Adalat - instructions for use, dose, side effects, contraindications

Nifedipine is a selective blocker of "slow" calcium channels (BCCC), a derivative of 1,4-dihydropyridine. Has antianginal and antihypertensive effect. Reduces the current of calcium ions through the "slow" calcium channels inside the cells, mainly inside the cardiomyocytes, smooth muscle cells of the coronary and peripheral arteries, while reducing the overall peripheral vascular resistance (OPSS) and dilating the coronary arteries, especially large vessels, as well as intact segment walls of partially stenotic vessels. Besides, nifedipine reduces the tone of the smooth muscles of the coronary arteries, thereby preventing angiospasm, poststenotic blood flow improves and oxygen delivery to the myocardium increases, myocardial oxygen demand decreases due to reduction of the total peripheral vascular resistance (afterload). With prolonged use nifedipine is able to prevent the development of new atherosclerotic lesions in the coronary arteries.

Nifedipine reduces the tone of the smooth muscle arterioles, thereby reducing the increased OPSS and, consequently, blood pressure (BP). At the beginning of treatment with nifedipine, a temporary reflex increase in the heart rate (heart rate) and, as a consequence, cardiac output can occur. However, this increase is not so significant as to compensate for the dilatation of blood vessels. Besides, nifedipine with short-term and long-term use increases the excretion of sodium and water from the body. Antihypertensive effect of nifedipine is especially pronounced in patients with arterial hypertension.

In patients with Raynaud's syndrome nifedipine can prevent or reduce cases of spasm of the vessels of the fingers.

Pharmacokinetics:

Distribution

The connection with blood plasma proteins (albumin) is about 95%. After intravenous administration nifedipine quickly distributed in the body; 50% of the administered dose is distributed in the body after 5-6 minutes.

Metabolism

After parenteral administration nifedipine almost completely metabolized in the liver mainly as a result of oxidative processes. Metabolites do not have pharmacodynamic activity.

Excretion

Nifedipine is excreted from the body in the form of inactive metabolites mainly by the kidneys, to a lesser extent (5-15%) through the intestine. Unchanged in the urine in small amounts (less than 1%).

The half-life (T_1/2) of nifedipine after parenteral administration is about 1.7 hours.

In patients with impaired renal function the pharmacokinetics of nifedipine does not change significantly compared to healthy volunteers.

In a comparative study of the pharmacokinetics of nifedipine in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic dysfunction and in patients with normal liver function, the clearance of nifedipine for oral administration was reduced by an average of 48% (Child-Pugh class A) and 72% (class B by Child-Pugh). Consequently AUC and C_mOh nifedipine increased by an average of 93% and 64% (Child-Pugh class A) and 253% and 171% (Child-Pugh class B), respectively, compared with patients with normal liver function. The pharmacokinetics of nifedipine has not been studied in patients with severe hepatic impairment.

Penetrates through the placental barrier, excreted in breast milk.

Hemodialysis and peritoneal dialysis do not affect the pharmacokinetics of nifedipine, plasmapheresis enhances its excretion.

Indications:

- Angina of Prinzmetal.

- Hypertensive crisis.

Contraindications:

- Hypersensitivity to nifedipine or any other component of the drug;

- Pregnancy (up to 20 weeks) and the period of breastfeeding (see section "Application during pregnancy and during breast-feeding");

- cardiogenic shock;

- unstable angina;

- acute myocardial infarction (in the first 4 weeks after myocardial infarction);

- concomitant use with rifampicin (cm.section "Interaction with other medicinal products");

- age to 18 years (safety and efficacy not established).

Carefully:

Acute congestive heart failure, chronic heart failure III-IV functional class by classification NYHA, severe aortic stenosis, severe bradycardia (heart rate less than 50 beats per minute), hepatic insufficiency, severe arterial hypotension (systolic blood pressure less than 90 mm Hg), in patients with malignant hypertension and hypovolemia on hemodialysis, pregnancy 20 weeks).

