Адалат®

General characteristics. Structure:

One bottle contains 5 mg of nifedipine (active agent) in 50 ml of infusion solution. Excipients: ethanol of 96% 7,500 g, a macrogoal 400 7,500, sodium hydroxide 0,1 N to pH 4,5-7,5, water for injections of 34,995 g.
Description: transparent, yellowish color solution.

Pharmacological properties:

Pharmacodynamics. Nifedipine - the selection blocker of "slow" calcium channels, derivative 1,4 dihydropyridines. Has anti-anginal and hypotensive effect. Reduces current of calcium ions through "slow calcium channels" in cells, preferential in cardiomyocytes, smooth muscle cells of coronary and peripheral arteries, lowering at the same time peripheric vascular resistance and expanding coronary arteries, especially large krovosnabzhayushchy vessels, and even intact segments of walls of partially stenosed vessels. Besides, nifedipine lowers a tone of smooth muscles of coronary arteries, thereby, the vasomotor spasm is prevented, the blood stream in post-stenotic departments of vessels amplifies and delivery of oxygen to a myocardium increases, the need of a myocardium for oxygen due to decrease in the peripheric vascular resistance (afterload) decreases, and at long reception it is capable to prevent development of new atherosclerotic damages to coronary arteries.
Nifedipine reduces a tone of smooth muscles of arterioles, thereby, reducing the increased peripheric vascular resistance and, therefore, the arterial pressure (AP). In an initiation of treatment temporary reflex increase in heart rate and, as a result of it, the size of cordial emission can happen nifedipine. However, this increase is not so considerable to compensate expansion of blood vessels. Besides, nifedipine at short-term and at prolonged use, increases removal of sodium and water from an organism. Hypotensive effect of nifedipine is especially expressed at the patients having arterial hypertension.

Pharmacokinetics.

Distribution. After intravenous administration nifedipine is quickly distributed in an organism; 50% of the entered dose are distributed in an organism in 5-6 min. Contacts proteins of a blood plasma (albumine) for 95%.

Metabolism
After parenteral administration nifedipine is almost completely metabolized in a liver to inactive metabolites.

Removal
It is brought out of an organism preferential by kidneys in the form of inactive metabolites, to a lesser extent (5-15%) with bile. In urine only traces (less than 1%) of not changed active agent are found.
The elimination half-life (T1/2) of nifedipine after parenteral administration makes 1,7 h. At patients with a renal failure    the nifedipine pharmacokinetics  significantly does not change.
At a liver failure considerable lengthening of T1/2 of drug and decrease in its general clearance is noted that can demand a dose decline. Gets through a placental barrier, it is allocated with breast milk. The hemodialysis and peritoneal dialysis do not influence nifedipine pharmacokinetics, the plasma exchange strengthens its elimination.

Indications to use:

• Printsmetal's stenocardia
• Hypertensive crisis

Route of administration and doses:

50 ml of solution of the drug Adalat® enter intravenously infusionally within, about, 4-8 hours (with a speed of 6,3-12,5 ml/h that corresponds to 0,63-1,25 mg/h).
The maximum dose of the drug administered within 24 hours should not exceed 150-300 ml
(that corresponds
15-30 mg / 24 h).
With a renal failure it is not required from patients.
Infusional therapy can continuously be carried out within 3 days. Then transition to therapy by nifedipine inside is recommended.

Special groups of patients
Children and teenagers
Safety and efficiency of use of the drug Adalat® for children and teenagers up to 18 years is not established.
Patients of advanced age
At patients of advanced age because of disturbances of pharmacokinetics reduction of a maintenance dose can be required (in comparison with younger patients). Patients with abnormal liver functions
At patients with abnormal liver functions drug is used with care under control of function of a liver, at heavy abnormal liver functions it is necessary to reduce
dose.
Patients with renal failures
With renal failures of dose adjustment it is not required from patients.
The instruction for administration of solution for infusions of Adalat®:
Adalat® infusion solution, ready to use, should be entered only via the special syringe and the carrying-out system of the brand Perfuzor® or Инжектомат® attached to solution. On condition of use of the ordered infusional accessories of losses of nifedipine through the carrying-out system it is possible not to be afraid.
 
Nifedipine, active agent of Adalat® infusion solution, is extremely sensitive to light influence therefore it is necessary to provide protection of solution against this influence. The bottle supplied with a protective plastic cover should be taken out from packaging only just before use.
When performing the mixed infusion it is also necessary to provide protection of Adalat® solution against light influence therefore it needs to be entered directly into an infusional tube on which other solution already arrives, at the same time introduction to system should be carried out as it is possible closer to the place of a puncture of a vein. It is strictly forbidden to mix Adalat® solution rolled into one with other solutions.
If solution was stored in the refrigerator, then before introduction its temperature needs to be brought to room.

