ISOPTIN - PACKAGE LEAFLET - LEAFLETS

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Isoptin - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Verapamil

ISOPTIN 40 mg Coated tablets

Isoptin package inserts are available for pack sizes:

ISOPTIN 40 mg Coated tablets
ISOPTIN 80 mg Film-coated tablets
ISOPTIN 120 mg Prolonged-release tablets
ISOPTIN 240 mg Prolonged-release tablets

Indications Why is Isoptin used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

Selective calcium channel blockers with direct cardiac effect-Phenylalkylamine derivatives.

THERAPEUTIC INDICATIONS

Acute and chronic coronary insufficiency. Treatment of sequelae of myocardial infarction. Supraventricular hyperkinetic arrhythmias such as paroxysmal supraventricular tachycardia, atrial fibrillation and flutter with rapid ventricular response, extrasystoles. Arterial hypertension.

Contraindications When Isoptin should not be used

Hypersensitivity to the active substance or to any of the excipients.

Cardiogenic shock.

Recent myocardial infarction complicated by marked bradycardia.

Contractile insufficiency of the left ventricle.

Severe conduction disturbances such as total AV block, partial AV block; incomplete branch block, sinus node disease (except those with ventricular artificial pacemakers), grade II-III AV block (except in patients with functioning artificial ventricular pacemaker).

Decompensated congestive heart failure.

Wide complex ventricular tachycardia.

Atrial fibrillation / flutter and concomitant Wolff-Parkinson-White syndrome, Lown-Ganong-Levine syndrome, short PR syndromes.

Marked bradycardia (<50 beats / min.).

Hypotension (systolic blood pressure <90 mm of Hg) (see also Precautions for use).

Association with MAO inhibitors and beta-blockers and after quinidine treatments.

Precautions for use What you need to know before taking Isoptin

Use in patients with impaired hepatic function: As verapamil is predominantly metabolised by the liver, it should be administered with caution to patients with impaired hepatic function. Severe hepatic dysfunction prolongs the elimination half-life of verapamil to approximately 14-16 hours; therefore, these patients should be given approximately 30% of the usual dose used in patients with normal liver function. Careful monitoring should be undertaken for abnormal Prolongation of the PR interval or other signs of excessive pharmacological effects.
Use in patients with impaired renal function: Approximately 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data become available, verapamil should be administered with caution to patients with impaired renal function. These patients should be monitored closely for PR interval prolongation or other signs of overdose. Although consistent clinical data from comparative studies conducted in patients with end stage renal failure have shown that decreased renal function has no effect on the pharmacokinetics of verapamil, case reports suggest that verapamil should be used with caution and under close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis.
Use with caution in bradycardia and hypotensive patients (see also Contraindications).
Use with caution in patients with disorders in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).

Interactions Which drugs or foods can modify the effect of Isoptin

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.

In vitro studies have shown that verapamil is metabolised by cytochrome P450, CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Furthermore, verapamil has been shown to be an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Patients undergoing concomitant therapies during verapamil administration should be monitored closely as clinically significant interactions have been demonstrated with CYP3A4 inhibitors (leading to elevated plasma levels of verapamil) and with CYP3A4 inducers (which instead they cause a lowering).

The table below provides a list of drugs with which interactions may occur for pharmacokinetic reasons:

Potential interactions associated with the CYP-450 enzyme system Associated drug Potential effect on verapamil or associated drug Comment Alpha blockers Prazosin Increased Cmax of prazosin (≈40%) with no effect on half-life Terazosin Increased AUC (≈24%) and Cmax (≈25%) of terazosin Antiarrhythmics Flecainide Minimal effect on plasma clearance of flecainide (<≥10%); no effect on the plasma clearance of verapamil Quinidine Decreased oral clearance of quinidine (≥35%) Anti-asthmatics Theophylline Decrease in oral and systemic clearance by 20% The reduction in clearance is more diminished in smokers (≈11%). Anticoagulants Dabigatran etexilate Increased dabigatran Cmax by approximately 180% and AUC by approximately 150% Observed with the first dose of an immediate-release oral formulation of verapamil. Anticonvulsants Carbamazepine Increased AUC of carbamazepine (≥46%) in patients with partially refractory epilepsy Antidepressants Imipramine Increased AUC of imipramine (≈15%) It has no effect on the level of the active metabolite desipramine. Antidiabetics Glyburide Increased Cmax (≈28%) and AUC (≈26%) of glyburide Antiinfectives Clarithromycin Possible increase in verapamil levels Erythromycin Possible increase in verapamil levels Rifampicin Decreased AUC (≈94%), Cmax (≈97%) and oral bioavailability (≈92%) of verapamil May reduce the hypotensive effect of verapamil. No change in pharmacokinetics with intravenous administration of verapamil Telithromycin Possible increase in verapamil levels Antineoplastics Doxorubicin Doxorubicin AUC (104%) and Cmax (61%) increase following oral administration of verapamil In patients with small cell lung cancer. No significant change in doxorubicin pharmacokinetics following intravenous administration of verapamil In patients with advanced malignancies. Barbiturates Phenobarbital Increased clearance (≥5 fold) of orally administered verapamil Benzodiazepines and other anxiolytics Buspirone 3.4-fold increase in AUC and Cmax of buspirone Midazolam Increased AUC (≈3-fold) and Cmax (≈2-fold) of midazolam Beta blockers Metoprolol Increase in AUC (≈32.5%) and Cmax (≈41%) of metoprolol in patients with angina Propranolol Increased AUC (≈65%) and Cmax (≈94%) of propranolol in patients with angina Cardiac glycosides Digitoxin Decreased total body clearance (≈27%) and extrarenal clearance (≈29%) of digitoxin Digoxin Healthy patients: increased Cmax (≈44%), increased C12h (≈53%), increased Css (44%) and increased AUC (50%) of digoxin See Special Warnings H2 receptor antagonists Cimetidine Increased AUC R- (≈25%) and S- (≈40%) of verapamil with corresponding decrease in clearance of verapamil R- and S- Immunological Ciclosporine Increased AUC, Css, Cmax of cyclosporins by approximately 45% Everolimus Everolimus: increased AUC (≈3.5-fold) and increased Cmax (≈2.3-fold); verapamil: increased Ctrough (≈2.3-fold) Sirolimus Sirolimus: AUC increased (≈2.2-fold); S-verapamil: AUC increased (≈1.5-fold) Tacrolimus Possible increase in tacrolimus levels Lipid-lowering agents Atorvastatin Possible increase in atorvastatin levels, increase in verapamil AUC by 43% Lovastatin Possible increase in lovastatin levels, increase in AUC (≈63%) and Cmax (≈32%) of verapamil Simvastatin Increased AUC (2.6-fold) and Cmax (≈4.6-fold) of simvastatin Serotonin receptor agonists Almotriptan Increased AUC (20%) and Cmax (≈24%) of almotriptan Uricosuric agents Sulfinpyrazone Increased clearance (≈3 fold) and decrease in bioavailability (≈60%) of verapamil after oral administration Others Grapefruit juice Increased AUC of verapamil R- (≈49%) and S- (≈37%), increased Cmax of verapamil R- (≈75%) and S- (≈51%) It does not affect the half-life and renal clearance St. John's wort (Hypericum) Decreased AUC of verapamil R- (≈78%) and S- (≈80%) with corresponding decrease in Cmax

Other interactions and additional information

Antiarrhythmics, Beta-blockers: reciprocal potentiation of cardiovascular effects (increase in degree of AV block, potentiation of the decreased heart rate in advanced stages, induction of myocardial infarction and possibility of intensifying hypotension).
Plasma protein binding drugs: verapamil is highly bound to plasma proteins; for this reason it should be administered with caution to those patients taking other drugs with a high degree of binding to plasma proteins.
Prazosin, Terazosin: potentiation of the hypotensive effect.
Anti-HIV agents: The plasma concentration of verapamil may increase due to the potential metabolic inhibition of some of the anti-HIV agents such as ritonavir. Therefore, great caution should be exercised in combining or the dose of verapamil should be decreased.
Quinidine: hypotension and possible pulmonary edema in patients with hypertrophic obstructive cardiomyopathy.
Sulfinpyrazone: May reduce the hypotensive effect of verapamil.
Neuromuscular blockers: The action of neuromuscular blockers may be enhanced. For this reason it may be necessary to decrease the dose of verapamil and / or that of the neuromuscular blocker when the two drugs are taken in combination.
Acetylsalicylic acid: increased bleeding tendency.
Ethanol: increase in plasma levels of ethanol.
HMG Co-A reductase inhibitors (statins): Treatment with HMG Co-A reductase inhibitors (simvastatin, atorvastatin or lovastatin) in patients taking verapamil, should be started at the lowest possible doses which subsequently need to be corrected. . If patients taking HMG Co-A reductase inhibitors (such as simvastatin, atorvastatin, or lovastatin) are prescribed verapamil therapy, a statin dose reduction should be considered and serum cholesterol readings re-examined.
Digitalis: Clinical use of verapamil in digitized patients has shown that the combination is well tolerated if digoxin doses are adequately regulated. Chronic treatment with verapamil can increase serum digoxin levels by 50-75% during the first week of therapy, which can lead to digitalis toxicity. Maintenance doses of digitalis should be reduced when verapamil is administered and the patient should be carefully monitored to avoid hyper or hypodigitalization. Whenever hyperdigitalization is suspected, the dose of digoxin should be temporarily reduced or discontinued. After discontinuation of ISOPTIN 40 mg Coated tablets the patient should be re-examined to avoid hypodigitalization.
Antihypertensive drugs, diuretics and vasodilators: Verapamil given concurrently with other oral antihypertensive drugs (for example: vasodilators, angiotensin I converting enzyme inhibitors, diuretics, beta blockers) usually has an additive lowering effect. In one study, the simultaneous administration of verapamil and prazosin resulted in an "excessive drop in blood pressure."
Disopyramide: Until data on possible interactions between verapamil and disopyramide have been obtained, disopyramide should not be administered within 48 hours prior to or 24 hours following verapamil administration.
Nitrates: Verapamil has been administered concomitantly with short- and long-acting nitrates, without any undesirable drug interactions.
Cimetidine: Cimetidine reduces the clearance of verapamil and increases its elimination half-life.
Lithium: Oral therapy with verapamil may cause lowering of serum lithium levels in patients receiving oral, stable and chronic therapy with lithium. Adjustment of the lithium dose may be necessary due to a possible increase in neurotoxicity.
Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combination therapy. This can produce unwanted effects such as diplopia, headache, ataxia or dizziness.
Rifampicin: May reduce the hypotensive effect of verapamil.
Inhalation Anesthetics: Clinical data and animal experiments indicate that verapamil may enhance the activity of neuromuscular blockers and inhalation anesthetics.
Grapefruit juice: Data indicating increased plasma levels of calcium channel blockers have been reported when taken concomitantly with grapefruit juice. The simultaneous intake of oral verapamil and grapefruit juice should therefore be avoided.
Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are co-administered, inhibition of P-gp and / or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.
Dabigatran: careful clinical monitoring (looking for signs of bleeding or anemia) is required when verapamil is co-administered with dabigatran etexilate (substrate of the efflux transporter P-gp) and with extra care in the case of patients with mild renal impairment Increased plasma levels of dabigatran (Cmax el "AUC) were observed when oral verapamil was co-administered with dabigatran etexilate but the magnitude of this change varied with time of administration and formulation of verapamil . In patients with moderate renal impairment treated with verapamil and dabigatran etexilate concurrently, a dose reduction of dabigatran should be considered. Conversely, no significant interaction was observed when verapamil was administered 2 hours after taking dabigatran etexilate. This is explained by the complete absorption of dabigatran after 2 hours.
Dronedarone: Caution should be exercised when verapamil is administered in combination with dronedarone. Administer verapamil initially in low doses and increase the dose only after evaluation by ECG.
Ivabradine: Verapamil results in an increase in ivabradine concentration (2-3 fold increase in AUC) and an additional 5 bpm decrease in heart rate. Concomitant use of verapamil with ivabradine is not recommended.
Aliskiren: Concomitant administration of verapamil and aliskiren resulted in a 97% increase in the AUC of aliskiren as an effect of the P-gp inhibitory activity of verapamil.
Dantrolene: In animal studies, fatal cases of ventricular fibrillation have been observed during intravenous administration of verapamil and dantrolene. The combination of verapamil and dantrolene is therefore potentially dangerous.

Warnings It is important to know that:

Heart failure: verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload-reducing properties (decreased peripheral resistance) with no distinct impairment of ventricular function. Verapamil is contraindicated in patients with severe left ventricular dysfunction ( for example: Ejection fraction less than 30% or severe symptoms of heart failure, pulmonary pressure greater than 20 mmHg) Patients with milder ventricular dysfunction, if possible, should be controlled with optimal doses of digitalis and / or diuretics before treatment with verapamil. Sometimes the pharmacological action of verapamil can produce a decrease in blood pressure below normal levels, which can lead to symptomatic dizziness or hypotension. In hypertensive patients, a decrease in blood pressure below normal is unusual.
Liver enzyme elevations: Transaminase elevations have been reported with and without concomitant increases in alkaline phosphatase and bilirubin. These elevations were sometimes transient and may disappear even with continued verapamil treatment. Some cases of hepatocellular damage have been related to verapamil using the "rechallenge" technique; half of these cases had clinical symptoms (malaise, fever and / or right upper quadrant pain) in addition to increased SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function is therefore advisable in patients treated with verapamil.
Accessory conduction pathway (Wolff-Parkinson-White or Lown-Ganong-Levine): Patients with paroxysmal and / or chronic atrial flutter or fibrillation with a coexisting accessory AV pathway have developed an increase in antegrade conduction through the accessory pathway that bypasses the AV node resulting in a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil or digitalis. Although this phenomenon has not been reported with oral verapamil, it should be considered a potential risk. Treatment usually consists of direct current cardioversion. Cardioversion has been used with safety and efficacy following administration of ISOPTIN.
Atrioventricular block: the effect of verapamil on AV conduction and the SA node can lead, in particular cases, to asymptomatic grade I AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. Prolongation of the PR segment is related with plasma concentrations of verapamil, especially during the initial titration phase of therapy. However, higher degrees of AV block have been rarely observed. Severe degree I block or progressive evolution to degree II or III AV block requires reduction of the dose or, in rare cases, the suspension of therapy with verapamil and the institution of an appropriate therapy depending on the clinical situation.

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine

Pregnancy

Reproduction studies were performed in rabbits and rats at an oral dose of verapamil greater than 1.5 times (15 mg / kg / day) and 6 times (60 mg / kg / day) higher than the daily oral dose taken. by humans, and showed no evidence of teratogenicity. In rats, however, the multiple dose administered was found to be embryocidal and retard the growth and development of the fetus, probably due to adverse effects on the mothers which are reflected in a reduced ability to put on weight It has also been shown that this dose taken orally causes hypotension in rats.

There have been no adequate and well-controlled trials in pregnant women so the safety of verapamil during pregnancy has not been established. Verapamil crosses the placental barrier and was found in the umbilical cord. Since animal reproduction studies are not always able to predict the response in humans, as a precaution, verapamil should only be used during pregnancy if strictly necessary.

Feeding time

Verapamil hydrochloride is secreted in breast milk. Limited data regarding oral administration have shown that the dose of verapamil which is ingested through milk by the infant is low (0.1-1% of the oral dose taken by the mother). Due to the severity of the potential undesirable effects in the infant, verapamil should only be administered to the breastfeeding woman if it is considered essential for the well-being of the mother.

Effects on ability to drive and use machines

Verapamil impairs the ability to drive or use machines. This mostly occurs at the beginning of therapy, when the dose is increased, when changing treatment from a different drug to verapamil and drinking alcohol concomitantly.

Important information about some of the ingredients:

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

ISOPTIN 40 mg Coated tablets contain lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

ISOPTIN 40 mg Coated tablets contain sucrose, therefore patients with rare hereditary problems of fructose intolerance, sucrase isomaltase deficiency, or glucose-galactose malabsorption should not take this medicine.

Dosage and method of use How to use Isoptin: Dosage

Adults: 1-2 coated tablets 3 times a day

Boys: 1-3 coated tablets 2-3 times a day

In infancy: ½ coated tablet 2-3 times a day

Overdose What to do if you have taken too much Isoptin

Symptoms

Hypotension, bradycardia up to high grade AV block and sinus arrest, hyperglycemia, apathy and metabolic acidosis. Deaths have occurred as a result of overdose.

Treatment

Treatment of overdose should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions and intestinal irrigation can increase the flow of calcium ions through slow channels and these methods have been used successfully in the treatment of a voluntary overdose with verapamil.

Due to the delayed absorption of modified release products, some patients may require further observation and hospitalization for longer than 48 hours or an observation period.

Clinically significant hypotensive reactions or high-grade AV block should be treated with vasopressors or cardiac pacing, respectively. Asystole should be treated with the usual measures, including cardiopulmonary resuscitation. Verapamil cannot be eliminated by hemodialysis.

In case of accidental ingestion / intake of an excessive dose of Isoptin, notify your doctor immediately or go to the nearest hospital.

If you have any questions about the use of Isoptin, ask your doctor or pharmacist.

Side Effects What are the side effects of Isoptin

Like all medicines ISOPTIN can cause side effects, although not everybody gets them.

The following adverse reactions to verapamil administered orally were clearly related to drug intake in clinical trials [very common (≥ 1/10); common (≥ 1/100 to

Table 1: Adverse reactions reported with oral administration of verapamil in controlled clinical trials

Organic system classification Adverse reaction Frequency Nervous system disorders Dizziness Headache Municipality Municipality Cardiac pathologies Heart failure / Pulmonary edema Atrioventricular bradycardia Atrioventricular block Complete atrioventricular block Common Common Common Uncommon Vascular pathologies Hypotension Flushing Common Uncommon Gastrointestinal disorders Constipation Nausea Municipality Municipality General disorders and administration site conditions Fatigue edema Municipality Municipality

In the ventricular response control clinical trial in scanned patients who had atrial fibrillation or flutter, a ventricular rate of less than 50 beats / min at rest occurred in 15% of patients and asymptomatic hypotension in 5% of patients.

The following adverse reactions have been reported with verapamil in postmarketing experience or in Phase IV clinical studies and were grouped by system organ class [frequency not known (cannot be estimated from the available data)].

Table 2: Adverse reactions reported with verapamil in post-marketing experience or in Phase IV clinical trials

Organic system classification Adverse reaction Disorders of the blood and lymphatic system Bruising Disorders of the immune system Hypersensitivity Psychiatric disorders Psychiatric symptoms Nervous system disorders Headache Dizziness Paraesthesia Tremor Extrapyramidal disorders Cerebrovascular accidents Confusional state Balance disorders Insomnia Somnolence Eye disorders Blurred vision Ear and labyrinth disorders Vertigo Tinnitus Cardiac pathologies Atrioventricular block Sinus bradycardia Sinus arrest Peripheral edema Palpitations Tachycardia Heart failure Angina pectoris Chest pain Myocardial infarction Syncope Vascular pathologies Hypotension Flushing Intermittent claudication Purpura Respiratory, thoracic and mediastinal disorders Dyspnea Gastrointestinal disorders Nausea Vomiting Constipation Ileus Gingival hyperplasia Abdominal pain Abdominal discomfort Diarrhea Dry mouth Gastrointestinal disorders Skin and subcutaneous tissue disorders Angioedema Stevens-Johnson syndrome Erythema multiforme Maculopapular rash Alopecia Urticaria Purpura Pruritus Skin rash Rash Hyperkeratosis Patches Hyperhidrosis Spontaneous bruising Musculoskeletal and connective tissue disorders Muscle weakness Myalgia Arthralgia Muscle spasms Renal and urinary disorders Pollakiuria Reproductive system and breast disorders Erectile dysfunction Gynecomastia Galactorrhea Metrorrhagia General disorders and administration site conditions Fatigue Diagnostic tests Elevation of liver enzymes Elevation of prolactin levels Endocrine pathologies Impaired glucose tolerance

In post-marketing experience, a case of paralysis (tetraparesis) associated with the co-administration of verapamil and colchicine has been reported. This may have been caused by the fact that colchicine crosses the blood-brain barrier due to inhibition of CYP3A4 and of P-gp by verapamil. The combined use of verapamil and colchicine is not recommended. Treatment of acute cardiovascular side effects The frequency of cardiovascular side effects requiring therapy is rare, therefore experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, appropriate emergency measures should be applied immediately, for example intravenous administration of isoproterenol, norepinephrine, atropine (all at the usual doses) or calcium gluconate ( 10% solution). If further support is required, inotropic drugs (dopamine or dobutamine) can be administered. Treatment and dose should depend on the severity and clinical situation as well as the judgment and experience of the physician.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avversei". By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Expiry: see the expiry date printed on the package.

The expiry date indicated refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date shown on the package.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Keep this medicine out of the sight and reach of children.

COMPOSITION

One coated tablet contains: Verapamil hydrochloride 40.0 mg. Excipients: corn starch, potato starch, calcium carbonate, glycolated mountain wax, acacia, lactose monohydrate, magnesium stearate, povidone, sucrose, anhydrous colloidal silica, croscarmellose sodium, talc, titanium dioxide, yellow iron oxide.

PHARMACEUTICAL FORM AND CONTENT

"40 mg coated tablets" 30 tablets

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Isoptin can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other Forms of interaction H20 receptor antagonists 4.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06 .0 PHARMACEUTICAL PARTICULARS06.1 Excipients06.2 Incompatibilities06.3 Shelf life06.4 Special precautions for storage06.5 Nature of the immediate packaging and contents of the package06.6 Instructions for use and handling07.0 HOLDER OF THE "ALL AUTHORIZATION" PLACING ON MARKET 08.0 NUMBER OF AUTHORIZATION FOR PLACING IN THE COMM MERCIO09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

ISOPTIN

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

• Isoptin 40 mg Coated tablets

One coated tablet contains:

Active principle:

Verapamil hydrochloride 40.0 mg.

Excipients with known effects: lactose, sucrose

• Isoptin 80 mg Film-coated tablets

One film-coated tablet contains:

Active principle:

Verapamil hydrochloride 80.0 mg.

• Isoptin 120 mg Prolonged-release tablets

One prolonged-release tablet contains:

Active principle:

Verapamil hydrochloride 120.0 mg

Excipients with known effects: lactose

• Isoptin 180 mg Prolonged-release tablets

One prolonged-release tablet contains:

Active principle:

Verapamil hydrochloride 180.0 mg

• Isoptin 240 mg Prolonged-release tablets

One prolonged-release tablet contains:

Active principle:

Verapamil hydrochloride 240.0 mg

For the full list of excipients see section 6.1

03.0 PHARMACEUTICAL FORM

Coated tablets

Film-coated tablets

Prolonged-release tablets

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

• Isoptin 40 mg Coated tablets and Isoptin 80 mg Film-coated tablets

• Isoptin 120 mg and 180 mg Prolonged-release tablets

Chronic coronary insufficiency. Treatment of sequelae of myocardial infarction. Supraventricular hyperkinetic arrhythmias such as paroxysmal supraventricular tachycardia, atrial fibrillation and flutter with rapid ventricular response, extrasystoles. Arterial hypertension.

Prevention of reinfarction in patients who cannot tolerate beta-blockers and who have no signs of heart failure.

• Isoptin 240 mg Prolonged-release tablets

Treatment of mild or moderate arterial hypertension.

04.2 Posology and method of administration

• Isoptin 40 mg Coated tablets

Adults: 1-2 coated tablets 3 times a day;

lads: 1-3 coated tablets 2-3 times a day.

• Isoptin 80 mg Film-coated tablets

Isoptin 80 mg Film-coated tablets it can be used with a dosage between 40 and 80 mg 3 times a day; the tablets are divisible.

Adults: Isoptin 80 mg Film-coated tablets it is administered at a dose of 1 tablet 3 times a day, preferably during meals.

In relapsing tachyarrhythmias, Isoptin 80 mg to maintain a normal ventricular rate Film-coated tablets it can also be administered at shorter intervals (1 tablet every 3-4 hours);

lads: 1 tablet 2-3 times a day.

• Isoptin 120 mg Prolonged-release tablets

Isoptin 120 mg Prolonged-release tablets simplifies long-term therapy in patients requiring doses of 240 mg / day or more.

In the "coronary insufficiency of medium severity and for the prophylaxis of tachycardia disorders it is generally sufficient to administer 1 tablet in the morning and 1 in the evening (240 mg / day). If necessary this dose can be increased to 2 tablets twice a day (480 mg). /day).

• Isoptin 180 mg Prolonged-release tablets

Isoptin 180 mg Prolonged-release tablets it is particularly suitable for long-term therapy in patients who require a dosage of 360 mg / day or more.

In the "coronary insufficiency of medium severity it is generally sufficient to administer 1 tablet in the morning and 1 in the evening (360 mg / day).

• Isoptin 240 mg Prolonged-release tablets

The dose of Isoptin 240 mg Prolonged-release tablets it must be adapted to the individual patient by titration and the drug must be administered with food. The usual daily dose of Isoptin 240 mg Prolonged-release tablets, in clinical trials it was 240 mg administered orally once daily in the morning. However, starting doses of 120 mg per day may be given to patients who may have a greater response to verapamil (for example: elderly, small, etc.). Dose determination should be based on therapeutic efficacy and undesirable effects which should be evaluated approximately 24 hours after drug administration. The antihypertensive effects of Isoptin 240 mg Prolonged-release tablets are evident within the first week of therapy.

If an adequate response is not achieved with 1 tablet, the dose can be increased as follows:

a) 240 mg (1 tablet) every morning plus 120 mg every evening;

b) 240 mg (1 tablet) every 12 hours.

04.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Cardiogenic shock.

- Acute myocardial infarction complicated by marked bradycardia.

- Contractile insufficiency of the left ventricle.

- Severe conduction disturbances such as total AV block, partial AV block, incomplete branch block, sinus node disease (except those with artificial pacemakers), grade II-III AV block (except in patients with functioning artificial pacemaker).

- Heart failure with reduced ejection fraction less than 35% and / or pulmonary pressure greater than 20 mm Hg (except if derived from supraventricular tachycardia sensitive to verapamil therapy).

- Wide complex ventricular tachycardia.

- Atrial fibrillation / flutter in bypass carriers (i.e. Wolff-Parkinson-White, Lown-Ganong-Levine and short PR syndromes) These patients are at risk of developing ventricular tachyarrhythmia including ventricular fibrillation if verapamil hydrochloride is administered.

- Marked bradycardia (beats / min).

- Hypotension (systolic pressure

- Association with MAO inhibitors and beta-blockers and after quinidine treatments.

- Concomitant intake with ivabradine (see section 4.5).

04.4 Special warnings and appropriate precautions for use

• Heart failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload-reducing properties (decreased peripheral resistance) with no marked alteration of ventricular function.

Patients with heart failure with an ejection fraction greater than 35% should be compensated before starting verapamil treatment and should be adequately treated during treatment.

• Hypotension

Sometimes the pharmacological action of verapamil can produce a decrease in blood pressure below normal levels, which can lead to symptomatic lightheadedness or hypotension.

In hypertensive patients, a decrease in blood pressure below normal is unusual.

• HMG-CoA Reductase Inhibitors (Statins)

See section 4.5.

• Increase in liver enzymes

Elevations in transaminases have been reported with and without concomitant increases in alkaline phosphatase and bilirubin. These elevations were sometimes transient and may disappear even with continued verapamil treatment. Some cases of hepatocellular damage have been related to verapamil using the "rechallenge" technique; half of these cases had clinical symptoms (malaise, fever and / or right upper quadrant pain) in addition to increased SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function is therefore advisable in patients treated with verapamil.

• Accessory conduction route (Wolff-Parkinson-White or Lown-Ganong-Levine)

Patients with paroxysmal and / or chronic atrial flutter or atrial fibrillation with a coexisting accessory AV pathway have developed an increase in antegrade conduction through the accessory pathway that bypasses the AV node resulting in a very rapid ventricular response or ventricular fibrillation after receiving verapamil or digitalis for intravenously. Although this phenomenon has not been reported with oral verapamil, it should be considered a potential risk. Treatment usually consists of direct current cardioversion. Cardioversion has been used safely and effectively following the administration of Isoptin.

• Cardiac arrest / Atrioventricular block / Bradycardia / Asystole

Verapamil hydrochloride acts on the AV and SA nodes and prolongs the AV conduction time.

Use with caution as the development of second or third degree AV block (contraindications) or unifascicular, bifascicular or trifascicular branch block requires discontinuation of subsequent doses of verapamil hydrochloride and instituting appropriate therapy if necessary.

Verapamil hydrochloride acts on the AV and SA nodes and can rarely cause second or third degree AV block, bradycardia and, in rare cases, asystole. This is much more likely to occur in patients with sinus node disease (a disease of the SA node), which mainly affects older people.

The asystole that can occur in patients who have taken verapamil, except those who have sick sinus node disease, is usually short-lived (a few seconds or less), with spontaneous restoration of normal sinus rhythm or AV node If this is not achieved quickly, appropriate treatment should be given immediately, see section 4.8.

• Antiarrhythmics, Beta-blockers

Mutual enhancement of cardiovascular effects (higher degree AV block, higher degree lowering of heart rate, induction of heart failure and enhanced hypotension).

Asymptomatic bradycardia (36 beats per minute) was observed in subjects taking timolol eye drops (beta-adrenergic blocker) combined with oral verapamil, asymptomatic bradycardia (36 beats per minute) was observed with "Wandering atrialpacemaker'.

• Digoxin

If verapamil is administered concomitantly with digoxin, reduce the digoxin dosage. See section 4.5.

• Disorders of neuromuscular transmission

Use with caution in patients with disorders in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).

Special populations:

Hepatic insufficiency

Since verapamil is predominantly metabolised by the liver, it should be administered with caution to patients with impaired hepatic function. Severe hepatic dysfunction prolongs the elimination half-life of verapamil to approximately 14-16 hours; therefore, these patients should be given approximately 30% of the usual dose used in patients with normal liver function. Careful monitoring should be undertaken for abnormal Prolongation of the PR interval or other signs of excessive pharmacological effects.

Insufficiency renal

Approximately 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data become available, verapamil should be administered with caution to patients with impaired renal function. These patients should be followed closely to ascertain a possible prolongation of the PR interval or other signs of overdose.

Although consistent clinical data from comparative studies conducted in patients with end stage renal failure have shown that decreased renal function has no effect on the pharmacokinetics of verapamil, case reports suggest that verapamil should be used with caution and under close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis.

Pediatric use

The safety and efficacy of Isoptin 240 mg have not been established Prolonged-release tablets in individuals under the age of 18.

Isoptin 40 mg Coated tablets And Isoptin 120 mg Prolonged-release tablets contain lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Isoptin 40 mg Coated tablets contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, sucrase isomaltase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

On rare occasions, including those in which patients with severe cardiomyopathies, congestive heart failure or recent myocardial infarction have been treated with intravenous administration of beta-adrenergic blockers or disopyramide in combination with intravenous verapamil hydrochloride.

Concomitant use of injectable verapamil hydrochloride with agents that depress adrenergic function may result in an excessive hypotensive response.

Education in vitro demonstrated that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Furthermore, verapamil has been shown to be an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Patients undergoing concomitant therapies during verapamil administration should be monitored closely as clinically significant interactions have been demonstrated with CYP3A4 inhibitors (leading to elevated plasma levels of verapamil) and with CYP3A4 inducers (which instead they cause a lowering).

The table below provides a list of drugs with which interactions may occur for pharmacokinetic reasons:

Potential interactions associated with the CYP-450 enzyme system Associated drug Potential effect on verapamil or associated drug Comment Alpha blockers Prazosin Increased Cmax of prazosin (≈40%) with no effect on half-life Potentiation of the hypotensive effect. Terazosin Increased AUC (≈24%) and Cmax (≈25%) of terazosin Antiarrhythmics Flecainide Minimal effect on plasma clearance of flecainide ( See also section 4.4. Quinidine Decreased oral clearance of quinidine (≥35%) Hypotension. Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy. Anti-asthmatics Theophylline Decrease in oral and systemic clearance by 20% The reduction in clearance is more diminished in smokers (≈11%). Anticoagulants Dabigatran etexilate Increased dabigatran Cmax by approximately 180% and AUC by approximately 150% Observed with the first dose of an immediate-release oral formulation of verapamil. Increased dabigatran Cmax by approximately 90% and AUC by approximately 70% Observed with administration of an oral extended-release formulation of verapamil. Anticonvulsants / Antiepileptics Carbamazepine Increased AUC of carbamazepine (≥46%) in patients with partially refractory epilepsy Increased levels of carbamazepine. This can produce carbamazepine dependent side effects such as diplopia, headache, ataxia or dizziness. Phenytoin Decreased plasma concentrations of verapamil Antidepressants Imipramine Increased AUC of imipramine (≈15%) It has no effect on the level of the active metabolite desipramine. Antidiabetics Glyburide Increased Cmax (≈28%) and AUC (≈26%) of glyburide Anti-gout Colchicine Increase in AUC (≈2.0-fold) and Cmax (≈1.3-fold) Reduce your colchicine dose (see information on colchicine). Antiinfectives Clarithromycin Possible increase in verapamil levels Erythromycin Possible increase in verapamil levels Rifampicin Decreased AUC (≈94%), Cmax (≈97%) and oral bioavailability (≈92%) of verapamil May reduce the hypotensive effect of verapamil. No change in pharmacokinetics with intravenous administration of verapamil Telithromycin Possible increase in verapamil levels Antineoplastics Doxorubicin Doxorubicin AUC (104%) and Cmax (61%) increase following oral administration of verapamil In patients with small cell lung cancer. No significant change in doxorubicin pharmacokinetics following intravenous administration of verapamil In patients with advanced malignancies. Barbiturates Phenobarbital Increased clearance (≥5 fold) of orally administered verapamil Benzodiazepines and other anxiolytics Buspirone 3.4-fold increase in AUC and Cmax of buspirone Midazolam Increased AUC (≈3-fold) and Cmax (≈2-fold) of midazolam Beta blockers Metoprolol Increase in AUC (≈32.5%) and Cmax (≈41%) of metoprolol in patients with angina See section 4.4. Propranolol Increased AUC (≈65%) and Cmax (≈94%) of propranolol in patients with angina Cardiac glycosides Digitoxin Decreased total body clearance (≈27%) and extrarenal clearance (≈29%) of digitoxin Digoxin Healthy patients: increased Cmax (≈44%), increased C12h (≈53%), increased Css (44%) and increased AUC (50%) of digoxin Reduce digoxin dosage. See section 4.4.

H2 receptor antagonists

Cimetidine Increased AUC R- (≈25%) and S- (≈40%) of verapamil with corresponding decrease in clearance of verapamil R- and S- Cimetidine reduces the clearance of verapamil following intravenous administration of verapamil. Immunological / immunosuppressants Ciclosporine Increased AUC, Css, Cmax of cyclosporins by approximately 45% Everolimus Everolimus: increased AUC (≈3.5-fold) and increased Cmax (≈2.3-fold); verapamil: increased Ctrough (≈2.3-fold) Concentration determinations and dose adjustment of everolimus may be required. Sirolimus Sirolimus: AUC increased (≈2.2-fold); S-verapamil: AUC increased (≈1.5-fold) Concentration determinations and dose adjustments of sirolimus may be required. Tacrolimus Possible increase in tacrolimus levels Lipid-lowering agents (HMG-CoA reductase inhibitors or statins) Atorvastatin Possible increase in atorvastatin levels, increase in verapamil AUC by 43% Additional information follows. Lovastatin Possible increase in lovastatin levels, increase in AUC (≈63%) and Cmax (≈32%) of verapamil Simvastatin Increased AUC (2.6-fold) and Cmax (≈4.6-fold) of simvastatin Serotonin receptor agonists Almotriptan Increased AUC (20%) and Cmax (≈24%) of almotriptan Uricosuric agents Sulfinpyrazone Increased clearance (≈3 fold) and decrease in bioavailability (≈60%) of verapamil after oral administration May reduce the hypotensive effect of verapamil. No change in pharmacokinetics with intravenous administration of verapamil Others Grapefruit juice Increased AUC of verapamil R- (≈49%) and S- (≈37%), increased Cmax of verapamil R- (≈75%) and S- (≈51%) Avoid the simultaneous intake of verapamil and grapefruit juice. St. John's wort (Hypericum) Decreased AUC of verapamil R- (≈78%) and S- (≈80%) with corresponding decrease in Cmax

Other interactions and additional information

• Anti-HIV agents: The plasma concentration of verapamil may increase due to the potential metabolic inhibition of some of the anti-HIV agents such as ritonavir. Therefore, great caution should be exercised in combining or the dose of verapamil should be decreased.

• Neuromuscular blocking agents: Clinical data and animal studies suggest that verapamil may potentiate the action of neuromuscular blocking agents (curare-like and depolarizing). For this reason it may be necessary to decrease the dose of verapamil and / or that of the neuromuscular blocker when two drugs are taken in combination.

• Acetylsalicylic acid: increased bleeding tendency.

• Ethanol (alcohol): increase in plasma levels of ethanol.

• HMG-CoA reductase inhibitors (statins): Treatment with HMG-CoA reductase inhibitors (ie simvastatin, atorvastatin or lovastatin) in patients taking verapamil, should be started at the lowest possible doses which subsequently need to be corrected. . If patients taking HMG-CoA reductase inhibitors (such as simvastatin, atorvastatin, or lovastatin) are prescribed verapamil therapy, a statin dose reduction should be considered and serum cholesterol readings re-examined.

Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.

• Digitalis: The clinical use of verapamil in digitalised patients has shown that the combination is well tolerated if digoxin doses are adequately regulated. Chronic treatment with verapamil can increase serum digoxin levels by 50-75% during the first week of therapy, which can lead to digitalis toxicity. Maintenance doses of digitalis should be reduced when verapamil is administered and the patient should be carefully monitored to avoid hyper or hypodigitalization. Whenever hyperdigitalization is suspected, the dose of digoxin should be temporarily reduced or discontinued. After discontinuation of Isoptin the patient should be re-examined to avoid hypodigitalization.

• Antihypertensive drugs, diuretics and vasodilators: verapamil administered concomitantly with other oral antihypertensive drugs (for example: vasodilators, angiotensin I converting enzyme inhibitors, diuretics, beta blockers) usually has an additive effect on "lowering of blood pressure. In one study, the simultaneous administration of verapamil and prazosin resulted in an" excessive drop in blood pressure.

• Disopyramide: Until data on possible interactions between verapamil and disopyramide have been obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

• Nitrates: verapamil has been administered concomitantly with short- and long-acting nitrates, without any undesirable drug interactions.

• Cimetidine: Cimetidine reduces the clearance of verapamil and increases its elimination half-life.

• Lithium: "increased sensitivity to the effects of lithium (neurotoxicity) during combination therapy with verapamil" has been demonstrated, without however changing or increasing serum lithium levels. Oral therapy with verapamil may cause lowering of serum lithium levels in patients receiving oral, stable and chronic lithium therapy. Individuals undergoing associated therapy should be closely monitored.

• Dabigatran: careful clinical monitoring (looking for signs of bleeding or anemia) is required when verapamil is co-administered with dabigatran etexilate (substrate of the efflux transporter P-gp) and with extra care in the case of patients with renal impairment from When oral verapamil was co-administered with dabigatran etexilate increased plasma levels of dabigatran (Cmax el "AUC) were observed but the magnitude of this change varied as a function of time of administration and formulation of verapamil. In patients with moderate renal impairment treated with verapamil and dabigatran etexilate concurrently, a dose reduction of dabigatran should be considered. Conversely, no significant interaction was observed when verapamil was administered 2 hours after taking dabigatran etexilate. This is explained by the complete absorption of dabigatran after 2 hours.

• Dronedarone: Caution should be exercised when verapamil is given in combination with dronedarone. Administer verapamil initially in low doses and increase the dose only after evaluation by ECG.

• Ivabradine: verapamil causes an increase in ivabradine concentration (2-3 fold increase in AUC) and an additional 5 bpm decrease in heart rate. Concomitant use of verapamil with ivabradine is contraindicated (see section 4.3).

• Aliskiren: Concomitant administration of verapamil and aliskiren resulted in a 97% increase in the AUC of aliskiren as an effect of the P-gp inhibitory activity of verapamil.

• Dantrolene: In animal studies, fatal cases of ventricular fibrillation have been observed during intravenous administration of verapamil and dantrolene. The combination of verapamil and dantrolene is therefore potentially dangerous.

04.6 Pregnancy and lactation

Pregnancy

There are no adequate and well-controlled data in pregnant women. Verapamil crosses the placental barrier and was found in the umbilical cord.

Since animal reproduction studies are not always able to predict human response, verapamil should only be used during pregnancy if strictly necessary (see section 5.3).

Feeding time

Verapamil hydrochloride and its metabolites are excreted in breast milk. Limited data regarding oral administration have shown that the dose of verapamil which is ingested through milk by the infant is low (0.1-1% of the oral dose taken by the mother). However, a risk to the newborns / infants cannot be excluded. Due to the severity of the potential undesirable effects in the infant, verapamil should only be administered to the breastfeeding woman if it is considered essential for the well-being of the mother.

04.7 Effects on ability to drive and use machines

Due to the individual response-dependent antihypertensive effect, verapamil may affect the ability to react to the extent of impairing the ability to drive, use machinery or work in hazardous conditions. This mostly occurs at the onset of treatment. therapy, when the dose is increased, when changing treatment by switching from a different drug to verapamil and drinking alcohol concomitantly. Verapamil can increase blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol can be enhanced.

04.8 Undesirable effects

The adverse reactions listed below refer to administrations of verapamil in clinical studies, post-marketing surveillance or Phase IV clinical trials and are listed below by system organ class. Frequencies are defined as: very common (≥1 / 10); common (≥1 / 100 to

The most commonly reported adverse reactions were headache, dizziness, gastrointestinal disturbances: nausea, constipation and abdominal pain as well as bradycardia, tachycardia, palpitations, hypotension, flushing, peripheral edema and fatigue.

Table: Adverse reactions reported with administration of verapamil in clinical studies and in post-marketing surveillance activities

Organic system classification common Uncommon Rare Not known Disorders of the immune system Hypersensitivity Nervous system disorders Dizziness, headache Paresthesia, tremor Extrapyramidal disorders, paralysis (tetraparesis) 1, convulsions Metabolism and nutrition disorders Hyperkalemia Psychiatric disorders Drowsiness Ear and labyrinth disorders Tinnitus Vertigo Cardiac pathologies Bradycardia Palpitations, tachycardia Atrioventricular block (1st, 2nd, 3rd), heart failure, sinus arrest, sinus bradycardia, asystole Vascular pathologies Flushing, Hypotension Respiratory, thoracic and mediastinal disorders Bronchospasm, dyspnoea Gastrointestinal disorders Constipation, nausea Abdominal pain He retched Abdominal discomfort, gingival hyperplasia, ileus Skin and subcutaneous tissue disorders Hyperhidrosis Angioedema, Stevens-Johnson syndrome, erythema multiforme, alopecia, skin rash, pruritus, purpura, maculopapular rash, urticaria Musculoskeletal and connective tissue disorders Arthralgia, muscle weakness, myalgia Renal and urinary disorders Kidney failure Reproductive system and breast disorders Erectile dysfunction, galactorrhea, gynecomastia General disorders and administration site conditions Peripheral edema Fatigue Diagnostic tests Elevation of prolactin levels, elevation of liver enzymes Endocrine pathologies Impaired glucose tolerance

1 In post-marketing experience a case of paralysis (tetraparesis) associated with the co-administration of verapamil and colchicine has been reported. This may have been caused by the fact that colchicine crosses the blood-brain barrier due to inhibition of CYP3A4. and of P-gp by verapamil. The combined use of verapamil and colchicine is not recommended. See section 4.5 "Interactions with other medicinal products and other forms of interaction".

Treatment of acute cardiovascular side effects

The frequency of cardiovascular side effects requiring therapy is rare; therefore experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs after oral administration of verapamil, appropriate emergency measures should be applied immediately, eg intravenous administration of isoproterenol, norepinephrine, atropine (all at the usual doses) or calcium gluconate (10% solution). If additional support is needed, inotropic drugs (dopamine or dobutamine) can be given. Treatment and dose should depend on the severity and clinical situation as well as the physician's judgment and experience.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse

04.9 Overdose

Symptoms

Hypotension, bradycardia up to high grade AV block and sinus arrest, hyperglycemia, apathy and metabolic acidosis. Deaths have occurred as a result of overdose.

Treatment

Treatment of overdose should be supportive and individualized. Beta-adrenergic stimulation and / or parenteral administration of calcium (calcium chloride) solutions and intestinal irrigation can increase the flow of calcium ions through slow channels and these methods have been used successfully in the treatment of voluntary overdose with verapamil.

Clinically significant hypotensive reactions or high-grade AV block should be treated with vasopressors or "pacingCardiac. Asystole should be treated with usual measures, including the use of beta-adrenergic stimulation (ie isoproterenol hydrochloride), other vasopressor agents, or cardiopulmonary resuscitation. Due to delayed absorption of modified release products, some patients may require further observation and hospitalization for longer than 48 hours.

Verapamil cannot be removed by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effect - Phenylalkylamine derivatives.

ATC code: C08DA01

Mechanism of action and pharmacodynamic effects

Verapamil is an inhibitor of the transmembrane fluxes of the calcium ion, equactive on the vascular smooth muscle and on the myocardial fibrocell in reducing tone and contractility; it is also endowed with antiarrhythmic properties.

Verapamil exerts its antianginal action:

1. Through the decrease of myocardial oxygen requirement, secondary to the inhibition of calcium flow through the membrane with consequent reduction of cardiac energy metabolism and to the reduction of peripheral resistance with consequent reduction of cardiac pressure work.

2. By increasing the coronary flow resulting from the dilation of the coronary vessels and the powerful preventive action against coronary spasm.

The antihypertensive action of verapamil is due to the decrease in peripheral resistance not accompanied by a reflex increase in heart rate, heart volume / minute and salt and water retention. Normal blood pressures are not appreciably affected.

Verapamil exerts its antiarrhythmic action on "physiological" slow fibers such as those of the atrioventricular node of which it reduces the conduction speed and increases the refractory periods, and on "pathological" slow fibers, that is to say on the normally rapid, sodium-dependent fibers (myocardium of work, His-Purkinje system) which, in particular situations (such as ischemia), become slow, calcium-dependent and can give rise to focal or reentry hyperkinetic arrhythmias. During the therapy with Isoptin, the sympathetic regulation capacity of the heart remains unchanged and therefore no decreases in systolic output or in the volume / minute of the heart are observed in patients in cardiocirculatory compensation.

Verapamil has strong antiarrhythmic effects, in particular in the case of supraventricular arrhythmia; in fact, it slows down conduction at the level of the atrioventricular node. The consequence, depending on the type of disturbance, is the restoration of the sinus rhythm and / or the regularization of the ventricular rate. Normal heart rhythm remains unchanged or slightly decreased.

In Isoptin 120 mg and 180 mg Prolonged-release tabletsthanks to their galenic formulation, the release of the active principle is prolonged over time.

The onset of action is delayed: the maximum intensity, with different plasma levels, is reached after 4-6 hours and persists until the 12th hour after administration of the drug.

05.2 Pharmacokinetic properties

Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R enantiomer and S enatiomer. Verapamil is extensively metabolised. Norverapamil is one of 12 metabolites identified in urine, has a pharmacological activity ranging from 10% to 20% of that of verapamil, and accounts for 6% of the drug excreted. The steady-state plasma concentrations of norverapamil and verapamil are similar. Steady state after multiple once daily dosing is reached after 3-4 days.

Absorption

Approximately 92% of verapamil is rapidly absorbed from the small intestine following oral administration. The mean systemic availability of the parent compound after a single dose of immediate-release verapamil is 23% and that of prolonged-release verapamil is approximately 32% due to extensive hepatic first pass metabolism. Bioavailability is approximately 2 times higher with repeated administration. Peak plasma levels of verapamil are reached 1 to 2 hours after immediate release administration. The peak plasma concentration of norverapamil is reached approximately 1 to 5 hours after immediate-release or prolonged-release administration, respectively. The presence of food has no effect on the bioavailability of verapamil.

Distribution

Verapamil is widely distributed in all body tissues, the volume of distribution ranges from 1.8 to 6.8 L / kg in healthy subjects.

Plasma protein binding is approximately 90%.

Biotransformation

Verapamil is extensively metabolised. Metabolic studies in vitro indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride is extensively metabolised in the liver, resulting in the formation of 12 identified metabolites, many of which are present only in trace amounts. The major metabolites have been identified as various N- and O-dealkylated verapamil products. Of these metabolites, only norverapamil has an appreciable pharmacological effect (approximately 20% of that of the parent compound), which was observed in a study with dogs.

Elimination

Following intravenous infusion, verapamil is eliminated bi-exponentially, with a first phase of rapid distribution (half-life of approximately 4 minutes) and a final, slower elimination phase (half-life of 2 to 5 hours).

Approximately 50% of the dose is eliminated within 24 hours and 70% within 5 days. Up to 16% of the dose is excreted in the faeces.

3-4% of the drug was found unchanged in the urine after 48 hours.

Total clearance of verapamil is nearly equal to hepatic blood flow, approximately 1 L / h / kg (range: 0.7-1.3 L / h / kg).

Pediatric population

There is limited information on pharmacokinetics in the pediatric population.

After intravenous administration, the mean half-life of verapamil was 9.17 hours and the mean clearance was 30 L / h, while for a 70 kg adult it is approximately 70 L / h.

Steady-state plasma concentrations appear to be somewhat lower in the pediatric population after oral administration than in adults.

Senior citizens

Age may affect the pharmacokinetics of verapamil given to hypertensive patients. The elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found to be unrelated to age.

Kidney failure

Impaired renal function has no effect on verapamil pharmacokinetics, as demonstrated in comparative studies conducted in patients with end stage renal failure and healthy subjects (see section 4.4).

Verapamil and norverapamil are not significantly eliminated by hemodialysis.

Hepatic insufficiency

The half-life of verapamil is prolonged in patients with hepatic impairment due to low oral clearance and increased volume of distribution.

05.3 Preclinical safety data

Acute toxicity: toxicological tests have shown that in the most common laboratory animals (rat, Mus musculus) verapamil is well tolerated (LD50 rat i.p. 52.47 mg / kg; Mus musculus bit. 229.60 mg / kg, with no substantial differences between the two sexes).

Repeated dose toxicity: verapamil administered daily orally, in rats and dogs, for 180 consecutive days, did not cause any death, nor any signs of local or systemic toxicity. Verapamil does not cause harmful effects on pregnant animals, nor does it negatively affect gestation, embryo-fetal development and the reproductive cycle.

Reproduction studies were performed in rabbits and rats at an oral dose of verapamil greater than 1.5 times (15 mg / kg / day) and 6 times (60 mg / kg / day) higher than the daily oral dose taken. by humans, and showed no evidence of teratogenicity. In rats, however, the multiple dose administered was found to be embryocidal and retard the growth and development of the fetus, probably due to adverse effects on the mothers which are reflected in a reduced ability to gain weight. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled data in pregnant women.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

• Isoptin 40 mg Coated tablets

Corn starch, potato starch, calcium carbonate, glycolated mountain wax, acacia, lactose monohydrate, magnesium stearate, povidone, sucrose, colloidal anhydrous silica, croscarmellose sodium, talc, titanium dioxide, yellow iron oxide.

• Isoptin 80 mg Film-coated tablets

Dibasic calcium phosphate dihydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, macrogol 6000, magnesium stearate, anhydrous colloidal silica, sodium lauryl sulfate, talc, titanium dioxide.

• Isoptin 120 mg Prolonged-release tablets

Microcrystalline cellulose, lactose monohydrate, magnesium stearate, opadry OY-S-8754G orange (hypromellose, talc, titanium dioxide, E110, macrogol 8000), povidone K 30, silicone antifoam emulsion (polydimethylsiloxane, polyglycolstearyl ether), sodium alginate.

• Isoptin 180 mg Prolonged-release tablets

Microcrystalline cellulose, E 172 dye, montanic acid and ethanediol esters, hypromellose, magnesium stearate, macrogol 400, macrogol 6000, povidone, sodium alginate, talc, titanium dioxide.

• Isoptin 240 mg Prolonged-release tablets

Microcrystalline cellulose, magnesium stearate, hypromellose, talc, titanium dioxide E171, macrogol 400, macrogol 6000, povidone, sodium alginate, glycolated mountain wax, quinoline yellow and indigo carmine, aluminum lake E104 + E132 (Green Lake E104 / E132).

06.2 Incompatibility

Not relevant.

06.3 Period of validity

Isoptin 80 mg Film-coated tablets: 3 years.

Isoptin 40 mg Coated tablets: 2 years.

Isoptin 120 mg Extended-release tablets: 3 years.

Isoptin 180 mg Prolonged-release tablets: 3 years.

Isoptin 240 mg Extended-release tablets: 3 years.

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

Isoptin 120 mg Prolonged-release tablets, Isoptin 240 mg Prolonged-release tablets, Isoptin 180 mg Prolonged-release tablets: store at a temperature not exceeding 25 ° C.