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

Tablet Excipients 40 mg: calcium hydrophosphate dihydrate - 70.0 mg; cellulose microcrystalline - 23.0 mg; silicon dioxide colloid - 0.7 mg; croscarmellose sodium - 1.8 mg; magnesium stearate - 1.5 mg.

Film coating tablets 40 mg: hypromellose 3 mPa - 1.7 mg; sodium lauryl sulfate - 0.1 mg; macrogol 6000 -2.0 mg; talc-4.0 mg; titanium dioxide 1.0 mg.

Tablet Excipients 80 mg: calcium hydrophosphate dihydrate - 140.0 mg; microcrystalline cellulose - 46.0 mg; silicon dioxide colloidal - 1.4 mg; croscarmellose sodium - 3.6 mg; magnesium stearate - 3.0 mg.

Film coating tablets 80 mg: hypromellose 3 mPa - 2.0 mg; sodium lauryl sulfate - 0.1 mg; macrogol 6000 - 2.3 mg; talcum - 4,5 mg; titanium dioxide -1,1 mg.

Description:

Tablets of 40 mg. Round, biconvex tablets covered with a white film shell, with an engraving "40" on one side and a triangle on the other side.

Tablets 80 mg. Round, biconvex tablets, covered with a film shell of white color, with engraving "ISOPTIN 80 "on one side and "KNOLL" above the risk for division on the other side.

Pharmacotherapeutic group:The blocker of "slow" calcium channels

ATX: & nbsp

C.08.D.A.01 Verapamil

C.08.D.A Phenylalkylamine derivatives

Pharmacodynamics:

Verapamil blocks transmembrannoe intake of calcium ions (and possibly sodium ions) through the "slow" channels into the cells of the conductive system of the myocardium and smooth muscle cells of the myocardium and vessels. The antiarrhythmic effect of verapamil is probably due to its effect on the "slow" channels in the cells of the conduction system of the heart.

Electrical activity of sinoatrial (SA) and atrioventricular (AV) nodes largely depends on the intake of calcium in the cells through the "slow" channels. Inhibiting this intake of calcium, verapamil slows atrioventricular (AV) conduct and increase the effective refractory period in AV The site is proportional to the heart rate (heart rate). This effect leads to a decrease in the frequency of ventricular contractions in patients with atrial fibrillation and / or atrial flutter. Terminating the re-entry of excitation in AV node, verapamil can restore the correct sinus rhythm in patients with paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome (WPW).

Verapamil does not interfere with conduction on additional conductive pathways, does not affect the normal atrial action potential or the time of intraventricular conduction, but decreases the amplitude, speed of depolarization, and conduction in altered atrial fibers.

Verapamil does not cause spasm of the peripheral arteries and does not change the total content of calcium in the blood serum. Reduces afterload and contractility of the myocardium. In most patients, including patients with organic heart lesions, the negative inotropic effect of verapamil is offset by a decrease in postload, the cardiac index usually does not decrease, but in patients with moderate and severe heart failure (pulmonary artery wedge pressure more than 20 mm Hg, ejection fraction left ventricle less than 35%), acute decompensation of chronic heart failure can be observed.

Pharmacokinetics:

Verapamil hydrochloride is a racemic mixture consisting of the same amount R-enantiomer and Senantiomer.

Noraveramil is one of the 12 metabolites found in urine. The pharmacological activity of norverapamil is 10-20% of the pharmacological activity of verapamil, and the share of noraveramil is 6% of the drug being withdrawn. Equilibrium concentrations of noraveramil and verapamil in blood plasma are similar. Equilibrium concentration with long-term use once a day is achieved after 3-4 days.

Suction

More than 90% of verapamil is rapidly absorbed into the small intestine after ingestion. The average systemic bioavailability after a single oral administration of verapamil is 22%, which is due to the pronounced effect of "primary transmission" through the liver. Bioavailability of verapamil with repeated application increases approximately 2-fold. Time to reach the maximum concentration (TC_max) verapamil in blood plasma is 1-2 hours. The maximum concentration of noraveramil in blood plasma is reached approximately 1 hour after the administration of verapamil. Food intake does not affect the bioavailability of verapamil.