Features of use:

The dose of the drug Adalat® needs to be selected individually taking into account disease severity and reaction of the patient to the carried-out treatment, and also to strictly control the arterial pressure and heart rate.
Simultaneous use of the drug Adalat® and beta adrenoblockers because of risk of development of the expressed lowering of arterial pressure, and in certain cases - aggravation of a course of chronic heart failure is not recommended. In need of simultaneous use of nifedipine with beta adrenoblockers observation of the patient is necessary.
The drug Adalat® should not be used at patients at whom the interrelation of pains of ischemic character with the previous therapy is supposed nifedipine.
As well as at use of other vazodilatator, at drug Adalat® use very seldom there can be stenocardia attacks, and also deterioration the course of stenocardia with weighting, lengthening and increase of attacks of stenocardia, especially in the initiation of treatment. Development of a myocardial infarction is in some cases registered, however at the same time it is not possible to establish disease relationship of cause and effect using nifedipine as the myocardial infarction can result from the natural course of coronary heart disease.
Patients with an abnormal liver function at administration of the drug Adalat® demand careful observation; in hard cases reduction of a dose of the drug Adalat® is necessary.

Nifedipine is metabolized by means of CYP3A4 isoenzyme. Thus, medicines - inhibitors or inductors of an isoenzyme CYP3A4 can influence metabolism of "the first passing" of nifedipine through a liver and its clearance at combined use (see the section "Interaction with Other Medicines").
In case of combined use of nifedipine and medicines - weak or moderate inhibitors of an isoenzyme CYP3A4 which are listed below increase in concentration of nifedipine in a blood plasma in this connection, careful observation of arterial pressure and if necessary a nifedipine dose decline is necessary is possible:
antibiotics of group of macroleads (for example, erythromycin), HIV protease inhibitors (for example, ритонавир), antifungal drugs from group of azoles (for example, кетоконазол), antidepressants (нефазодон and fluoxetine), hinupristin/dalfopristin, valproic acid, Cimetidinum.
The drug Adalat® contains 18 volume % of alcohol that corresponds to 45 g of ethanol at the rate on a day dose of drug. It needs to be taken into account at use for patients with alcoholism or having ethanol metabolism disturbances, and also at use for pregnant women and the feeding women, for children, also at patients from group of high risk (having diseases of a liver or epilepsy).
The ethanol which is contained in composition of the drug Adalat® can influence effect of other medicines applied along with   the drug Adalat® (see the section "Interaction with Other Medicines"). The ethanol which is contained in composition of the drug Adalat® can break ability to driving of motor transport and to work with the mechanisms requiring special attention.

Extracorporal fertilization
In isolated cases when carrying out extracorporal fertilization at use of blockers of "slow" calcium channels of a dihydropyridinic row reversible biochemical changes in a head of spermatozoa were noted that led to sperm dysfunction. In unsuccessful attempts of extracorporal fertilization and at an exception of other reasons of infertility, it is necessary to take into account probability of influence of blockers of "slow" calcium channels of a dihydropyridinic row on sperm on condition of their reception.
Nifedipine causes false positive increase in concentration of vanilil-mandelic acid in urine when determining by a spectrophotometric method and does not influence result of this reaction when using a method of highly effective liquid chromatography (VEZhH).
The drug Adalat® in the bottle supplied with a plastic light-protective cover remains stable at daylight within 1 hour, and at artificial lighting - within 6 hours.

Side effects:

