Изоптин®

General characteristics. Structure:

Active agent: verapamil a hydrochloride — 5,0 mg;

Excipients: sodium chloride — 17,0 mg, 36% Acidum hydrochloricum — before finishing pH, water for injections — to 2 ml.

Description: transparent colourless solution.

Pharmacological properties:

Pharmacodynamics. Verapamil blocks transmembrane receipt of calcium ions (and perhaps sodium ions) in cells of the carrying-out system of a myocardium smooth muscle cells of a myocardium and vessels. Antiarrhytmic effect of verapamil is possibly connected with its impact on "slow" channels in cells of the carrying-out system of heart.

Electric activity of sinuatrial (SA) and atrioventricular (AV) of nodes substantially depends on receipt in calcium cells on "slow" channels.

Inhibiting this intake of calcium, verapamil slows down atrioventricular carrying out and increases the effective refractory period in AV a node in proportion to the heart rate (HR). This effect leads to decrease in frequency of reductions of ventricles at patients with a ciliary arrhythmia and/or an atrial flutter. Stopping a repeated entrance of excitement to AV a node, verapamil can recover the correct sinoatrial rate at patients with Bouveret's supraventricular disease, including a WPW-syndrome (WPW).

Verapamil does not exert impact on carrying out on дополнительньм to conduction paths, does not influence not changed action potential of auricles and time of intra ventricular carrying out, but reduces amplitude, speed of depolarization of carrying out in the changed fibers of auricles.

Verapamil does not cause a spasm of peripheral arteries and does not change the general content of calcium in a blood plasma. Reduces an afterload and contractility of a myocardium. At most of patients, including patients with organic lesions of heart, negative inotropic effect of verapamil is leveled by decrease in an afterload, cardiac index usually does not change, but at patients with moderate and heavy heart failure (jamming pressure in a pulmonary artery more than 20 mm of mercury., the fraction of emission less than 30%), can be observed acute compensation of chronic heart failure. The maximum of therapeutic action is noted in 3-5 minutes after bolyusny intravenous administration of verapamil.

Standard therapeutic doses of verapamil of 5-10 mg at intravenous administration cause passing usually asymptomatic decrease in the normal arterial pressure (AP), system vascular resistance and contractility, pressure of filling of a left ventricle slightly increases.

Pharmacokinetics. Verapamil at intravenous administration is quickly metabolized. The concentration curve in blood has bieksponentsialny character with a bystry early phase of distribution (an elimination half-life about 4 minutes) which is followed by slower terminal phase of removal (an elimination half-life of 2-5 hours).

Communication with proteins of a blood plasma makes about 90%. Drug is exposed to intensive metabolism with formation of a large number of metabolites (at administration of drug it is inside identified 12, the majority of which are found only in trace concentration). Among metabolites only norverapamit possesses pharmacological action.

Within five days of 70% of a dose of drug only 3-4% — in not changed look are removed by kidneys, 16%-through intestines. It is not removed at a hemodialysis. Verapamil gets through hematoencephalic and placental barriers, is excreted with breast milk.

Renal failure

Recently received results of comparative researches demonstrate that there are no distinctions of pharmacokinetics of verapamil at patients with normal function of kidneys and at patients in an end-stage of a renal failure.

Abnormal liver function

At patients with an abnormal liver function the elimination half-life is extended because of lower peroral clearance of drug and bigger volume of distribution.

Indications to use:

For treatment of supraventricular tachyarrhythmias, including:
Recovery of a sinoatrial rate at Bouveret's supraventricular disease, including the states connected with existence of additional conduction paths at a WPW-syndrome (WPW) and Launa-Ganonga-Levina (LGL).

In the presence of clinical indications it is reasonable to try to carry out before use of the drug Izoptin® impact on a vagus nerve (for example, Valsalva's maneuver).
Temporary control of frequency of reductions of ventricles during the trembling and atrial fibrillation (takhiaritmichesky option) except for cases when trembling or atrial fibrillation is connected with existence of additional conduction paths (syndromes of WPW and LGL).

Route of administration and doses:

Only intravenously.

Intravenous administration should be carried out slowly for, at least, 2 minutes at continuous control of the ECG (electrocardiogram) and arterial pressure. At patients of advanced age introduction is carried out for, at least, 3 minutes for reduction of risk of undesirable effects.

The initial dose makes 5-10 mg (0, 075-

0, 15 mg/kg of body weight).

The repeated dose of 10 mg (0, 15 mg/kg of body weight) is entered in 30 minutes after the first introduction at the inadequate response to the first introduction.

