Adalat^® SL (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer HealthCare AG (Germany)

ATC Code

C08CA05 (Nifedipine)

Active Substance

Nifedipine (Rec.INN registered by WHO)

Dosage Form

Adalat® SL

Rapid-retard tablets, coated, 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

Nifedipine is a selective blocker of “slow” calcium channels, a derivative of 1,4-dihydropyridine. It has antianginal and antihypertensive effects.

It reduces the flow of calcium ions through the “slow” calcium channels into cardiomyocytes and smooth muscle cells of coronary and peripheral arteries, thereby lowering peripheral vascular resistance and dilating coronary arteries, especially large supplying vessels, and even intact wall segments of partially stenotic vessels.

Furthermore, Nifedipine reduces the tone of the smooth muscles of the coronary arteries, thus preventing angiospasm, enhances blood flow in poststenotic sections of the vessels, increases oxygen delivery to the myocardium, and reduces myocardial oxygen demand due to a decrease in peripheral vascular resistance (afterload).

With long-term use, it is capable of preventing the development of new atherosclerotic lesions in the coronary arteries.

Nifedipine reduces the tone of arteriolar smooth muscle, thereby reducing elevated peripheral vascular resistance and, consequently, blood pressure.

At the beginning of nifedipine treatment, a temporary reflex increase in heart rate and, as a consequence, cardiac output may occur. However, this increase is not significant enough to compensate for the vasodilation.

Moreover, Nifedipine, with both short-term and long-term use, increases the excretion of sodium ions and fluid from the body. The antihypertensive effect of nifedipine is especially pronounced in patients suffering from arterial hypertension.

Nifedipine is capable of preventing the development of vasospasm in Raynaud’s syndrome.

Pharmacokinetics

Absorption

After oral administration, Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract. The bioavailability of nifedipine with uncontrolled release is 45-56% due to the “first-pass” effect through the liver.

Food intake slightly reduces the initial rate of absorption but does not affect the extent of bioavailability. When taking Adalat^® SL at a dose of 20 mg, the C_max in blood plasma is 47-76 mg/l (C_max= 47 – 76 mg/l), and the time to reach this concentration is 1.6-3.6 hours (t max = 1.6 – 3.6 hours).

About 95% of nifedipine binds to blood plasma proteins (albumin).

Metabolism

After oral administration, Nifedipine is metabolized in the wall of the small intestine and in the liver to form inactive metabolites.

Excretion

The elimination half-life (T 1/2) of Adalat^® SL ranges from 3.7 to 4.3 hours due to delayed absorption. No accumulation effect is observed when taking the drug at usual doses.

Nifedipine is excreted from the body in the form of its metabolites through the kidneys and about 5-15% with bile through the intestines. Unchanged Nifedipine is detected in urine in insignificant amounts (about 0.1%).

Renal impairment

Pharmacokinetics are not altered.

Hepatic impairment

The clearance of nifedipine is reduced; in severe cases, adjustment of the dosage regimen may be necessary.

Indications

• Ischemic heart disease: chronic stable angina (angina pectoris).
• Arterial hypertension.

ICD codes

Dosage Regimen

For oral administration.

The Adalat^® SL tablet should be taken whole, with a small amount of water, regardless of meals. The tablet must not be broken; it should be removed from the foil immediately before taking.

The recommended interval between doses of the drug is on average 12 hours, the minimum allowable interval is 6 hours. The therapeutic dose should be reached gradually, depending on the individual characteristics of the clinical picture.

For patients over 18 years of age, in the absence of other prescriptions, the following dosage regimen is recommended.

Ischemic heart disease: stable angina (angina pectoris)

1 tablet of Adalat SL (20 mg) 2 times a day. If necessary, the dose of the drug can be gradually increased to a maximum daily dose of 60 mg. When using high doses, discontinuation of the drug should also be carried out gradually.

Arterial hypertension

1 tablet of Adalat SL (20 mg) 2 times a day.

The duration of therapy is determined by the doctor.

Hepatic impairment

Patients with impaired liver function during drug administration should be under medical supervision; in severe hepatic insufficiency, a reduction in the nifedipine dose may be required.

Adverse Reactions

Frequency of occurrence >1% < 0%

General: asthenia (fatigue), edema of the lower extremities.

Cardiovascular system: vasodilation (facial redness, feeling of heat), palpitations, peripheral edema.

Digestive system: nausea.

Nervous system: dizziness, headache.

Frequency of occurrence >0.1% <1.0%

General: abdominal pain, chest pain, malaise.

Cardiovascular system: angina attacks, postural hypotension, tachycardia, syncope.

Digestive system: constipation, diarrhea, dry mouth, dyspepsia, vomiting.

Musculoskeletal system: myalgia, arthralgia.

Nervous system: insomnia, irritability, paresthesia, drowsiness, tremor, dizziness.

Respiratory system: dyspnea.

Skin: sweating, itching, rash, skin redness.

Urinary system: polyuria, nocturia.

Frequency of occurrence >0.01% <0.1%

General: increase in abdominal volume due to subcutaneous adipose tissue, allergic reactions, photosensitivity reaction.

Cardiovascular system: pronounced decrease in blood pressure.

Digestive system: gastrointestinal disorders, flatulence, changes in transaminase levels, increased gamma-glutamyl transpeptidase content.

Nervous system: hyperesthesia.

Skin: urticaria.

Blood and hematopoietic system: purpura (thrombocytopenia).

Sensory organs: visual impairment, amblyopia.

Urinary system: frequent urination.

Frequency of occurrence <0.01%

Digestive system: gingival hyperplasia.

Blood and hematopoietic system: agranulocytosis.

Skin: erythromelalgia, exfoliative dermatitis.

Other: allergic reactions (anaphylactic reaction), gynecomastia.

In patients on hemodialysis with severe arterial hypertension and hypovolemia, a significant decrease in blood pressure is possible due to the vasodilatory effect of nifedipine.

Contraindications

• Hypersensitivity to nifedipine and other 1,4-dihydropyridine derivatives;
• Cardiovascular shock;
• Concomitant use with rifampicin.

With caution: arterial hypotension (systolic blood pressure below 90 mm Hg), acute myocardial infarction, systolic heart failure III – IV functional class according to NYHA, severe aortic stenosis, severe hepatic insufficiency, hemodialysis, age under 18 years (efficacy and safety not established).

Use in Pregnancy and Lactation

Adalat LS is contraindicated during pregnancy.

If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

Use in Hepatic Impairment

Use with caution in severe hepatic insufficiency.

Pediatric Use

Use with caution under 18 years of age (efficacy and safety not established).

Special Precautions

The use of nifedipine in patients with impaired liver function should be monitored; in severe cases, a reduction in the drug dose may be required. With the simultaneous use of Adalat^® SL and beta-adrenergic receptor blockers, patients require careful monitoring, as the development of a pronounced decrease in blood pressure and worsening of symptoms of heart failure is possible.

In isolated cases of in-vitro fertilization, a relationship was found between the use of “slow” calcium channel blockers (CCBs), in particular nifedipine, and reversible biochemical changes in the sperm head, leading to altered sperm function.

Thus, if multiple attempts at in-vitro fertilization are unsuccessful, in the absence of other reasons, the possibility of influence of the CCB, in particular nifedipine, used by the man cannot be excluded.

When using CCBs, the development of bradycardia is possible.

Nifedipine causes a false-positive increase in the concentration of vanillylmandelic acid in urine when determined by the spectrophotometric method. It does not affect the indicators obtained by high-performance liquid chromatography (HPLC).

Nifedipine, the active substance of Adalat^® SL tablets, is highly sensitive to light exposure. The tablets must not be crushed to avoid damaging the coating, which provides the necessary protection for the drug from this exposure.

Effect on ability to drive vehicles and operate machinery

Individual reaction to the drug may negatively affect the ability to drive a car and operate complex machinery, especially at the beginning of treatment, during changes in the dosage regimen, and with simultaneous alcohol consumption.

Overdose

Symptoms: impaired consciousness up to coma, sharp drop in blood pressure, heart rhythm disturbances – tachycardia/bradycardia, hyperglycemia, metabolic acidosis, hypoxia. Cardiogenic shock accompanied by pulmonary edema.

Emergency measures should primarily be aimed at removing nifedipine from the body and restoring stable hemodynamic parameters.