At nifedipine use side effects were estimated at placebo - controlled researches.
Below the listed side effects classified as follows: "often" (> 1/100, <1/10), "infrequently" (> 1/1000, <1/100), is "rare" (> 1/10000, <1/1000). Degree of gradation of side reactions was "often" estimated as less than 3%, except for hypostasis (9.9%) and a headache (3.9%). Side effects which were noted only during post-marketing observations and which frequency was not estimated are designated "in some cases".
From cardiovascular system: often - peripheral hypostases, vazodilatation symptoms (erubescence of the person, feeling of heat), infrequently - tachycardia, tachycardia, a lowering of arterial pressure, a faint; in some cases - pain behind a breast (stenocardia).
From the central nervous system: often - a headache, infrequently - dizziness, migraine, a tremor, вертиго, uneasiness, sleep disorders, is rare - paresthesias, dizesteziya; in some cases - hypesthesias, drowsiness.
From the alimentary system: often - a lock, infrequently - gastrointestinal and abdominal pain (pain in a stomach and intestines), nausea, dyspepsia, a meteorism, dryness of a mucous membrane of an oral cavity, passing increase in activity of "hepatic" transaminases, it is rare - a hyperplasia of gums, in some cases - vomiting, a cardiochalasia, jaundice.
From respiratory system: infrequently - nasal bleeding, a nose congestion; in some cases - an asthma.
From a musculoskeletal system: infrequently - muscular spasms, puffiness of joints; in some cases - an arthralgia, a mialgiya.
From an urinary system: infrequently - a polyuria, a dysuria.
From immune system: infrequently - allergic reactions in the form of an allergic/Quincke's disease (including potentially life-threatening hypostasis of a throat); seldom - a skin itch, rash, a small tortoiseshell; in some cases-анафилактические / anaphylactoid reactions.
From integuments and a hypodermic fatty tissue: infrequently - an erythema; in some cases - a toxic epidermal necrolysis, a photosensitization, allergic reactions, a purpura.

From an organ of sight: infrequently - disturbance of clearness of sight; in some cases - eye pain.
From reproductive system: infrequently - erectile dysfunction.
From the hemopoietic system: in some cases - an agranulocytosis, a leukopenia.
Metabolic disturbances: in some cases - a hyperglycemia.
Disturbances of the general state: often - feeling sick, infrequently - a nonspecific pain syndrome, a fever.
Local _reaktion: infrequently - reactions in an injection site (including thrombophlebitis).

At patients with malignant arterial hypertension and a hypovolemia and the ABP who are on dialysis falling it can be caused by a vazodilatation.

Interaction with other medicines:

The medicines influencing nifedipine metabolism
Nifedipine is metabolized by means of an isoenzyme of CYP3A4 localized in a liver and a mucous membrane of intestines. Therefore, the medicines inhibiting or inducing this fermental system can affect effect of "the first passing" through a nifedipine liver (at its intake) and clearance (see the section "Special Instructions"). Nifedipine - medicine with high clearance. As the hepatic clearance is defined mainly by the volume of a hepatic blood-groove, the listed below possible interactions able to affect pharmacokinetic indicators of nifedipine at combined use inside, it is impossible to compare to interactions at use of nifedipine in the form of solution for infusions.

Rifampicin
Rifampicin - the powerful inductor of an isoenzyme CYP3A4. At combined use with rifampicin bioavailability of nifedipine considerably decreases and respectively its efficiency decreases. Use of nifedipine together with rifampicin is contraindicated (see the section "Contraindications").

The concomitant use of nifedipine with weak and moderate inhibitors of an isoenzyme CYP3A4 demands regular control of arterial pressure and in need of a nifedipine dose decline. Treat such drugs: Antibiotics of group of macroleads (for example, erythromycin)
Clinical trials of interaction of nifedipine with macroleads were not conducted. It is known that some macroleads are CYP3A4 isoenzyme inhibitors. Thereof it is impossible to exclude a possibility of increase in concentration of nifedipine in a blood plasma at combined use of these drugs (see the section "Special Instructions").
The azithromycin relating to group of macroleads is not CYP3A4 isoenzyme inhibitor. HIV protease inhibitors (for example, ритонавир)
Clinical trials of interaction of nifedipine with inhibitors of HIV protease were not conducted. It is known that drugs of this group are CYP3A4 isoenzyme inhibitors. These drugs inhibit the metabolism of in vitro nifedipine caused by an isoenzyme CYP3A4. In case of combined use with nifedipine perhaps essential increase in concentration of nifedipine in a blood plasma owing to the slowed-down metabolism at "the first passing" through a liver and the slowed-down removal (see the section "Special Instructions").

Antifungal drugs from group of azoles (for example, кетоконазол)
Clinical trials of interaction of nifedipine with drugs of this group were not conducted. It is known that drugs of this group are CYP3A4 isoenzyme inhibitors. In case of combined use with nifedipine it is impossible to exclude noticeable increase in concentration of nifedipine in a blood plasma owing to the slowed-down metabolism at "the first passing" through a liver (see the section "Special Instructions").

Fluoxetine
Clinical trials of interaction of nifedipine with fluoxetine were not conducted. It is known that fluoxetine is CYP3A4 isoenzyme inhibitor. Fluoxetine inhibits the metabolism of in vitro nifedipine caused by an isoenzyme CYP3A4. In case of combined use with nifedipine perhaps essential increase in concentration of nifedipine in a blood plasma (see the section "Special Instructions").

