Updated SmPC format only.

Section 4.2 Posology and method of administration

·         The following information has been added: 

The dose of verapamil hydrochloride should be adjusted individually in accordance with the severity of disease. Long-standing clinical experience shows that the average daily dose in all indications is between 240 mg and 360 mg. The daily dose should not exceed 480 mg on a long-term basis, although a higher dose may be used for a short period. There is no limitation on the duration of use. Verapamil hydrochloride should not be discontinued abruptly after long-term use. It is recommended to taper the dosage.

Veramil Tablets should be used for patients likely to display a satisfactory response to low doses (e.g. patients with hepatic dysfunction of elderly patients). For patients requiring higher doses (e.g., 240 mg to 480 mg verapamil hydrochloride per day), formulations with a more suitable active drug content should be used.

Special Populations

Renal Impairment

Currently available data are described in Special Warnings and Precautions for Use section. Verapamil hydrochloride should be used cautiously and with close monitoring in patients with impaired renal function.

Liver Impairment

In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special cautions in patients with impaired liver function and low doses should be given initially (see Special Warnings and Precautions for Use section).

Section 4.3 Contraindications

·         The following information expands on and is in addition:

Atrial flutter or atrial fibrillation in the presence of an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil hydrochloride is administered.

Heart failure with reduced ejection fraction of less than 35%, and/or pulmonary wedge pressure above 20 mm Hg (unless secondary to a supraventricular tachycardia amenable to verapamil therapy).

Section 4.4 Special warnings and precautions for use

·         The following information has been added:

Acute Myocardial Infarction
Use with caution in acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.

Heart Block/1st Degree AV block/Bradycardia/Asystole
Verapamil hydrochloride affects the AV and SA nodes and prolongs AV conduction time. Use with caution as development of second-or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation reduction in subsequent doses or discontinuation of verapamil hydrochloride and institution of appropriate therapy, if needed.

Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second-or third-degree AV block bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients.

Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. See Undesirable Effects Section.

Digoxin
If verapamil is administered concomitantly with digoxin, reduce digoxin dosage. See Interactions with other medicinal drug products and other forms of interaction section.

Heart Failure
Heart failure patients with ejection fraction higher than 35% should be compensated before starting verapamil treatment and should be adequately treated throughout.

Hypotension
Intravenous verapamil hydrochloride often products a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness.

HMG-CoA Reductase Inhibitors (“Statins”) – See 4.5 Interaction with other medicinal products and other forms of interaction section

Section 4.5 Interaction with other medicinal products and other forms of interaction

·         The following information has been added:

In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil hydrochloride, serious adverse effects have occurred.

Concomitant use of verapamil hydrochloride injection with agents that decrease adrenergic function may result in an exaggerated hypotensive response.

·         Potential Drug Interactions associated with Verapamil, the following information has been added:

Phenytoin:       verapamil plasma concentrations
Colchicine:      ↑ colchicine AUC (~2.0fold) and Cmax (~1.3fold), Reduce colchicine dose (see colchicine label)
Doxorubicin:    ↑ doxorubicin AUC (104%) and Cmax (61%) with oral verapamil administration           
Digoxin:           Healthy subjects: ↑ digoxin Cmax (~44%), ↑ digoxin C12h (~53%),  ↑ Css by ~45-53%42% and ↑ AUC (50%)
Cimetidine:     Cimetidine reduces verapamil clearance following intravenous verapamil administration
Everolimus:     everolimus: ↑ AUC (~3.5fold) and ↑ Cmax (2.3fold), verapamil: ↑ Ctrough (~2.3fold), Concentration determinations and dose adjustments of everolimus may be necessary.
Sirolimus:        sirolimus levels: ↑ AUC (~2.2fold), S-verapamil: ↑ AUC (~1.5fold), Concentration determinations and dose adjustments of sirolimus may be necessary.
Sulfinpyrazone:           No change in PK with intravenous verapamil administration

·         Other additional information:

Lithium:
Increased lithium neurotoxicity has been reported during concomitant verapamil hydrochloride-lithium therapy with either no change or an increase in serum lithium levels. The addition of verapamil hydrochloride, however, has also resulted in the lowering of the serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs should be monitored carefully.

Neuromuscular blockers
Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the effectactivity of neuromuscular blocking agents may be potentiated(curare-like and depolarizing). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Section 4.6 Fertility, pregnancy and lactation

·         The information has been expanded:

Pregnancy
Teratogenic Effects
There are no adequate and well-controlled study data in pregnant woman.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Because animal reproduction studies are not always predictive of human response during pregnancy (especially in the first trimester), Veramil Tabletsverapamil should only be used if considered essential by the physician.