Distribution

Verapamil is well distributed in the tissues of the body, the volume of distribution (V_d) in healthy volunteers is 1.8-6.8 l / kg. The connection with blood plasma proteins is about 90%.

Metabolism

Verapamil undergoes intensive metabolism. Metabolic Research in vitro showed that verapamil is metabolized by isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 cytochrome P450. In healthy volunteers after oral administration verapamil is subject to intensive metabolism in the liver, with 12 metabolites found, most of which are trace amounts. The main metabolites were identified as forms N and O-dealkylated derivatives of verapamil. Among the metabolites, only noravapamil has a pharmacological effect (about 20% compared to the parent compound), which was revealed during the study on dogs.

Excretion

Half-life (T_1/2) after taking verapamil inside is 3-7 hours. Within 24 hours about 50% of the dose of verapamil is excreted by the kidneys, within five days - 70%. Up to 16% of the dose of verapamil is excreted through the intestine. Approximately 3 - 4% of verapamil is excreted by the kidneys unchanged. The total clearance of verapamil roughly coincides with the hepatic blood flow, i.e. about 1 l / h / kg (in the range: 0.7 - 1.3 l / h / kg).

Special patient groups

Elderly patients

Age can affect the pharmacokinetic parameters of verapamil when it is taken by patients with hypertension. T_1/2 can be increased in elderly patients. The relationship between the antihypertensive effect of verapamil and age was not revealed.

Impaired renal function

Impaired renal function does not affect the pharmacokinetic parameters of verapamil, which was found in comparative studies involving patients with terminal renal failure and patients with normal renal function. Verapamil and norverapamil are practically not excreted in hemodialysis.

Impaired liver function

In patients with impaired liver function T_1/2 lengthened due to lower oral clearance of verapamil and greater V_d.

Indications:

- Arterial hypertension.

- Ischemic heart disease, including chronic stable angina (classic angina pectoris); unstable angina; angina due to coronary artery spasm (Prinzmetal angina).

Paroxysmal supraventricular tachycardia.

- Atrial fibrillation / flutter accompanied by tachyarrhythmia (except for Wolff-Parkinson-White and Laun-Ganong-Levin syndrome).

Contraindications:

- Hypersensitivity to the active substance or auxiliary components of the drug.

- Cardiogenic shock.

- Atrioventricular blockade of II or III degree, except for patients with an artificial pacemaker.

- Syndrome of weakness of the sinus node, except for patients with an artificial pacemaker.

- Heart failure with a reduced left ventricular ejection fraction of less than 35% and / or a pulmonary artery wedge pressure of more than 20 mm Hg. with the exception of heart failure caused by supraventricular tachycardia to be treated with verapamil.

- Atrial fibrillation / flutter in the presence of additional pathways (Wolff-Parkinson-White syndrome, Launa-Ganong-Levin syndrome). These patients are at risk of developing ventricular tachyarrhythmia, incl. ventricular fibrillation in the case of verapamil.

- Pregnancy, the period of breastfeeding (efficacy and safety not established).

- Age to 18 years (effectiveness and safety not established).

Carefully:

The pronounced decrease in blood pressure, acute myocardial infarction, left ventricular dysfunction, AV- blockade I degree, bradycardia, asystole, hypertrophic obstructive cardiomyopathy, heart failure.

Impaired renal function and / or severe liver dysfunction.

Diseases affecting neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy).

Simultaneous reception with cardiac glycosides, quinidine, flecainide, simvastatin, lovastatin, atorvastatin; ritonavir and other antiviral drugs for the treatment of HIV infection; beta-adrenoblockers for oral administration; means that bind to blood plasma proteins (see section "Interactions with other drugs").

Elderly age.

Pregnancy and lactation:

There is insufficient data on the use of Isoptin® in pregnant women. Studies in animals do not reveal direct or indirect toxic effects on the reproductive system. Due to the fact that animal studies do not always predict the response to treatment in humans, Isoptin® can be used in pregnancy only if the benefit to the mother exceeds the potential risk to the fetus / child.

