Lendidip 10 mg & 20 mg FC tablet

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

Posology
The recommended starting dosage 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. LENDIDIP is not recommended for use in patients with severe hepatic dysfunction or in patients with severe renal dysfunction (creatinine clearance < 10 mL/min).

Method of administration
Orally at least 15 minutes before a meal.

• Hypersensitivity to the lercanidipine hydrochloride, to any dihydropyridine or to any of the excipients listed in section 6.1.
• Left ventricular outflow tract obstruction.
• Untreated congestive cardiac failure.
• Unstable angina pectoris.
• Within 1 month of a myocardial infarction.
• Severe hepatic impairment.
• Severe renal impairment (GFR < 30 mL/min, including patients undergoing dialysis.
• Co-administration with:
• strong inhibitors of CYP3A4 (see section 4.5),
• cyclosporin (see section 4.5),
• grapefruit juice (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• Women of child-bearing potential unless effective contraception is used.

Sick sinus syndrome
Lercanidipine should be administered with caution in patients with sick sinus syndrome (without a pacemaker).

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 rarely lead to precordial pain or angina pectoris. Very rarely 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 exercised when treatment is commenced 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 should 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. Lercanidipine is contraindicated in patients with severe hepatic impairment or renal impairment (GFR < 30 mL/min), including patients undergoing haemodialysis (see sections 4.2 and section 4.3).

Peritoneal Dialysis
Lercanidipine 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. Whilst the mechanism is unknown, the turbidity tends to resolve soon after withdrawal of lercanidipine. 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 lercanidipine plasma levels and therefore the efficacy of lercanidipine may be less than expected (see section 4.5).

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

Lactose
LENDIDIP contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take LENDIDIP.

Sodium
LENDIDIP contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u201csodium - freeu201d.

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

Contraindications of concomitant use
Inhibitors of CYP3A4
Lercanidipine is known to be 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 lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (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 lercanidipine with ciclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC. Ciclosporin and lercanidipine should not be administered together (see section 4.3).

Grapefruit or grapefruit juice
As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit or grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section 4.3).

Concomitant use not recommended
Inducers of CYP3A4
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin, phenobarbitone, carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect 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 lercanidipine is co-prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine, sotalol.

Midazolam
When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers, lercanidipine absorption was increased (by approximately 40%) and the rate of absorption was decreased (t max was delayed from 1,75 to 3 hours). Midazolam concentrations were not modified.

Metoprolol
When lercanidipine 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, lercanidipine may be safely administered with u03b2-adrenoceptor blocking medicines, but dose adjustment may be required.

Digoxin
Co-administration of 20 mg lercanidipine 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
An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age of 65 u00b1 7 years (mean u00b1 s.d.), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine.

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
When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the AUC of lercanidipine was not significantly modified, while simvastatin AUC increased by 56 % and that of its active metabolite u03b2-hydroxyacid by 28 %. It is unlikely that such changes are of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such medicine.

Diuretics and ACE inhibitors
Lercanidipine has been safely administered with diuretics and ACE inhibitors.

Other medications affecting blood pressure
As for all antihypertensive medications, an increased hypotensive effect may be observed when lercanidipine is administered with other medications affecting blood pressure, such as alpha-blockers for the treatment of urinary symptoms, tricyclic antidepressants, 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 LENDIDIP in pregnancy and lactation; LENDIDIP should therefore not be administered during pregnancy or to woman with child-bearing potential unless effective contraception is used.

Breastfeeding
Because of high lipophilicity of LENDIDIP, distribution in milk may be expected. LENDIDIP should therefore not be administered mothers who are breastfeeding their babies.

LENDIDIP has minor influence on the ability to drive and use machines. However, caution should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

Tabulated summary of adverse reactions
SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION
Immune system disorders Less frequent Hypersensitivity
Nervous system disorders Frequent Headache
Less frequent Dizziness, somnolence, syncope, mental depression
Eye disorders Less frequent Eye pain
Cardiac disorders Frequent Tachycardia, palpitations
Less frequent angina pectoris, precordial pain, myocardial infarction, chest pain
Vascular disorders Less frequent Flushing, hypotension, oedema peripheral
Gastrointestinal disorders Less frequent Dyspepsia, nausea, abdominal pain upper, vomiting, diarrhoea, gingival hypertrophy 1 , peritoneal cloudy effluent 1
Hepatobiliary disorders Less Frequent Isolate and reversible serum transaminase increased 1
Skin and subcutaneous tissue disorders Less Frequent Rash, pruritus, urticaria, angioedema 1
Musculoskeletal and connective tissue disorders Less Frequent Myalgia
Renal and urinary disorders Less Frequent Polyuria, pollakiuria, increased micturition frequency
General disorders and administration site conditions Less Frequent Asthenia, fatigue, chest pain
Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

1 adverse reactions from spontaneous reporting in the worldwide post-marketing experience.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of LENDIDIP is important. It allows continued monitoring of the benefit/risk balance of LENDIDIP. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website or to the Holder of certificate of registration through the mail: [email protected].

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and reflex tachycardia. 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 at least 24 hours. Treatment is symptomatic and supportive.