Stability

The drug Izoptin® is compatible to the most eurysynusic solutions for parenteral administration of large volume and is chemically stable in them, at least, within 24 hours at 25 °C in the place protected from light.

Before use the dosage form for parenteral administration should be estimated visually on existence of a deposit and discoloration. Not to use if solution muddy or there are damages of a seal of a bottle.

The solution which remained unused has to be destroyed immediately after a fence of a portion of contents of any volume.

Incompatibility

In order to avoid disturbance of stability it is not recommended to part Izoptin® with lactate sodium solutions for injections in packages from polyvinylchloride. It is necessary to avoid mixing with solutions of albumine, Amphotericinum In, a gidralazina of a hydrochloride or a trimetoprinem and sulfamethoxazole.

Verapamil pretsipitirut in any solutions with рН more than 6,0.

Features of use:

Development of life-threatening side effects is seldom possible (a blinking/atrial flutter with high frequency of reduction of ventricles, with existence of additional conduction paths, heavy arterial hypotension or the expressed bradycardia/asystolia).

Arterial hypotension

Intravenous administration of the drug Izoptin® often causes decrease in the ABP below reference values, usually short-term and proceeding asymptomatically, however can be followed by dizziness.

The expressed bradycardia/asystolia

Verapamil can cause development of AV of blockade of II or III degrees, bradycardia and, in extreme cases, an asystolia owing to influence on AV and SA (sinuatrial) nodes that is the most probable at patients with a sick sinus syndrome and at advanced age. The asystolia at the patients who do not have weakness of a sinus node is usually short-term (several seconds) with spontaneous recovery of an atrio-ventricular or sinoatrial rate. If the sinoatrial rate timely is not recovered, it is necessary to appoint the corresponding treatment immediately.

Disturbance of cordial conductivity (blockade)

Verapamil slows down AV conductivity. During the controlled clinical trials conducted in the USA, cases of AV of blockade of high degree at use of verapamil were not observed, however in the international literature it is known of cases of emergence of such reactions with a low frequency (less than in

0,5% of cases, according to literature). Development of AV of blockade of II or III degrees or blockade of legs of a ventriculonector demands a dose decline or cancellation of verapamil and performing the corresponding antiarrhytmic therapy if necessary.

Chronic heart failure

Chronic heart failure (except heavy or caused by arrhythmia) should be compensated by cardiac glycosides and diuretics prior to therapy by the drug Izoptin®. At patients with HSN III-IV of a functional class on NYHA classification (jamming pressure in a pulmonary artery more than 20 mm of mercury., the fraction of emission of a left ventricle less than 30%) at purpose of the drug Izoptin® can be observed an acute decompensation of chronic heart failure.

Renal failure

The conducted comparative researches show that the pharmacokinetics of verapamil remains invariable at patients with an end-stage of a renal failure. However some available messages give the grounds to assume that the drug Izoptin® at patients with renal failures should be used with care and under careful control.

Ventricular tachycardia

Intravenous administration of the drug Izoptin® to patients with ventricular tachycardia with the wide QRS complexes (≥ 0,12 sec.) can lead to the expressed deterioration in a hemodynamics and fibrillation of ventricles. Before an initiation of treatment carrying out appropriate diagnosis and an exception of ventricular tachycardia with the wide QRS complexes is obligatory.

Influence on ability to manage transport and work with mechanisms

Can exert impact on speed of reaction. During treatment it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The possible side effects revealed during clinical trials of the drug Izoptin® are given below on systems of an organism and frequency of their emergence: often (≥1/100, <1/10), infrequently (≥1/1000, <1/100).

From the central nervous system:

Often: dizziness, headache.

From cardiovascular system:

Often: bradycardia, the expressed lowering of arterial pressure

Infrequently: tachycardia

From the alimentary system: Infrequently: nausea, feeling of discomfort in an abdominal cavity.

It was reported about several cases of development of spasms during administration of drug

Изоптин®.

In rare instances there were hypersensitivity reactions, the bronchospasm which is followed by a skin itch and a small tortoiseshell.

Other side effects which met at drug Izoptin® use solution for intravenous administration or in other dosage forms are given below.

From the central nervous system: drowsiness, extrapyramidal frustration.

From sense bodys: вертиго.

From integuments and hypodermic cellulose: Stephens-Johnson's syndrome, a mnogoformny exudative erythema, the increased sweating.

During post-registration use of the drug Izoptin® it was reported about an isolated case of development of paralysis (tetraparesis) connected with combined use of verapamil and colchicine (see the section "Interaction with Other Medicines").

