary artery spasm (including that caused by smoking). In patients with stable angina a single daily dose increases exercise tolerance, slows down the development of angina and “coronary” ST-segment depression, reduces the frequency of angina attacks and the use of nitroglycerin and other nitrates.

It has a long-term dose-dependent hypotensive effect. The hypotensive effect is due to a direct vasodilatory effect on the vascular smooth muscles. In arterial hypertension a single dose provides clinically significant reduction of BP during 24 hours (in “lying” and “standing” position of the patient).

Orthostatic hypotension when prescribing amlodipine is quite rare. It does not cause a decrease in exercise tolerance, left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy.

It does not influence myocardial contractility and conduction, does not cause reflex increase of heart rate, inhibits platelet aggregation, increases glomerular filtration rate, has weak natriuretic action. It does not increase the severity of microalbuminuria in diabetic nephropathy.

It has no adverse effect on metabolism and concentration of plasma lipids and can be used for treatment of patients with bronchial asthma, diabetes mellitus and gout.

The time of onset of effect is 2-4 hours, the duration of effect is 24 hours.

Pharmacokinetics

Intake

Intake slowly and almost completely absorbed from the gastrointestinal tract. Food intake has no effect on absorption. Cmax in plasma is reached after 6-9 h in both elderly and young patients. Average absolute bioavailability is 64%.

Distribution

The Css of amlodipine in plasma is reached after continuous use for 7-8 days.

The Vd is approximately 21 L/kg, indicating prevailing tissue distribution. It penetrates through the HEB and into the breast milk.

The binding to plasma proteins is 97%.

Metabolism

About 90% of amlodipine is biotransformed in the liver to form inactive metabolites.

Amlodipine is excreted from the body with urine (10% of dose – unchanged and 60% – as inactive metabolites) and in the feces (20-25% as metabolites). Excretion is biphasic, T1/2 is on average 31-48 hours. Total clearance of amlodiline is 7 ml/min/kg. Amlodipine is not eliminated by hemodialysis.

Pharmacokinetics in special clinical cases

The excretion of amlodipine is slower (T1/2 – 65 h) in elderly patients (older than 65 years) compared to younger patients, but these differences are not clinically relevant.

The prolonged T1/2 in patients with hepatic impairment suggests that long-term administration will result in higher cumulation of the drug in the body (T1/2 is up to 60 h).

The presence of renal impairment in a patient has no significant effect on the pharmacokinetics of amlodipine.

Indications

Stable angina pectoris (as monotherapy or in combination with other antianginal agents); arterial hypertension (as monotherapy or in combination with other antihypertensive agents); vasospastic angina (Prinzmetal angina) (as monotherapy or in combination with other antianginal agents).

Active ingredient

Composition

Active ingredient:

amlodipine;

Associates:

Magnesium stearate;

Sodium carboxymethyl starch;

calcium hydrophosphate anhydrous;

MCC

How to take, the dosage

In the oral route, the initial dose for treatment of arterial hypertension and angina pectoris is 5 mg/day. The maximum daily dose is 10 mg once. For arterial hypertension, the maintenance dose may be 5 mg/day (1 tablet of 5 mg).

In elderly patients, the T1/2 of amlodipine may increase and creatinine clearance may decrease. No dose changes are required, but closer monitoring of patients is necessary.

Dose changes are not required when concomitantly prescribed with thiazide diuretics, β-adrenoblockers and ACE inhibitors.

Dose changes are not required in patients with renal impairment.

Interaction

Amlodipine may be concomitantly used with NSAIDs (especially indomethacin), antibacterials and hypoglycemic agents for oral administration. Strengthening of antianginal and hypotensive effect of dihydropyridine slow calcium channel blockers is possible in concomitant use with thiazide and “loop” diuretics, verapamil, ACE inhibitors, beta-adrenoblockers and nitrates, as well as strengthening of their hypotensive effect when used together with alpha 1-adrenoblockers, neuroleptics.

Amlodipine may be safely used for the treatment of arterial hypertension together with thiazide diuretics, alpha-adrenoblockers, beta-adrenoblockers or ACE inhibitors.

In patients with stable angina pectoris, the drug may be combined with other antianginal agents, such as long-acting nitrates, beta-adrenoblockers or short-acting nitrates. Although no negative inotropic effects have generally been observed with amlodipine, some slow calcium channel blockers may exacerbate the negative inotropic effects of QT-prolonging antiarrhythmic agents (e.g., amiodarone and quinidine).

A single use of sildenafil 100 mg in patients with essential hypertension has no effect on pharmacokinetic parameters of amlodipine. Repeated use of amlodipine in dose of 10 mg and atorvastatin in dose of 80 mg is not accompanied by significant changes in parameters of pharmacokinetics of atorvastatin.