Pregnancy and lactation:

The use of Adalat® is contraindicated in pregnancy up to 20 weeks.

Data of controlled clinical studies on the safety and efficacy of Adalat® in pregnant women are not available.

Studies in animals have shown the presence of embryotoxicity, placental toxicity, fetotoxicity and teratogenicity when taking nifedipine during and after the organogenesis period.

According to available clinical data, it is impossible to judge the specific prenatal risk.At the same time, there are data on the increase in the probability of perinatal asphyxia, cesarean section, premature birth and intrauterine growth retardation. It is unclear whether these cases are due to a major illness (arterial hypertension), treatment performed, or a specific effect of Adalat®. The information available is insufficient to exclude the possibility of side effects, which are dangerous for the fetus and the newborn.

Therefore, the use of Adalat® after the 20th week of pregnancy requires a careful individual assessment of the risk-benefit ratio for the patient, fetus and / or newborn and can only be considered if other therapies are contraindicated or ineffective.

Careful monitoring of blood pressure in pregnant women with Adalat® should be carried out simultaneously with the intravenous administration of magnesium sulfate due to the possibility of excessive reduction in blood pressure, which is dangerous for both the mother and the fetus.

Nifedipine is excreted in breast milk, so if Adalat® is needed during lactation, breastfeeding should be discontinued.

Fertility / In Vitro Fertilization

In isolated cases, when performing in vitro fertilization with the use of BCCC, in particular nifedipine, reversible biochemical changes in the sperm head were noted, which led to a disruption of the sperm function. With unsuccessful attempts of in vitro fertilization and with the exclusion of other causes of infertility, one should take into account the probability of influencing sperm of BCCC, in particular, nifedipine, provided they are used.

Dosing and Administration:

The dose of Adalat ® should be selected individually, taking into account the severity of the disease and the patient's response to ongoing treatment, and strictly control blood pressure and heart rate.

50 ml of Adalat® solution is administered intravenously infusion for about 4-8 hours (at a rate of 6.3-12.5 ml / h, corresponding to 0.63-1.25 mg nifedipine / h). The maximum dose of the drug administered within 24 hours should not exceed 150-300 ml (corresponding to 15-30 mg of nifedipine / 24 hours).

Infusion therapy can be carried out for 3 days.Then it is recommended to switch to nifedipine therapy inside.

Special patient groups

Children

The safety and efficacy of Adalat® in children under 18 years of age have not been established.

Elderly patients

In elderly patients, a reduction in maintenance dose may be required due to pharmacokinetics disorders (compared to younger patients).

Patients with hepatic impairment

In patients with mild, moderate or severe impairment of liver function, careful monitoring and reduction of the dose of the drug may be required. The pharmacokinetics of nifedipine has not been studied in patients with severe hepatic impairment.

Patients with impaired renal function

In patients with impaired renal function, dose adjustment is not required.

Instructions for the administration of Adalat® infusion solution

Ready-to-use infusion Adalat® solution should be administered through a special syringe and infusion tube attached to the solution, only with Perfusor® or Injectomat® devices. If you use the prescribed infusion accessories, nifedipine loss through the conductive system can not be feared.

Nifedipine, the active substance of the infusion solution Adalat®, is highly sensitive to light, therefore it is necessary to protect the solution from this effect. The vial supplied with a protective plastic sheath should only be removed from the package immediately before use.

When carrying out mixed infusion, it is also necessary to protect the Adalat® solution from exposure to light, so it must be injected directly into the infusion tube, which already receives another solution, with the introduction into the system to be carried out as close as possible to the venous puncture site. It is strictly forbidden to mix Adalat® solution in one bottle with other solutions.

If the solution is stored in the refrigerator, then before the introduction of its temperature must be brought to room temperature.

Fig. 1: Using a syringe needle with an extended piston, pierce the vial lid, increase the pressure in the vial by repeatedly pumping air with a syringe, and collect the contents of the vial.

Fig. 2: Remove the needle and attach the infusion tube to the syringe. Remove all air from the syringe and the conductive system.