Interaction with other medicines:

It is established that verapamil is inhibitor of SYRZA4 enzyme, P450 cytochrome and the R-glycoprotein. The list of possible interaction of medicines where Cmax — the maximum concentration, is presented to Css in the table — average equilibrium concentration, AUC — the area under a curve "concentration time".

Drug                                                       Possible medicinal interaction
 
 Alpha adrenoblockers
 
Prazoz                                                      Uvelicheniye Prazozinum Cmax (~ 40%),

                                                                  does not influence Prazozinum elimination half-life

Prazozinum
Terazozin                                                  Increase in AUC of a terazozin (~ 24%) and Cmax (~ 25%)
 
Antiarrhytmic means
Flekainid                                          the Minimum action on clearance of a flekainid in plasma 
                                                           blood (<~ 10%); does not influence clearance of verapamil in a blood plasma.
Quinidine                                                 Reduction of peroral clearance of quinidine (~ 35%)
Means for treatment of bronchial asthma
Theophylline                                             Reduction of peroral and system clearance  
                                                          theophylline (~ 20%). The smoking patients have a reduction on ~ 11%
Anticonvulsants
Carbamazepine                                          Increase in AUC of carbamazepine (~ 46%) at patients with steady partial epilepsy
Antidepressants
Imipraminum                                          Increase in AUC of Imipraminum (~ 15%).

                                                          Does not influence the level of an active metabolite, desipramine
Hypoglycemic means
Glibenclamidum                                      Increases Glibenclamidum Cmax (~ 28%), AUC (~ 26%)
 
Antimicrobic means
Klaritromitsin                                    Vozmozhno increase in concentration of verapamil in a blood plasma
Erythromycin                                        increase in concentration of verapamil in a blood plasma is possible
Rifampicin                                         Reduction of AUC of verapamil (~ 97%), 
                                                            Cmax (~ 94%), bioavailability ~ 92%
Telitromitsin                                       Vozmozhno increase in concentration of verapamil in a blood plasma.
 
Antineoplastic means
Doxorubicine                                      Increase in AUC of doxorubicine (89%) and Cmax 
                                                          (61%) at verapamil reception inside at patients with small-celled

                                                            lung cancer. Administration of verapamil intravenously at 
                                                           patients with the progressing new growths

                                                            does not influence pharmacokinetic parameters of doxorubicine
Barbiturates
Phenobarbital                                       Increase in peroral clearance of verapamil ~ by 5 times
Benzodiazepines and other tranquilizers
Buspiron                                              Increase in AUC of a buspiron, Cmax ~ in 3, 4 times
Midazolam                                            Increase in AUC of midazolam (~ by 3 times) and Cmax (~ twice)
Beta adrenoblockers
Metoprolol                                           Increase in AUC of a metoprolol (~ 32, 5%) and Cmax (~ 41%) 
                                                             at patients with stenocardia
Propranolol                                        Increase in AUC of propranolol (~ 65%) and Cmax (~ 94%)
                                                             at patients with stenocardia

Cardiac glycosides
Digitoxin                                            Reduction of the general clearance (~ 27%) and extrarenal

                                                             clearance (~ 29%) digitoxin
Digoxin                                                At healthy volunteers Cmax increase

                                                           digoxin on ~ 45-53%, digoxin Css on ~ 42%
                                                            and digoxin AUC on ~ 52%

Immunological means
Cyclosporine                                        Increase in AUC, Css, cyclosporine Cmax on ~ 45%
Everolimus                                          Vozmozhno increase in level of an everolimus in a blood plasma
Sirolimus                                            Vozmozhno increase in level of a sirolimus in a blood plasma
Takrolimus                                           Vozmozhno increase in level of a takrolimus in a blood plasma.
Hypolipidemic means (GMG-KOA-reduktazy inhibitors)
Atorvastatin                                        Vozmozhno increase in level of an atorvastatin in a blood plasma.