Lactation
Verapamil is crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Verapamil hydrochloride/metabolites are excreted in human breast milk. Verapamil concentrations in human milk

Limited data from oral administration has shown that the infant relative dose of verapamil is low (0.1-1% of the mothers oral dose) and that verapamil use may be variable but similar concentrations to those found in maternal plasma have been reportedcompatible with breastfeeding.

A risk to the newborns/infants cannot be excluded. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.

4.7 Effects on ability to drive and use machines

·         This section has been reworded and expanded:

Due to its antihypertensive effect, depending on individual response, verapamil hydrochloride may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug, and also in conjunction with alcohol.  Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Undesirable effects

·         This section has the following information added:

The most commonly reported ADRs were:

headache,

dizziness,

gastrointestinal disorders: nausea, constipation and abdominal pain,

bradycardia,

tachycardia,

palpitations,

hypotension,

flushing,

oedema peripheral,

fatigue.

Of unknown frequency:  paralysis (tetraparesis)¹, Seizures, asystole, Muscular weakness, Myalgia, Arthralgia, Erectile dysfunction, Gynaecomastia, Galactorrhoea,

Rare:    Somnolence

¹ There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-gp inhibitions by verapamil. See Interactions with other medicinal products and other forms of interaction section.

4.9  Overdose

·         The following information has been added:

Asystole should be handled by the usual measures including beta adrenergic stimulation (e.g. isoproterenol hydrochloride).

5.1 Pharmacodynamic properties

The following information has been added or updated:

Pharmacotherapeutic group: PhenylalkylamineSelective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.

Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odourless and has a bitter taste. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether.

The chemical name of verapamil hydrochloride is benzeneacetonitrile, α-[3-[{2-(3, 4dimethoxyphenyl) ethyl} methylaminol] propyl]-3. 4-dimethoxy-α-(1-methylethyl) hydrochloride.

It has a molecular weight of 491.07 and the molecular formula is C27H38N204•HCl.

5.2 Pharmacokinetic properties

·         The following information has been added:

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

Absorption

Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral administration.  Mean systemic availability of the unchanged compound after a single dose of IR verapamil is 22% and that of SR verapamil approximately 33%, owing to an extensive hepatic first-pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasms levels are reached one to two hours after IR administration, and four to five hours after SR administration. The peak plasma concentration of norverapamil is attained approximately one and five hours after IR or SR administration, respectively. The presence of food has no effect on the bioavailability of verapamil.

Distribution

Verapamil is metabolised almost completely. The mainwidely distributed throughout the body tissues, the volume of distribution ranging from 1.8-6.8 L/kg in healthy subjects. Plasma protein binding verapamil is approximately 90%.

Metabolism

Verapamil is extensively metabolized. In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites are having been identified, most in only trace amounts. The major metabolites have been identified as various N and O-dealkylated products of verapamil. Of these metabolites, only norverapamil and the primary and secondary amines. In animal studies, only norverapamil showedhas any appreciable pharmacological activity, while the other metabolites were practically ineffective.effect (approximately 20% that of the parent compound), which was observed in a study with dogs

Elimination

Following intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours). Following oral administration, the elimination half-life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Special Populations

Paediatric:

Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing the mean half-life of verapamil was 9.17 hours and the mean clearance was 30L/h, whereas it is around 70 L/h for a 70kg adult. Steady-state plasma concentrations appear to be somewhat lower in the paediatric population after oral dosing compared to those observed in adults.

Geriatric: Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypersensitive effect of verapamil was found not to be age-related.

Renal insufficiency: Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by haemodialysis.

Hepatic insufficiency: The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.

Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolized.

5.3 Preclinical safety data

·         The following  information has been added:

Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well-controlled studies in pregnant women.

• Patients with heart failure or those who are susceptible to heart failure should be fully digitalised before verapamil therapy as it may aggravate or precipitate cardiac failure.
• In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending
  on the severity of the liver disease, due to diminished drug metabolism. In these patients, dosage interval
  should be prolonged and low doses used.
• Respiratory standstill has been reported for one patient with progressive muscular dystrophy following
  administration of Veramil Tablets.
• Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome,
  advanced Duchenne muscular dystrophy).
• Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
• If acute cardiovascular side effects arise, treat as for overdose

Section 4.5 - the drug interactions table has been updated
Section 4.6 - During pregnancy (especially in the first trimester), Veramil Tablets should only be used if considered essential by the physician.
Section 4.7 - Warnings on ability to drive and use machines updated
Section 4.8 - Undesirable effects table updated
Section 4.9 - Overdose section updated
Section 5 - Pharmacological properties updated