Fig. 3a: Place the syringe in Perfusor® and set the infusion rate.

Fig. 3b: Place the syringe in the Injectomat® and set the infusion rate.

Fig. 4: Connect the tube to the infusion needle.

It is recommended that you read further the manuals on the use of Perfusor® and Injectomat® systems.

Side effects:

When using Adalat®, side effects were evaluated in placebo-controlled studies.

The following side effects were classified as follows: "often" (≥1 / 100, <1/10), "infrequently" (≥1 / 1000, <1/100), "rarely" (≥1 / 10000, <1 / 1000). Within the limits of each group, allocated depending on the incidence, adverse reactions are presented in order of decreasing severity.

The degree of incidence of adverse reactions was "often" estimated to be less than 3%, except for peripheral edema (9.9%) and headache (3.9%). Side effects, which were noted only during post-marketing observations, and whose frequency was not assessed, are designated as "frequency unknown."

Violations of the blood and lymphatic system: frequency unknown - agranulocytosis, leukopenia.

Immune system disorders: infrequently - allergic reactions, allergic edema / angioedema (including laryngeal edema¹); rarely - hives, itching, skin rashes; frequency unknown - anaphylactic / anaphylactoid reactions.

Disorders of the psyche: infrequent - anxiety, sleep disturbances.

Disorders from the metabolism and nutrition: frequency unknown - hyperglycemia.

Disturbances from the nervous system: often - headache; infrequently - vertigo, migraine, dizziness, tremor; rarely - paresthesia, dysesthesia; frequency unknown - hypoesthesia, drowsiness.

Disturbances on the part of the organ of sight: infrequently - impaired vision; frequency unknown - pain in the eyes.

Heart Disease: infrequently - tachycardia, palpitation; frequency unknown - chest pain (angina).

Vascular disorders: often - peripheral edema, vasodilation; infrequent - marked decrease in blood pressure, fainting.

Disturbances from the respiratory system of the chest and mediastinal organs: infrequently - nosebleeds, nasal congestion; frequency is unknown - dyspnoea (dyspnea).

Disorders from the gastrointestinal tract: often constipation; infrequently - gastrointestinal and abdominal pain (pain in the stomach and intestines), nausea, indigestion, bloating, dryness of the oral mucosa; rarely - gingival hyperplasia; frequency unknown - vomiting, insufficiency of gastroesophageal sphincter.

Disturbances from the liver and bile ducts: infrequently - a transient increase in the activity of "liver" transaminases; frequency is unknown - jaundice.

Disturbances from the skin and subcutaneous tissues: infrequently, erythema; frequency unknown - Lyell syndrome, photosensitivity, purpura.

Disturbances from musculoskeletal system and connective tissue: infrequently - muscle cramps, swelling of the joints; frequency unknown - arthralgia, myalgia.

Disorders from the kidneys and urinary tract: infrequently - polyuria, dysuria.

Violations of the genitals and mammary gland: infrequently erectile dysfunction.

General disorders and disorders at the site of administration: often - poor health; infrequently - nonspecific pain, chills, reactions at the injection site (including thrombophlebitis).

¹ - can be life-threatening.

In patients with malignant hypertension and hypovolemia on dialysis, a marked decrease in blood pressure may result from vasodilation.

Overdose:

Symptoms: loss of consciousness up to coma, lowering blood pressure, tachycardia / bradycardia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock accompanied by pulmonary edema.

Treatment

Activities to provide emergency assistance in case of an overdose should first of all be aimed at removing nifedipine from the body and restoring stable parameters of hemodynamics.

Conducting hemodialysis is not advisable, because nifedipine not output during dialysis; it is recommended to conduct plasmapheresis (since nifedipine has a high degree of binding to plasma proteins and a relatively small volume of distribution).

With bradycardia - β-sympathomimetics, with life-threatening bradycardia - staging a temporary artificial pacemaker.