Verapamil penetrates the placental barrier and is found in the blood of the umbilical vein during childbirth. Verapamil and its metabolites are excreted in breast milk. The limited data available regarding Isoptin® oral administration show that the dose of verapamil given to infants with mother's milk is small (0.1-1% of the dose of verapamil taken by the mother), and the use of verapamil may be compatible with feeding the chest.

However, the risk to newborns and infants may not be ruled out. Given the potential for serious side effects in infants, Isoptin® during breastfeeding should be used only if the benefit to the mother exceeds the potential risk to the child.

Dosing and Administration:

Inside.

Tablets should be swallowed whole, washed down with water, taken preferably during meals or immediately after meals, they can not be dissolved or chewed.

The dose of Isoptin ® should be selected individually depending on the clinical picture and severity of the disease.

Initial dose - 40-80 mg 3-4 times a day.

The average daily dose for all recommended indications for use varies from 240 to 360 mg. For long-term treatment, the daily dose of 480 mg should not be exceeded, but with a short-term therapy, a higher daily dose may be used. In the maximum daily dose, Isoptin® should be taken only in a hospital. There are no limitations with regard to the duration of taking Isoptin®. Do not abruptly cancel Isoptin® after long-term therapy, it is recommended to gradually reduce the dose until the drug is completely discontinued.

Isoptin® preparation at a dose of 40 mg should be used in patients who are expected to respond satisfactorily to low doses (patients with impaired liver function or elderly patients).

Impaired renal function

The drug Isoptin® in patients with impaired renal function should be used with caution and with careful monitoring (See section "Special instructions").

Impaired liver function

In patients with impaired liver function, the metabolism of verapamil is slowed down to a greater or lesser degree depending on the severity of the impaired liver function, which leads to an increase and prolongation of the duration of verapamil.Therefore, the dose of Isoptin® in patients with impaired liver function should be selected with particular caution and treatment should begin with lower doses.

Side effects:

The side effects identified in clinical trials and in the post-marketing use of Isoptin® are presented below for organ systems and the frequency of their occurrence in accordance with the WHO classification: very often (≥1/10); often (from ≥ 1/100 to <1/10); infrequently (from ≥ 1/1000 to <1/100); rarely (from ≥ 1/10000 to <1/1000); very rarely (<1/10000); frequency is unknown (can not be determined from available data).

The most common side effects were: headache, dizziness, nausea, constipation, abdominal pain, bradycardia. tachycardia, palpitations, marked decrease in blood pressure, "tides" of blood to the skin of the face, peripheral edema and increased fatigue.

Immune system disorders:

frequency unknown: hypersensitivity.

Disorders from the metabolism and nutrition:

frequency unknown: hyperkalemia.

Disorders of the psyche:

rarely: drowsy.

Impaired nervous system:

often: dizziness, headache; rarely: paresthesia, tremor;

frequency unknown: extrapyramidal disorders, paralysis (tetraparesis)¹, convulsive seizures.

Hearing disorders and labyrinthine disturbances:

rarely: tinnitus; frequency unknown: vertigo.

Heart Disease:

often: aetiology; infrequent: a feeling of palpitations. tachycardia;

frequency is unknown: AV blockade of I, II, III degree; heart failure, stopping the sinus node ("sinus arrest"), sinus bradycardia, asystole.

Vascular disorders:

often: "hot flashes" of blood to the skin of the face, marked decrease in blood pressure;

Disturbances from the respiratory system, chest and mediastinal organs:

frequency unknown: bronchospasm, dyspnea.

Disturbances from the gastrointestinal tract:

often: constipation, nausea; infrequently: abdominal pain; rarely: vomiting;

frequency unknown: abdominal discomfort, gingival hyperplasia, intestinal obstruction.

Skin and nip disordersImportant tissues:

rarely: hyperhidrosis; frequency unknown: angioedema, Stevens-Johnson syndrome, erythema multiforme, alopecia, itching, itching, purpura, maculopapular rash, urticaria.

Disturbances from the musculoskeletal and connective tissue:

frequency unknown: arthralgia, muscle weakness, myalgia.

Disorders from the nights and urinary tract:

frequency unknown: renal failure.

Violations of the genitals and breast:

frequency unknown: erectile dysfunction, galactorrhea, gynecomastia.