Nefazodon
Clinical trials of interaction of nifedipine with nefazodony were not conducted. It is known what нефазодон is CYP3A4 isoenzyme inhibitor. In case of combined use with nifedipine perhaps essential increase in concentration of nifedipine in a blood plasma (see the section "Special Instructions").

Hinupristin/далфопристин
Owing to CYP3A4 isoenzyme inhibition combined use with nifedipine can lead to increase in concentration of nifedipine in a blood plasma (see the section "Special Instructions").

Valproic acid
Clinical trials of interaction of nifedipine with valproic acid were not conducted. As it was shown that valproic acid increases concentration in a blood plasma of a blocker of "slow" calcium channels of a nimodipin, structurally similar to nifedipine, at the expense of inhibition of microsomal enzymes of a liver, it is impossible to exclude probability of increase in concentration of nifedipine in a blood plasma (see the section "Special Instructions").

Cimetidinum
Owing to CYP3A4 isoenzyme inhibition combined use with nifedipine can lead to increase in concentration of nifedipine in a blood plasma (see the section "Special Instructions").

Other researches:
Tsizaprid
Combined use of a tsizaprid and nifedipine can result in the increased concentration of nifedipine in a blood plasma that demands regular control of arterial pressure and in need of reduction of a dose of nifedipine.
Antiepileptic means - CYP3A4 isoenzyme inductors (Phenytoinum, carbamazepine, phenobarbital)
Phenytoinum
Phenytoinum induces an isoenzyme of CYP3A4 and reduces bioavailability of nifedipine and, as a result of it, reduces its efficiency that demands clinical observation and, in case of need, increase in its dose. If the dose of nifedipine was increased during joint reception, after the termination of reception of Phenytoinum the dose of nifedipine should be lowered to initial.

Carbamazepine, phenobarbital
Clinical trials of interaction of nifedipine with carbamazepine and phenobarbital were not carried out. As it was shown that both drugs reduce concentration in a blood plasma of a blocker of "slow" calcium channels of a nimodipin, structurally similar to nifedipine, due to induction of microsomal enzymes of a liver, it is impossible to exclude probability of decrease in concentration of nifedipine in a blood plasma and, therefore, decrease in its efficiency.

Influence of nifedipine on other medicines:

Antihypertensives
Nifedipine can strengthen anti-hypertensive effect at combined use with others
antihypertensives, such, as: diuretics, beta adrenoblockers, inhibitors
angiotenziprevrashchayushchy  enzyme (APF), antagonists of receptors
angiotensin II, other blockers of "slow" calcium channels, alpha adrenoblockers, inhibitors of phosphodiesterase 5 (FDE5), Methyldopum.

At simultaneous use of nifedipine with beta adrenoblockers observation of patients as aggravation of a course of chronic heart failure is in some cases possible is necessary. Digoxin
Nifedipine reduces clearance of digoxin that leads to increase in concentration of digoxin in a blood plasma. Therefore for patients it is necessary to establish careful clinical and an ECG - observation for early identification of overdose by digoxin; if necessary the dose of digoxin has to be lowered taking into account its concentration in a blood plasma. Quinidine
In some cases combined use of nifedipine and quinidine decrease in concentration of quinidine in a blood plasma, and also noticeable increase in concentration of quinidine in a blood plasma after quinidine cancellation was observed. Therefore in case of combined use of nifedipine as additional tool, or refusal of nifedipine it is necessary to control concentration of quinidine in a blood plasma and in case of need quinidine dose adjustment is required. In certain cases at combined use of nifedipine and quinidine concentration of nifedipine in a blood plasma can increase. Therefore control of arterial pressure and in case of need a nifedipine dose decline is necessary.

Takrolimus
Takrolimus is metabolized by CYP3A4 isoenzyme. Increase in concentration of a takrolimus in a blood plasma at combined use with nifedipine is in some cases possible. Therefore in case of combined use it is necessary to control concentration of a takrolimus in a blood plasma and in case of need to reduce a dose of a takrolimus.
The following medicines do not exert impact on nifedipine pharmacokinetics:

Ajmalinum, benazeprit, debrisoquine, доксазозин, ирбесартан, омепразол, орлистат, пантопразол, ranitidine, росиглитазон, Talinololum, a Triamterenum/hydrochlorothiazide, acetylsalicylic acid and кандесартан.

Acetylsalicylic acid
Combined use of nifedipine and acetylsalicylic acid in a dose of 100 mg does not exert impact on nifedipine pharmacokinetics; nifedipine, in turn, does not change antiagregantny properties of acetylsalicylic acid in a dose of 100 mg (aggregation of thrombocytes and a bleeding time).