With a marked decrease in blood pressure, which develops due to cardiogenic shock and vasodilation, a slow intravenous injection of 10-20 ml of 10% calcium gluconate solution is recommended (until the upper limit of the normal calcium content is reached or a re-introduction is permissible). If calcium supplementation failed to achieve an adequate increase in blood pressure,recommended the use of vasoconstrictive drugs from the group of sympathomimetics - dopamine or norepinephrine. Doses of these drugs are selected depending on the therapeutic effect obtained.

The introduction of fluid should be done with caution in connection with the risk of cardiac overload.

Interaction:

Medicines, affecting nifedipine

Nifedipine is metabolized by isoenzyme CYP3A4, localized in the liver and intestinal mucosa. Consequently, drugs that inhibit or induce this enzyme system can affect the effect of the "first pass" through the liver (when taking nifedipine orally) or the clearance of nifedipine (see section "Special instructions"). Nifedipine - a drug with high clearance. Thus, the hepatic clearance is determined mainly by the volume of hepatic blood flow. Therefore, the possible interactions listed below that affect the pharmacokinetic performance of nifedipine when administered concomitantly can not be compared with interactions after intravenous nifedipine.

Rifampicin

Rifampicin is a potent inducer of isoenzyme CYP3A4. When combined with rifampicin, the bioavailability of nifedipine is significantly reduced and, accordingly, its effectiveness decreases. The use of nifedipine in conjunction with rifampicin is contraindicated (see section "Contraindications").

Simultaneous reception of nifedipine with weak and moderate isoenzyme inhibitors CYP3A4 requires regular monitoring of blood pressure and, if necessary, reducing the dose of nifedipine. These drugs include:

Antibiotics of the macrolide group (eg, erythromycin)

Clinical studies on the interaction of nifedipine with macrolides were not conducted. It is known that some antibiotics-macrolides are inhibitors of the isoenzyme CYP3A4. As a result, the possibility of increasing the concentrations of nifedipine in blood plasma can not be ruled out by the joint application of these drugs (see section "Special instructions").

Azithromycin, belonging to the macrolide group, is not an inhibitor of the isoenzyme CYP3A4.

HIV protease inhibitors (eg, ritonavir)

Clinical studies on the interaction of nifedipine with HIV protease inhibitors have not been conducted.It is known that the preparations of this group are inhibitors of the isoenzyme CYP3A4. These drugs suppress isoenzyme CYP3A4 metabolism of nifedipine in vitro. In the case of combined use with nifedipine, a significant increase in the concentrations of nifedipine in the blood plasma due to delayed metabolism in the "first passage" through the liver and delayed excretion (see section "Special instructions").

Antifungal preparations of the azole group (for example, ketoconazole)

Clinical studies on the interaction of nifedipine with drugs of this group have not been conducted. It is known that the preparations of this group are inhibitors of the isoenzyme CYP3A4. When administered orally with nifedipine, a significant increase in the systemic bioavailability of nifedipine due to delayed metabolism in the "first pass" through the liver (see section "Special instructions").

Fluoxetine

Clinical studies to study the possible interaction of nifedipine with fluoxetine have not been conducted. Fluoxetine inhibits due to isoenzyme CYP3A4 metabolism of nifedipine in vitro. In the case of combined use with nifedipine, an increase in the concentrations of nifedipine in blood plasma (see section "Special instructions").

Nefazodone

Clinical studies to study the possible interaction of nifedipine with nefazodone have not been conducted. It is known that nefazodone inhibits the metabolism of other drugs due to the action of the isoenzyme CYP3A4. In the case of combined use with nifedipine, an increase in the concentrations of nifedipine in blood plasma (see section "Special instructions").

Hinupristine / delfopristin

Joint use with nifedipine may lead to increased concentrations of nifedipine in blood plasma (see section "Special instructions").