Gastric lavage in combination with small intestine irrigation is recommended to prevent further absorption of the drug. Plasmapheresis is recommended, as nifedipine is characterized by a high degree of binding to blood plasma proteins and a relatively small V_d.

Hemodialysis is not advisable since Nifedipine is not excreted by dialysis.

For bradycardia – symptomatic treatment with β-sympathomimetics; in case of life-threatening bradycardia, implantation of a temporary artificial pacemaker is indicated.

For a pronounced decrease in blood pressure – treatment with calcium-containing drugs – slow intravenous administration of 10-20 ml of a 10% calcium gluconate solution is recommended; if necessary, the administration is repeated.

If there is no effect, sympathomimetics dopamine or norepinephrine are prescribed. The doses of these drugs are selected individually. Fluids should be administered with caution due to the risk of cardiac overload.

Drug Interactions

The hypotensive effect of nifedipine may be enhanced when used concomitantly with drugs that lower blood pressure.

Nifedipine is metabolized by the cytochrome P450 3A4 system in the liver and intestinal mucosa. Agents that inhibit or induce these enzymes may interact with orally administered nifedipine, impairing its clearance or the “first-pass” effect through the liver.

Digoxin

Nifedipine reduces the clearance of digoxin, leading to an increase in its plasma concentration. Therefore, patients require careful monitoring for symptoms of digoxin overdose and its dose should be reduced if necessary.

Phenytoin

It induces cytochrome P450 3A4 system enzymes, reduces the bioavailability of nifedipine, which may require an increase in its dose. Upon discontinuation of phenytoin, the nifedipine dose should be reduced.

Quinidine

Nifedipine reduces the plasma concentration of quinidine; however, upon its discontinuation, the quinidine content may increase significantly, requiring adjustment of its dose. In some cases, the plasma concentration of nifedipine may increase, so if indicated, its dose should be reduced. During combination therapy, the plasma concentration of quinidine and blood pressure levels should be monitored.

Cimetidine

Increases nifedipine plasma concentrations and may potentiate the hypotensive effect.

Rifampicin

Since rifampicin induces cytochrome P450 3A4 system enzymes, Adalat^® SL should not be used concomitantly with rifampicin. Because due to the decreased bioavailability of nifedipine, its therapeutic plasma concentration level decreases.

Diltiazem

Reduces the clearance of nifedipine. With this combination, a reduction in the nifedipine dose may be required.

Grapefruit juice inhibits cytochrome P450 3A4 system enzymes. As a result, simultaneous intake of grapefruit juice inhibits the metabolism of nifedipine, leading to an increase in its plasma concentrations and may cause a decrease in the therapeutic effect of the drug in arterial hypertension.

Cisapride

Concomitant administration of cisapride and nifedipine may lead to an increase in the plasma concentration of the latter. Therefore, blood pressure levels should be monitored and, if necessary, the nifedipine dose may be reduced.

Possible interactions

Erythromycin, Fluoxetine, Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Ketoconazole, Itraconazole, Fluconazole, Nefazodone

They inhibit the action of drugs whose metabolism is associated with the cytochrome P450 3A4 system. Although studies have not noted interaction between the aforementioned agents and nifedipine, a potential increase in nifedipine plasma concentration cannot be excluded. With simultaneous use of these agents and nifedipine, blood pressure levels should be monitored, and, if necessary, the nifedipine dose should be reduced.

Tacrolimus

It is metabolized by the cytochrome P450 3A4 system. Tacrolimus plasma concentration should be monitored, and, if necessary, the tacrolimus dose may be reduced.

Carbamazepine, Phenobarbital, Valproic acid

Although the interaction between these agents and nifedipine has not been studied, it is known that they can reduce the plasma concentration of another “slow” calcium channel blocker – nimodipine. Therefore, a decrease in nifedipine plasma concentration cannot be excluded.

The following agents do not affect the pharmacokinetics of nifedipine:

Ajmaline, Acetylsalicylic acid, Benazepril, Candesartan cilexetil, Debrisoquine, Doxazosin, Irbesartan, Omeprazole, Orlistat, Pantoprazole, Ranitidine, Rosiglitazone, Tachinolol, Triamterene, Hydrochlorothiazide.

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F), in a place protected from light, dry, and out of the reach of children.

Shelf Life

Shelf life– 5 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.