Amlodipine at a single and repeated use in a dose of 10 mg does not affect the pharmacokinetics of ethanol (beverages containing alcohol). Antiviral agents (ritonavir) increase plasma concentrations of slow calcium channel blockers, including amlodipine. Neuroleptics and isoflurane increase the hypotensive effect of dihydropyridine derivatives. Calcium preparations may reduce the effect of slow calcium channel blockers.

When concomitant use of amlodipine with lithium preparations an increase in neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) may occur. Amlodipine does not alter the pharmacokinetics of cyclosporine. It has no effect on the serum concentration of digoxin and its renal clearance.

There is no significant effect on the effect of warfarin (prothrombin time). Cimetidine does not affect the pharmacokinetics of amlodipine. In in vitro studies amlodipine does not affect the binding to blood proteins of digoxin, phenytoin, warfarin and indomethacin. Simultaneous single administration of 240 mg of grapefruit juice and 10 mg of oral amlodipine is not accompanied by significant changes in pharmacokinetics of amlodipine.

Special Instructions

Impact on driving and operating machinery

There have been no reports about the effect of Normodipine® on driving or operating machinery.

However, drowsiness, dizziness and other nervous system side effects may occur in some patients, mainly at the beginning of treatment. If they occur, the patient should take special precautions for driving and operating complex mechanisms.

When treating with Normodipine® it is necessary to control body weight and sodium intake, administration of appropriate diet is indicated. It is necessary to maintain dental hygiene and to observe the dentist (for prevention of pain, bleeding and gingival hyperplasia). Patients with low body weight, short patients and patients with significant liver dysfunction may require a lower dose.

The T1/2 of the drug may also be prolonged if liver function is impaired. Therefore, Normodipine® should be prescribed with caution in these patients.

While discontinuation of Normodipine® is not associated with development of withdrawal syndrome, it is advisable to discontinue treatment by gradually reducing the drug dose. Efficacy and safety of the drug in hypertensive crisis have not been established.

Contraindications

Clinically significant aortic stenosis; collapse; cardiogenic shock; severe arterial hypotension (systolic BP less than 90 mm Hg); unstable angina (except for Prinzmetal angina); hypersensitivity to amlodipine and other dihydropyridine derivatives; pregnancy; lactation; age below 18 years (due to lack of clinical experience with the use).

Caution: The drug should be administered in chronic heart failure of non-ischemic etiology of III-IV functional class according to NYHA classification, liver function disorders, CCSU (marked bradycardia, tachycardia), arterial hypotension, elderly patients, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after it).

Side effects

Central and peripheral nervous system disorders:

often – headache, dizziness, increased fatigue, somnolence; infrequent – asthenia, general malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, vertigo, syncope, insomnia, mood lability, unusual dreams, increased excitability, depression, anxiety; very rare – apathy, ataxia, agitation, amnesia.

Cardiovascular system disorders:

often – palpitations, peripheral edema (swelling of ankles and feet), flushes of blood to the skin of the face; infrequently – excessive decrease in BP; Very rarely – development or worsening of heart failure, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation), myocardial infarction, chest pain, orthostatic hypotension, vasculitis.

Digestive system disorders:

often – nausea, abdominal pain; sometimes – vomiting, constipation or diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst; rarely – gingival hyperplasia, increased appetite; very rarely – pancreatitis, gastritis, jaundice (due to cholestasis), hyperbilirubinemia, increased liver transaminases activity, hepatitis.

With the organs of hematopoiesis:

very rare – thrombocytopenic purpura, leukopenia, thrombocytopenia.

Musculoskeletal system disorders:

sometimes – muscle cramps, myalgia (with prolonged use), arthralgia, back pain, arthrosis; rarely – myasthenia.

Urogenital system disorders:

Rarely – frequent urination, painful urination, nycturia, impotence; very rarely – dysuria, polyuria.

Skin disorders:

seldom – dermatitis; very rarely – purpura, xeroderma, pigmentation disorders.

Sensory organs:

seldom – visual disturbances, diplopia, conjunctivitis, eye pain, xerophthalmia, tinnitus.

Allergic reactions: infrequent – skin itching, rash (including erythematous, maculopapular rash); very rare – urticaria, angioedema, erythema multiforme.

Other: rarely – alopecia, gynecomastia, hyperuricemia, weight gain/loss, dyspnea, nasal bleeding, increased sweating; very rarely – cold sticky sweat, cough, rhinitis, parasmia, taste disorder, accommodation disorder, hyperglycemia.

Overdose

Symptoms: tachycardia, marked BP decrease, excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including development of shock and death).

The treatment: maintenance of cardiovascular function, elevated, gastric lavage, administration of activated charcoal, control of heart and lung function, above head level, position of the lower extremities, control of CPR and diuresis.

In order to restore vascular tone – administration of vasoconstrictors (if there are no contraindications for their use); in order to eliminate the effects of calcium channel blockade – IV administration of calcium gluconate as Hemodialysis is ineffective.

Pregnancy use

Contraindicated.

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