Valproic acid

Clinical studies to study the possible interaction of nifedipine with valproic acid have not been conducted. Since it was shown that valproic acid increases the concentration in the blood plasma of the nimodipine "slow" calcium channels structurally similar to nifedipine by inhibiting liver enzymes, it is impossible to exclude the possibility of increasing nifedipine concentrations in the blood plasma and enhancing its effectiveness (cm.section "Special instructions").

Cimetidine

Due to inhibition of the isoenzyme CYP3A4 combined use with nifedipine may lead to increased concentrations of nifedipine in the blood plasma and increase its antihypertensive action (see section "Special instructions").

Other studies

Cisapride

The combined use of cisapride and nifedipine may lead to an increased concentration of nifedipine in the blood plasma.

Antiepileptic agents - inducers of isoenzyme CYP3A4 (phenytoin, carbamazepine, phenobarbital)

Phenytoin induces isoenzyme CYP3A4. With the simultaneous use of nifedipine and phenytoin, there is a decrease in the bioavailability of nifedipine and, as a consequence, a reduction in its effectiveness, which requires clinical observation and, if necessary, an increase in the dose of nifedipine. After the withdrawal of phenytoin, the dose of nifedipine should be reduced.

Clinical studies on the interaction of nifedipine with carbamazepine or phenobarbital were not conducted. Since it has been shown that both drugs reduce the plasma concentrations of a structurally similar to nifedipine blocker of "slow" calcium channels of nimodipine,then it is impossible to exclude the possibility of reducing the concentrations of nifedipine in the blood plasma and, consequently, reducing its effectiveness.

Influence of nifedipine on other drugs

Antihypertensive drugs

Nifedipine may enhance the antihypertensive effect of other antihypertensive agents such as diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, other slow calcium channel blockers, alpha-blockers, phosphodiesterase 5 (PDE5) inhibitors, methyldopa when used simultaneously with them.

With the simultaneous use of nifedipine with beta-adrenoblockers, careful monitoring of patients is necessary, since in some cases it has been reported that the symptoms of heart failure worsen.

Digoxin

The simultaneous use of nifedipine and digoxin can lead to a decrease in digoxin clearance, which leads to an increase in the concentration of digoxin in the blood plasma. Therefore, patients need to establish a thorough clinical and ECG observation for early detection of an overdose of digoxin; if necessary, the dose of digoxin should be reduced taking into account its concentration in the blood plasma.

Quinidine

In some cases of combined use of nifedipine and quinidine, there was a decrease in the concentration of quinidine in the blood plasma, as well as a marked increase in the concentration of quinidine in the blood plasma after the withdrawal of nifedipine. Therefore, in the case of combined use of nifedipine as an additional remedy or a withdrawal from nifedipine, the concentration of quinidine in the blood plasma should be monitored and, if necessary, a dose adjustment of quinidine is required. In some cases, the combined use of nifedipine and quinidine may increase the concentration of nifedipine in the blood plasma, while in other cases no change in the pharmacokinetics of nifedipine has been observed. When prescribing quinidine as an additional therapy for nifedipine therapy, it is necessary to control blood pressure and, if necessary, reduce the dose of nifedipine.

Tacrolimus

Tacrolimus is metabolized by isoenzyme CYP3A4. In some cases, when combined with nifedipine, a dose reduction of tacrolimus may be required. Therefore, in case of joint application, it is necessary to monitor the concentration of tacrolimus in the blood plasma and, if necessary, to reduce its dose.

No interactions detected

Interactions with the simultaneous use of nifedipine with aymalin, benazepril, candesartan, debrisoquin, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone, talinolol, triamterene + hydrochlorothiazide was not detected.

Acetylsalicylic acid

The combined use of nifedipine and acetylsalicylic acid at a dose of 100 mg does not affect the pharmacokinetics of nifedipine; nifedipine, in turn, does not change the antiaggregant properties of acetylsalicylic acid (platelet aggregation and bleeding time).

Other types of interaction

The drug Adalat® contains 18 volume% of ethyl alcohol, which must be taken into account when combined with drugs that are incompatible with ethanol (see section "Special instructions").