General disorders:

often: peripheral edema; infrequently: increased fatigue.

Laboratory and instrumental data:

frequency is unknown: increased prolactin concentration, increased activity of liver enzymes.

¹ - During the period of post-marketing use of Isoptin®, a single case of development of paralysis (tetranarez) associated with the joint use of verapamil and colchicine was reported. This could be due to the penetration of colchicine through the blood-brain barrier due to the suppression of the activity of the isoenzyme CYP3A4 and P-glycoprotein under the action of verapamil (see the section "Interaction with other drugs").

Overdose:

Symptoms: marked decrease in blood pressure; bradycardia, turning into AV-blockade and stopping the activity of the sinus node ("sinus arrest"); hyperglycemia, stupor and metabolic acidosis.There are reports of deaths from overdose.

Treatment: should support symptomatic therapy. In case of an overdose, effective measures are beta-adrenergic stimulation and / or parenteral administration of calcium preparationscalcium chloride). With clinically significant hypotensive reactions or AV-blockade should be prescribed vasopressor drugs or pacing, respectively. With asystole, it is necessary to use beta-adrenergic stimulation (isoprenaline), other vasopressor drugs or resuscitation. Hemodialysis is not effective.

Interaction:

Metabolic Research in vitro evidence that verapamil metabolized by isozymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 cytochrome P450.

Verapamil is an inhibitor of the isoenzyme CYP3A4 and P-glycoprotein. A clinically significant interaction was observed with simultaneous application with isoenzyme inhibitors CYP3A4, with an increase in the concentration of verapamil in blood plasma, while isoenzyme inducers CYP3A4 reduced the concentration of verapamil in blood plasma.With the simultaneous use of such drugs should take into account the possibility of this interaction.

The table below shows the possible drug interactions due to pharmacokinetic parameters.

Possible types of interactions associated with the isoenzyme system CYP-450
A drug	Possible drug interactions	A comment
Alfa-adrenoblockers
Prazozin	Increase in C_m_Oh prazosin (~ 40%), does not affect the T_1/2prazosin.	Additional antihypertensive act.
Terazozin	Increase AUC terazosin (-24%) and C_m_Oh(~25 %).	Additional antihypertensive act.
Antiarrhythmics
Flecainide	The minimal effect on the clearance of flecainide in the blood plasma (<~ 10%); does not affect the clearance of verapamil in the blood plasma.
Quinidine	Decreased oral clearance of quinidine (~ 35%).	Pronounced decrease in blood pressure. There may be pulmonary edema in patients with hypertrophic obstructive cardiomyopathy.
Means for the treatment of bronchial asthma
Theophylline	Reduction of oral and systemic clearance (~ 20%).	Reduced clearance in smoking patients (~ 11%).
Anticonvulsants / antiepileptics
Carbamazepine	Increase AUC carbamazepine (~ 46%) in patients with stable partial epilepsy.	An increase in the concentration of carbamazepine, which can lead to the development of such side effects of carbamazepine as diplopia, headache, ataxia or dizziness.
Phenytoin	Reduction of the concentration of verapamil in the blood plasma.
Antidepressants
Imipramine	Increase AUC imipramine (~ 15%).	Does not affect the concentration of the active metabolite, desipramine.
Hypoglycemic agents
Glibenclamide	Increase in C_m_Oh glibenclamide (-28%), AUC (~26 %).
Anti-gouty agents
Colchicine	Increase AUC colchicine (~ 2.0 times) and C_m_Oh (~ 1.3 times).	Reduce the dose of colchicine (see instructions for the use of colchicine).
Antimicrobial medications
Clarithromycin	It is possible to increase the concentration of verapamil.
Erythromycin	It is possible to increase the concentration of verapamil.
Rifampicin	Decrease AUC (~ 97%), C_m_Oh(~ 94%), bioavailability (~ 92%) of verapamil.	Antihypertensive effect may decrease.
Telithromycin	It is possible to increase the concentration of verapamil.
Antineoplastic agents
Doxorubicin	Increase AUC (104%) and C_m_Oh(61%) of doxorubicin.	In patients with small cell lung cancer.
Barbiturates
Phenobarbital	Increase in oral clearance of verapamil ~ 5-fold.
Benzodiazepines and other tranquilizers
Buspirone	Increase AUC and C_m_Oh buspirone ~ 3.4 times.
Midazolam	Increase AUC (~ 3 times) and Cmah (~ 2-fold) of midazolam.
Beta-blockers
metoprolol	enlargement auc (-32.5%) and with_m_Oh(-41%) metoprolol in patients with angina pectoris.	see "special instructions".
propranolol	enlargement auc (-65%) and with_m_Oh(-94%) propranolol in patients with angina pectoris.	see "special instructions".
cardiac glycosides
digitoxin	a decrease in the total clearance (-27%) and extrarenal clearance (-29%) digitoxin.
digoxin	increase from_m_Oh (-44%), with₁₂h(by -53%), c_ss (-44%) and auc (-50%) digoxin in healthy volunteers.	reduce dose of digoxin. see "special instructions".
antagonists h₂ receptors
cimetidine	enlargement auc r- (-25%) and s- (-40%) verapamil with a corresponding decrease in clearance r- and s-verapamila.
immunological / immunosuppressive agents
ciclosporin	enlargement auc, c_ss, c_max(by -45%) of cyclosporine.
everolimus	everolimus: increase auc (~ 3.5 times) and with_m_Oh (~ 2.3 times) verapamil: an increase chough (the concentration of the drug in the blood plasma immediately before taking its next dose) (~ 2.3 times).	it may be necessary to determine the concentration and titration of the everolimus dose.
sirolimus	enlargement auc sirolimus (~ 2.2 times); enlargement auc s- verapamil (~ 1.5 times).	it may be necessary to determine the concentration and dose titration of sirolimus.
tacrolimus	an increase in tacrolimus concentration is possible.
lipid-lowering agents (inhibitors of gamma-co-reductase)
atorvastatin	may increase the concentration of atorvastatin in blood plasma, increase auc verapamil - 43%.	additional information is provided below.
lovastatin	may increase the concentration of lovastatin and auc verapamil (~ 63%) and with_m_Oh(~ 32%) in the blood plasma
simvastatin	enlargement auc (~ 2.6 times) and from_m_Oh (~ 4.6 times) of simvastatin.
serotonin receptor agonists
almotriptan	enlargement auc (~ 20%) and from_m_Oh(~ 24%) of almotriptan.
uricosuric means
sulfinpyrazone	an increase in oral clearance of verapamil (~ 3-fold), a decrease in its bioavailability (~ 60%).	antihypertensive effect may decrease.
others
grapefruit juice	enlargement auc r- (~ 49%) and s- (~ 37%) of verapamil and from_m_Oh r- (~ 75%) and s-c-51 %) verapamil.	t_1/2 and renal clearance did not change. Grapefruit juice should not be taken with verapamil.
St. John's wort	decrease auc r- (~ 78%) and s- (~ 80%) of verapamil with a corresponding decrease from_m_Oh.

other drug interactions

antiviral drugs for the treatment of HIV infection

ritonavir and other antiviral drugs for the treatment of HIV infection can inhibit the metabolism of verapamil, which leads to an increase in its concentration in the blood plasma. therefore, with the simultaneous use of such drugs and verapamil should be careful or reduce the dose of verapamil.

lithium

an increase in the neurotoxicity of lithium was observed during simultaneous reception of verapamil and lithium in the absence of changes or an increase in the concentration of lithium in the serum. However, an additional dose of verapamil also led to a decrease in serum lithium concentration in patients taking lithium for long periods of time. with the simultaneous use of these drugs need careful monitoring of patients.

Neuromuscular blocking agents

Clinical data and preclinical studies suggest that verapamil can potentiate the effect of drugs that block neuromuscular conduction (such as curare-like and depolarizing muscle relaxants).so there may be a need to reduce the dose of verapamil and / or a dose of drugs that block neuromuscular conduction when they are used simultaneously.

acetylsalicylic acid (as an antiplatelet agent)

increased risk of bleeding.

ethanol (alcohol)

an increase in the concentration of ethanol in the blood plasma and slowing its elimination. so the effect of ethanol can be enhanced.

rm-koa inhibitors - reductase (statins)

patients receiving verapamil, treatment with inhibitors of GMH-co-reductase (ie simvastatin, atorvastatin or lovastatin) should be started with the lowest possible dose, which is then increased. if it is necessary to appoint verapamil patients already receiving inhibitors of GMH-co-reductase, it is necessary to review and reduce their dose according to serum cholesterol concentration. fluvastatin, pravastatin and rosuvastatin Do not metabolize under the action of isoenzymes cyp3a4, so their interaction with verapamil is less likely.

antihypertensives, diuretics, vasodilators

increased antihypertensive action.

Special instructions:

Acute myocardial infarction

Isoptin® should be used with caution in patients with acute myocardial infarction complicated by bradycardia, severe lowering of blood pressure, or left ventricular dysfunction.

Heart block / Atrioventricular block of degree I / Bradycardia / Asystole

Verapamil affects AV and SA nodes and slows down AV conductivity. Preparation Isoptin^®should be used with caution, as development AV-blocks II or III degree (see the section "Contraindication") or a single-bundle, two-beam or three-beam blockade of the bundle of the bundle, requires the termination of the use of verapamil and appropriate therapy if necessary.

Verapamil affects AV and SA nodes and in rare cases can cause development AV- blockade II or III degree, bradycardia and, in extreme cases, asystole. These phenomena are most likely in patients with sinus node weakness syndrome, which is more common in patients in old age.

Asystole in patients who do not have sinus node weakness is usually short-term (several seconds) with spontaneous restoration of atrioventricular or normal sinus rhythm. If the sinus rhythm is not restored in time, it is necessary to immediately prescribe the appropriate treatment.

Beta-blockers and antiarrhythmics

Mutual strengthening of influence on the cardiovascular system (AV-blockade of a high degree, a significant decrease in IAS, an exacerbation of heart failure and a pronounced decrease in blood pressure). Asymptomatic bradycardia (36 beats per minute) with rhythm migration in the atrium was observed in a patient simultaneously receiving timolol (beta-blocker) in the form of eye drops and verapamil inside.

Digoxin

In the case of simultaneous administration of verapamil with digoxin, the dose of digoxin should be reduced. See section "Interaction with other medicinal products".

Heart failure

Patients with heart failure and a left ventricular ejection fraction greater than 35% should achieve a stable condition before starting the preparation of Isoptin® and conduct appropriate therapy in the future.

Inhibitors of HMG-CoA reductase (statins)

See section "Interaction with other medicinal products".

Violations of neuromuscular transmission

The drug Isoptin® should be used with caution in patients with diseases affecting neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy).

Impaired renal function

Comparative studies show that the pharmacokinetics of verapamil remains unchanged in patients with terminal stage of renal failure. However, some available reports suggest that Isoptin® in patients with impaired renal function should be used with caution and careful monitoring. Verapamil not excreted by hemodialysis.

Impaired liver function

The drug Isoptin® should be used with caution in patients with severe impairment of liver function.

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

The drug Isoptin® can influence the speed of psychomotor reactions due to antihypertensive action and as a result of individual sensitivity. During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions. This is especially important at the beginning of treatment, with an increase in the dose or when switching from another drug.

Form release / dosage:

The film coated tablets are 40 mg and 80 mg.

Packaging:

For 10 tablets in a blister of PVC / A1 foil. For 2 or 10 blisters in a cardboard pack together with instructions for use.

For 20 tablets in a blister of PVC / A1 foil. For 1 or 5 blisters in a cardboard pack together with instructions for use.

For 25 tablets in a blister of PVC / A1 foil. For 4 blisters in a cardboard pack together with instructions for use.

Storage conditions:

Store at a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years. Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015403 / 01

Date of registration:15.12.2008 / 23.03.2012

Expiration Date:Unlimited

The owner of the registration certificate:Abbott GmbH & Co. KGAbbott GmbH & Co. KG Germany

Manufacturer: & nbsp

ABBOTT, GmbH & Co. KG. KG Germany

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp23.10.2017

Illustrated instructions

Instructions

Isoptin® (Isoptin®)