                                                            Increase in AUC of verapamil on ~ 42, 8%

Lovastatin                                            Vozmozhno increase in level of a lovastatin in a blood plasma.
Simvastatin                                        Increase in AUC (~ in 2, 6 times) and Cmax (~ in 4, 6 times) a simvastatina
Agonists of receptors of serotonin  

Almotriptan                                       Increase in AUC (~ 20%) and Cmax (~ 24%) almotriptana
Uricosuric means
Sulfinpyrazonum                                  Increase in peroral clearance of verapamil

                                                           (~ by 3 times) and decrease in its bioavailability (~ 60%)
Others

Grapefruit juice                                 Increase in AUC R-(~ 49%) and S-(~ 37%) verapamil and

Cmax R-(~ 75%) and S-(~ 51%) verapamil. The elimination half-life and renal clearance did not change.
The St. John's Wort prodyyavlenny                      Decreases AUC R-(~ 78%) and S-(~ 80%) verapamil with the corresponding decrease in Cmax

Other medicinal interactions

Cimetidinum

Cimetidinum reduces clearance of verapamil at intravenous administration.

The means contacting proteins of a blood plasma

Verapamil as means highly contacting proteins of a blood plasma, has to be applied with care at a concomitant use with other drugs having similar ability.

Means for inhalation general anesthesia

At combined use of means for inhalation anesthesia and blockers of "slow" calcium channels to which verapamil belongs, it is necessary to titrate carefully a dose of each means before achievement of necessary effect to avoid excess oppression of cardiovascular system.

The means blocking neuromuscular conductivity

Researches show that verapamil can exponentiate effect of drugs,

blocking neuromuscular conductivity (such as the kurarepodobny and depolarizing muscle relaxants). Therefore it is necessary to reduce a dose of verapamil and/or a dose of the drugs blocking neuromuscular conductivity at their simultaneous use.

Lithium

Increase in a neurotoxicity of lithium is possible. At the same time lithium level in a blood plasma remains invariable or can increase. However verapamil can also reduce the content of lithium in blood serum at patients, is long the accepting lities inside. At simultaneous use of these drugs careful observation of patients is necessary.

Prazozinum, теразозин

The additive hypotensive action.

Antiviral (HIV) medicines

Ritonavir and other antiviral (HIV) drugs can inhibit metabolism

verapamil that leads to increase in its concentration in a blood plasma. Therefore at simultaneous use of such drugs and verapamil it is necessary to be careful and, whenever possible, to reduce verapamil doses.

Carbamazepine

At simultaneous use with verapamil concentration of carbamazepine in a blood plasma can increase that can lead to emergence of such side reactions as a diplopia, a headache, an ataxy or dizziness.

Rifampicin

Can reduce hypotensive effect of verapamil.

Colchicine

Colchicine is substrate for isoenzymes of CYP3A cytochrome and the R-glycoprotein. Verapamil inhibits CYP3A and the R-glycoprotein that in case of a concomitant use with colchicine can lead to increase in concentration of colchicine in blood and to strengthening of its action (see. "Contraindications").

Sulfinpyrazonum

Can lower hypotensive effect of verapamil.

Acetylsalicylic acid as antiagregantny means

Increase in bleeding.

Antihypertensives, diuretics, vazodilatator

Strengthening of hypotensive action.

Hypolipidemic means (GMG-KOA inhibitors — reductases (statins)

Simvastatin/lovastatin/atorvastatin

Simultaneous use with verapamil can lead to increase in serumal concentration of a simvastatin or lovastatin.

The patients receiving verapamil, treatment by HMG-CoA reductase inhibitors (i.e. simvastatiny, atorvastatiny, lovastatiny) should begin with perhaps lower doses which raise further. If the patients who are already receiving HMG-CoA reductase inhibitors need to appoint verapamil it is necessary to reconsider and lower their doses according to concentration of cholesterol in blood serum.

It is necessary to adhere to similar tactics also at co-administration of verapamil with atorvastatiny, though there are no clinical data confirming their interaction.

Fluvastatin, правастатин and розувастатин are not metabolized under the influence of SURZA4 isoenzymes therefore their interaction with verapamil is least probable.

Cardiac glycosides

Though intravenous verapamil was also applied together with cardiac glycosides without serious side effects, but, considering that these drugs slow down AV conductivity, observation of patients is necessary for early detection of AV of blockade or the expressed bradycardia.

Quinidine

In small group of patients it was shown that combined use of verapamil intravenously and quinidine did not lead to development of serious side effects. However there are several messages on cases of development of arterial hypotension at joint reception of quinidine inside and verapamil intravenously therefore this combination of medicines needs to be applied with care.

Beta adrenoblockers

Intravenous administration of verapamil to the patients accepting beta adrenoblockers inside did not lead to development of serious side effects. However it is necessary to consider possibility of adverse interactions because both medicines can reduce contractility of a myocardium or AV conductivity. Simultaneous intravenous administration of verapamil and beta adrenoblockers led to development of serious side effects (the expressed bradycardia, conductivity disturbances), especially at patients with a cardiomyopathy, heart failure or recently postponed myocardium heart attack (See the section "Contraindications").