Adalat® is compatible with the following solutions:

- 0.9% solution of sodium chloride

- 5% dextrose (glucose) solution

- 5% fructose solution

The infusion rate for Adalat® is 10 ml / h and not more than 40 ml / h for co-administered solutions.

Combination with other infusion solutions is not recommended.

Effect on laboratory parameters

Nifedipine can cause a false increase in the concentration of vanillylmandelic acid in urine when determined spectrophotometrically, but does not affect the measurement results when using the high performance liquid chromatography (HPLC) method.

Special instructions:

The simultaneous use of Adalat® and beta-blockers is not recommended because of the risk of a marked decrease in blood pressure, and in some cases, worsening of symptoms of heart failure. If simultaneous use of nifedipine with beta-blockers is necessary, careful monitoring of the patient is necessary.

Preparation Adalat^® Do not use in patients who are supposed to have an association of ischemic pain with previous nifedipine therapy.

As with the use of other vasodilators, anginal episodes (data obtained from spontaneous reports of nifedipine preparations in capsule dosage form) with the immediate release of nifedipine are very rare when using Adalat®, especially at the very beginning of treatment.The data obtained during the clinical studies of nifedipine in the dosage form of the capsule confirm the incidence of angina attacks as "infrequent".

In patients with angina pectoris, lengthening and weighting of angina attacks is possible, especially at the beginning of treatment.

In some cases, the development of myocardial infarction has been documented, but it is not possible to establish a cause-and-effect relationship of the disease with nifedipine, since myocardial infarction can arise as a result of the natural course of ischemic heart disease.

Patients with mild, moderate or severe impairment of liver function may need careful monitoring and a reduction in the dose of the drug. The pharmacokinetics of nifedipine has not been studied in patients with severe hepatic impairment (see the section "Pharmacological properties / Pharmacokinetics").

Nifedipine is metabolized by isoenzyme CYP3A4. Thus, drugs - inhibitors or inducers of isoenzyme CYP3A4 can affect the metabolism of the "first passage" of nifedipine through the liver or its clearance when combined (cm.section "Interaction with other medicinal products").

In the case of combined use of nifedipine and drugs - inhibitors of isoenzyme CYP3A4, listed below, it is possible to increase the concentration of nifedipine in the blood plasma, and therefore careful monitoring of arterial pressure and, if necessary, a reduction in the dose of nifedipine: antibiotics of the macrolide group (for example, erythromycin), HIV protease inhibitors (for example, ritonavir), antifungal agents of the azole group (for example, ketoconazole), antidepressants (nefazodone and fluoxetine), quinupristine / dalphopristin, valproic acid, cimetidine.

The preparation Adalat® contains 18 volumetric % ethanol, which corresponds to 45 g of ethanol per day of the drug (300 ml). This need to be taken into account when used in patients with alcoholism or having metabolic disorders of ethanol, as well as in pregnant and lactating women, children, as well as in patients at high risk (with liver disease or epilepsy).

Ethanol contained in the preparation Adalat ®, can affect the effects of other drugs,applied simultaneously with the preparation Adalat® (see the section "Interaction with other medicinal products").

The bottle provided with a plastic light-shielding coating provides sufficient protection of the Adalat® preparation against daylight for 1 hour and for 6 hours under artificial illumination.

Effect on the ability to drive transp. cf. and fur:

Ethanol, contained in the preparation Adalat®, can disrupt the ability to drive vehicles and work with the required mechanisms of attention.

Form release / dosage:Solution for infusions, 0.1 mg / ml

Packaging:

For 50 ml in bottles of brown glass, sealed with a plug of chlorobutyl rubber and equipped with a special light-protective plastic sheath; 1 bottle is placed in an individual cardboard pack; Individual cardboard pack with infusion solution together with a special disposable syringe, connecting tube for infusion and with instructions for use are placed in a common cardboard box.

Storage conditions:

Store at a temperature of no higher than 25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013727 / 01

Date of registration:14.03.2008 / 14.10.2014

Expiration Date:Unlimited

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp