Lerblok 10 & 20 mg FC tablets

LERBLOK is indicated for the treatment of mild to moderate hypertension.

Posology
The recommended starting dose is 10 mg orally once a day at least 15 minutes before a meal. In patients not responding adequately, the dose may be increased to 20 mg depending on the individual patientu2019s response. Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive effect is apparent.

Special populations
Use in the elderly
Although pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage is required, special care should be exercised when initiating treatment in the elderly.
Use in renal or hepatic dysfunction
Special care should be exercised when treatment is commenced in patients with renal or hepatic dysfunction. Although the recommended dosage schedule may be tolerated by these subgroups, an increase in dosage to 20 mg daily must be approached with caution.
LERBLOK is not recommended for use in patients with severe hepatic dysfunction or in patients with severe renal dysfunction (creatinine clearance < 10 mL/min); see sections 4.3 and 4.4.
Paediatric population
Since there is no clinical experience in patients under the age of 18 years, use in children is not recommended.
Method of administration
LERBLOK should be taken orally, at least 15 minutes before a meal. The score line is only to facilitate breaking if required for ease of swallowing, and not to divide the tablet into equal doses.

• Hypersensitivity to lercanidipine, dihydropyridine or any other ingredient of LERBLOK (see section 6.1).
• Patients with left ventricular outflow tract obstruction, untreated congestive cardiac failure, unstable angina pectoris or within 1 month of a myocardial infarction.
• Severe renal or hepatic dysfunction.
• LERBLOK should not be taken with grapefruit juice (see section 4.5)
• Co-administration with:
• inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin and fluoxetine - see section 4.5)
• ciclosporin (see section 4.5)
• Pregnancy and lactation (see section 4.6).
• Women of child-bearing potential unless effective contraception is used.
• Since there is no clinical experience in patients under the age of 18 years, use in children is not recommended.

Sick sinus syndrome
Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a pacemaker is not in situ) and in patients with left ventricular (LV) outflow tract obstruction.
Left ventricular dysfunction
Although hemodynamic controlled studies revealed no impairment of ventricular function, care is also required in patients with left ventricular dysfunction.
Ischaemic heart disease
It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischaemic heart disease. Although lercanidipine is long-acting, caution is required in such patients. Some dihydropyridines may lead to precordial pain or angina pectoris. Patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed (see section 4.8).

Use in renal or hepatic impairment
Special care should be taken when treatment is started in patients with mild to moderate renal impairment. Although the usual recommended dose of 10 mg daily may be tolerated, an increase to 20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients with moderate hepatic impairment and consequently an adjustment of the dosage should be considered. LERBLOK is contraindicated in patients with severe hepatic impairment or renal impairment (GFR < 30 mL/min), including patients undergoing haemodialysis (see section 4.3).

Peritoneal dialysis
Lercanidipine, contained in LERBLOK, has been associated with the development of cloudy peritoneal effluent in patients on peritoneal dialysis. The turbidity is due to an increased triglyceride concentration in the peritoneal effluent. While the mechanism is unknown, the turbidity tends to resolve soon after withdrawal of LERBLOK. This is an important association to recognise as cloudy peritoneal effluent can be mistaken for infective peritonitis with consequential unnecessary hospitalisation and empiric antibiotic administration.

Inducers of CYP3A4
Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce the plasma levels of lercanidipine and therefore the efficacy of LERBLOK may be less than expected (see section 4.5).

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive medicines, such as LERBLOK (see section 4.5).

Paediatric population
The safety and efficacy of LERBLOK have not been demonstrated in children.

Contraindications of concomitant use
Inhibitors of CYP3A4
Lercanidipine appears to be particularly sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in its systemic availability of up to 8-fold thereof. LERBLOK may not be taken with grapefruit juice (see section 4.3). Lercanidipine is metabolised by the CYP3A4 enzyme and therefore inhibitors of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine. An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the C max for the eutomer S-lercanidipine). Co-prescription of LERBLOK with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) is contraindicated (see section 4.3).

Ciclosporin
Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3 hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of ciclosporin increased by 27%. However, the co-administration of LERBLOK with ciclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC. Ciclosporin and LERBLOK should not be administered together (see section 4.3).

Concomitant use not recommended
Inducers of CYP3A4
Co-administration of LERBLOK with CYP3A4 inducers like anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution. The antihypertensive effect of LERBLOK may be reduced and blood pressure should be monitored more frequently than usual (see section 4.4).

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive medicines (see section 4.4).

Precautions including dose adjustment
Substrates of CYP3A4
Caution should be exercised when LERBLOK is co-prescribed with other substrates of CYP3A4, like terfenadine, class III antidysrhythmic medicines such as amiodarone, quinidine, sotalol.

Benzodiazepines
Caution is required if benzodiazepines like diazepam, midazolam are co-prescribed with LERBLOK. When concomitantly administered at a dose of 20 mg with midazolam, in elderly volunteers, absorption of lercanidipine was increased (by approximately 40%) and the rate of absorption decreased. The midazolam concentrations were not modified.

Metoprolol
When lercanidipine (contained in LERBLOK) was co-administered with metoprolol, a u03b2-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This effect may be due to the reduction in the hepatic blood flow caused by u03b2-blockers and may therefore occur with other medicines of this class. Consequently, LERBLOK may be safely administered with u03b2-adrenoceptor blocking medicines, but dose adjustment may be required.

Digoxin
Co-administration of 20 mg lercanidipine (contained in LERBLOK) in patients chronically treated with u03b2-methyldigoxin showed no evidence of pharmacokinetic interaction. However, a mean increase of 33% in digoxin C max was observed, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.

Concomitant use with other medicines
Fluoxetine
No clinically relevant modification of the pharmacokinetics of lercanidipine is expected with concomitant administration of LERBLOK and fluoxetine.

Cimetidine
Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased.

Simvastatin
No interaction is expected when LERBLOK is administered in the morning and simvastatin in the evening, as indicated for such medicine.

Diuretics and ACE inhibitors
Lercanidipine (contained in LERBLOK) has been safely administered with diuretics and ACE (angiotensin converting enzyme inhibitors) inhibitors.

Other medicines affecting blood pressure
Increased hypotensive effects may be observed when LERBLOK is administered with other medicines affecting blood pressure, such as beta-blockers which are metabolised in the liver (e.g. propranolol and metoprolol), alpha-blockers for the treatment of urinary symptoms, tricyclic antidepressants, and neuroleptics. On the contrary, a reduction of the hypotensive effect may be observed with a concomitant use with corticosteroids.

Pregnancy
There is no clinical experience with lercanidipine in pregnancy and lactation. LERBLOK should therefore not be prescribed during pregnancy or to women with child-bearing potential, unless effective contraception is used.
Breastfeeding
Because of the high lipophilicity of LERBLOK, distribution in milk may be expected. LERBLOK should therefore not be administered to mothers who are breastfeeding their babies.
Fertility
No clinical data are available with lercanidipine.

Dizziness, asthenia, fatigue and somnolence have been reported. Patients should be cautioned not to drive or handle machinery if these side effects occur.

a. Summary of the safety profile
The frequently reported adverse reactions are peripheral oedema, headache, flushing, tachycardia, and palpitations.
b. Tabulated list of adverse reactions
MedDRA System Organ Class/ Frequency
Immune system disorders
Less frequent: Hypersensitivity, angioedema
Frequency unknown: Angioedema
Psychiatric disorders
Less frequent: Somnolence, depression
Nervous system disorders
Frequent: Headache, dizziness
Less frequent: Fatigue, syncope
Eye disorders
Frequency unknown: Eye pain
Cardiac disorders
Frequent: Tachycardia, palpitations
Less frequent: Angina pectoris (see section 4.4)
Frequency unknown: Precordial pain, myocardial infarction (see section 4.4)
Vascular disorders
Frequent: Flushing, peripheral oedema
Less frequent: Hypotension
Gastrointestinal disorders
Less frequent: Nausea, dyspepsia, abdominal pain, diarrhoea, vomiting
Frequency unknown: Gingival hypertrophy, peritoneal cloudy effluent
Hepatobiliary disorders
Frequency unknown: Increased serum hepatic transaminases (reversible)
Skin and subcutaneous tissue disorders
Less frequent: Rash, pruritus, urticaria
Musculoskeletal and connective tissue disorders
Less frequent: Myalgia
Renal and urinary disorders
Less frequent: Polyuria, pollakiuria
General disorders and administration site conditions
Frequent: Asthenia
Less frequent: Fatigue, chest pain
c. Description of selected adverse reactions
Lercanidipine (contained in LERBLOK) does not appear to influence adversely blood sugar or serum lipid levels. Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Patients with pre-existing angina pectoris may less frequently experience increased frequency, duration, or severity of these attacks. Cases of myocardial infarction may be observed.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms
Excessive peripheral vasodilatation with marked hypotension and reflex tachycardia.
Treatment
In case of severe hypotension, bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for bradycardia. In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular status of patients who take an overdose is monitored for 24 hours at least. Treatment is symptomatic and supportive.