Disopyramidum

Before data acquisition about possible interaction between verapamil and Disopyramidum it is not necessary to appoint Disopyramidum in 48 hours prior to or 24 hours after verapamil use (See the section "Contraindications").

Flekainid

At combined use of verapamil and a flekainid the perhaps additive action with decrease in contractility of a myocardium, delay of AV of conductivity and repolarization of a myocardium.

Contraindications:

Hypersensitivity to active agent or auxiliary components of drug.
Cardiogenic shock.
Atrioventricular (AV) blockade of II or III degrees except for patients with an artificial pacemaker.
Sick sinus syndrome (bradycardia tachycardia syndrome) except for patients with an artificial pacemaker.
Sinuatrial blockade.
Chronic heart failure (pressure of jamming of a pulmonary artery more than 20 mm hg, fraction of emission of a left ventricle less than 30%), except for the caused supraventricular tachycardia which is subject to treatment by verapamil.
Heavy arterial hypotension (systolic ABP less than 90 mm of mercury).
WPW-syndrome (WPW) and Launa-Ganonga-Levina (LGL) in combination with trembling or fibrillation of auricles (except patients with a pacemaker).
Ventricular tachycardia with the wide QRS complexes (≥ 0, 12 sec.) (see the section "Special Instructions").
Concomitant use with colchicine.
Simultaneous use with beta adrenoblockers, intravenously (see the section "Interaction with Other Medicines").
Use of Disopyramidum in 48 hours prior to and 24 hours after verapamil reception.
Pregnancy, the breastfeeding period (efficiency and safety are not established).
Age up to 18 years (efficiency and safety are not established).

With care:

Atrioventricular block of the I degree, bradycardia, arterial hypotension, hypertrophic obstructive cardiomyopathy, chronic heart failure.

Renal failure and/or liver.

The diseases affecting neuromuscular transmission (a heavy myasthenia, Lambert-Eaton's syndrome, muscular dystrophy of Dyushen).

Concomitant use with cardiac glycosides, quinidine, flekainidy, simvastatiny, lovastatiny, atorvastatiny, ritonaviry and other antiviral (HIV) drugs; the means contacting proteins of a blood plasma (see the section "Interactions with Other Medicines").

Advanced age.

Use at pregnancy and during breastfeeding

Researches of influence of verapamil on reproductive function were conducted at rabbits and rats using verapamil inside in the doses exceeding daily doses at the person at intake in 1,5 (15 mg/kg of body weight a day) and 6 (60 mg/kg of body weight a day) time, respectively. These researches did not reveal teratogenic effect of verapamil. However at rats such doses which are repeatedly exceeding the daily doses recommended for treatment of the person had embriotsidny effect and slowed down growth and development of embryos, perhaps, owing to the undesirable effects on an organism of mother expressed in decrease in a weight gain of a uterus. Intake of such doses also caused arterial hypotension in rats.

There are no sufficient data about use of the drug Izoptin® for pregnant women. Because results of researches of influence of medicines on reproductive health at animals do not allow to predict the response to treatment at the person, the drug Izoptin® can be used at pregnancy only in case of strict need.

Verapamil gets through a placental barrier and it is found in blood of an umbilical vein at childbirth. It is allocated in breast milk. Now there are no data on use of the drug Izoptin® during breastfeeding in the form of injections or infusions. Considering possibility of side effects at the baby receiving verapamil with mother's milk, the drug Izoptin® during breastfeeding should be used only if the advantage of use for mother exceeds potential risk for the child.

Overdose:

Symptoms: the sinus bradycardia passing into an atrioventricular block, sometimes an asystolia, the expressed lowering of arterial pressure, a hyperglycemia, a stupor, sinuatrial blockade, a metabolic acidosis. There are messages on death cases as a result of overdose.

Treatment: it is necessary to carry out the supporting symptomatic therapy. For increase in the ABP appoint angiotonic drugs, at an atrioventricular block — an artificial pacemaker, at an asystolia — intravenous administration of an izoprenalin, other angiotonic drugs or resuscitation actions. The hemodialysis is not effective.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity of 5 years. Not to apply after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous administration of 5 mg / 2мл.

On 2 ml in ampoules from colourless hydrolytic glass like I with a point break of blue color. On 5, 10 or 50 ampoules in the pallet from a cardboard or the blister from PVC or polystyrene closed by a paper foil together with the application instruction in a cardboard pack.