Kandesartan
Combined use of nifedipine and kandesartan does not exert impact on pharmacokinetics of both drugs.

The drug Adalat® contains 18 volume % of alcohol that needs to be considered at a combination to drugs incompatible with ethanol (see the section "Special Instructions").

The drug Adalat® is compatible to the following solutions:
• 0,9% chloride sodium solution
• 5% solution of a dextrose (glucose)
• 5% fructose solution

Infusion speed for the drug Adalat® makes 10 ml/h, and in combination with
compatible solutions - 40 ml/h.
The combination to other infusion solutions is not recommended.

Contraindications:

• Hypersensitivity to nifedipine or any other component of drug.
• Pregnancy (up to 20 weeks) and the breastfeeding period (see the section "Use at Pregnancy and during Breastfeeding")
• Cardiogenic shock
• Unstable stenocardia
• An acute myocardial infarction (in the first 4 weeks after the postponed myocardial infarction)
• Simultaneous use with rifampicin (see the section "Interaction with Other Medicines")
• Age up to 18 years (safety and efficiency are not established).

With care
Acute heart failure, chronic heart failure of the III-IV functional class on NYHA classification, the expressed aortal stenosis, the expressed bradycardia (ChSS less than 50 уд. / mines), a liver failure, the expressed arterial hypotension (systolic the ABP less than 90 mm рт.ст), at the patients with malignant arterial hypertension and a hypovolemia who are on a hemodialysis, pregnancy (after 20 weeks).

Use at pregnancy and during breastfeeding
Use of the drug Adalat® is contraindicated at pregnancy up to 20 weeks. Controlled clinical trials of use of the drug Adalat® for pregnant women were not conducted;   respectively data of controlled clinical trials on safety and efficiency of use of the drug Adalat® for pregnant women are absent.
Tests for animals showed existence of embriotoxity, a platsentotoksichnost, fetotoksichnost and teratogenecity at reception of nifedipine during and upon termination of the organogenesis period.
According to the available clinical data it is impossible to judge specific prenatal risk. At the same time there are probabilities of perinatal asphyxia, Cesarean section, premature births given about increase and a delay of pre-natal fetation. Not clearly, whether the listed cases are a consequence of a basic disease (arterial hypertension), the carried-out treatment or specific effect of the drug Adalat®. The available information is insufficient to exclude probability of emergence of the side effects constituting danger to a fruit and the newborn. Therefore use of the drug Adalat® after the 20th week of pregnancy demands careful individual assessment of a ratio of risk and advantage for the patient, a fruit and/or the newborn and can be considered only when other ways of therapy are contraindicated or inefficient.
It is necessary to carry out careful control of arterial pressure at pregnant women at use of the drug Adalat® along with intravenous administration of magnesium of sulfate owing to a possibility of an excessive lowering of arterial pressure that constitutes danger both to mother, and to a fruit and/or the newborn.
Nifedipine is emitted in breast milk therefore if use of the drug Adalat® is necessary in the period of a lactation, breastfeeding should be stopped.

Overdose:

Symptoms: a loss of consciousness up to a coma, decrease in the ABP, tachycardia/bradycardia, a hyperglycemia, a metabolic acidosis, a hypoxia, the cardiogenic shock which is followed by a fluid lungs.
Treatment. Actions for rendering acute management at overdose first of all have to be directed to removal of nifedipine from an organism and recovery of a stable hemodynamics.
At bradycardia - R-sympathomimetics, at zhizneugrozhayushchy bradycardia - implantation of a temporary artificial pacemaker.
At the expressed decrease in the ABP slow intravenous administration of 10-20 ml of 10% of solution of calcium of a gluconate (repeated introduction is admissible), at which inefficiency - purpose of vasoconstrictive sympathomimetics (a dopamine or Norepinephrinum) is recommended. Doses of these drugs select depending on the gained therapeutic effect. Administration of liquid should be limited in connection with risk of an overload of heart. Carrying out a hemodialysis is inexpedient as nifedipine is not removed at dialysis; carrying out a plasma exchange is recommended.

Storage conditions:

Period of validity 2 years. Not to use after the expiry date specified on packaging. List B. At a temperature not above 25 °C, in protected from light and the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for infusions on 50 ml 0,1 mg/ml in the bottles of brown glass corked by a stopper from chlorbutyl rubber and the supplied special light-protective plastic cover; on 1 bottle place in an individual cardboard pack; the individual cardboard pack with solution for infusions together with the special one-time syringe, a connecting tube for infusions and with the application instruction is placed in the general cardboard box.