Enalapril and Lercanidipine

No clinical data are available with lercanidipine. Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers. In cases where repeated in vitro fertilisation is unsuccessful and where another explanation cannot be found, the possibility of calcium channel blockers as the cause should be considered.

For enalapril

The use of ACE-inhibitors (enalapril) is not recommended during the first trimester of pregnancy. The use of ACE-inhibitors (enalapril) is contra-indicated during the second and third trimesters of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE-inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE-inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE-inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE-inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Should exposure to ACE-inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE-inhibitors should be closely observed for hypotension.

For lercanidipine

There are no data from the use of lercanidipine in pregnant women. Studies in animals have not shown teratogenic effects, but these have been observed with other dihydropyridine compounds.

Lercanidipine is not recommended during pregnancy and in women of childbearing-potential not using contraception.

For enalapril and lercanidipine in association

There are no or limited amount of data from the use of enalapril maleate/lercanidipine HCl in pregnant women. Animal studies are insufficient with respect to reproductive toxicity.

Lercaril should not be used in the second and third trimester of pregnancy. It is not recommended in the first trimester of pregnancy and in women of childbearing potential not using contraception.

For enalapril

Limited pharmacokinetic data demonstrate very low concentrations in breast milk. Although these concentrations seem to be clinically irrelevant, the use of enalapril in breast-feeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of enalapril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

For lercanidipine

It is unknown whether lercanidipine/metabolite are excreted in human milk. A risk to the newborns/infants cannot be excluded. Lercanidipine should not be used during breast-feeding.

For enalapril and lercanidipine in association

Consequently, enalapril/lercanidipine should not be used during breast-feeding.

Fertility

No clinical data are available with lercanidipine. Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers. In cases where repeated in vitro fertilisation is unsuccessful and where another explanation cannot be found, the possibility of calcium channel blockers as the cause should be considered.

Enalapril/lercanidipine combination 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.

Summary of the safety profile

The safety of enalapril/lercanidipine has been evaluated in five double-blind controlled clinical studies and in two long term open-label extension phases. In total, 1,141 patients have received enalapril/lercanidipine at a dose of 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg. The undesirable effects observed with combination therapy have been similar to those already observed with one or the other of the constituents given alone. The most commonly reported adverse reactions during treatment with enalapril/lercanidipine were cough (4.03%), dizziness (1.67%) and headache (1.67%).

Tabulated summary of adverse reactions

In the table below, adverse reactions reported in clinical studies with enalapril/lercanidipine 10 mg/10 mg, 20 mg/10 mg and 20 mg/20 mg and for which a reasonable causal relationship exists are listed by MedDRA system organ class and frequency: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) not known (cannot be estimated from the available data).

Undesirable effects occurring in one patient only are reported under the frequency rare.

Description of selected adverse reactions

The incidence of selected listed adverse reactions frequently observed with enalapril and lercanidipine monotherapies, is shown in the table below, as reported in a double-blind, randomised, factorial clinical study:

Additional information on the individual components

Adverse reactions reported with one of the individual components (enalapril or lercanidipine) may be potential undesirable effect with enalapril/lercanidipine fixed-dose combiantion as well, even if not observed in clinical trials or during the post-marketing period.

Enalapril alone

Among the adverse drug reactions reported for enalapril are:

Blood and lymphatic system disorders

Uncommon: anaemia (including aplastic and haemolytic)

Rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders

Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

Uncommon: hypoglycaemia

Psychiatric disorders

Common: depression

Uncommon: confusion, nervousness, insomnia

Rare: dream abnormality, sleep disorders

Nervous system disorders

Very common: dizziness

Common: headache, syncope, taste alteration

Uncommon: somnolence, paraesthesia, vertigo

Eye disorders

Very common: blurred vision

Ear and labyrinth disorders

Uncommon: tinnitus

Cardiac disorders

Common: chest pain, rhythm disturbances, angina pectoris, tachycardia

Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients

^* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.

Vascular disorders

Common: hypotension (including orthostatic hypotension)

Uncommon: flushing, orthostatic hypotension

Rare: Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Very common: cough

Common: dyspnoea

Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma

Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia

Gastrointestinal disorders

Very common: nausea

Common: diarrhoea, abdominal pain

Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer

Rare: stomatitis/aphthous ulcerations, glossitis

Very rare: intestinal angioedema

Hepatobiliary disorders

Rare: hepatic failure, hepatitis – either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)

Skin and subcutaneous tissue disorders

Common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported

Uncommon: diaphoresis, pruritus, urticaria, alopecia

Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.

Musculoskeletal, connective tissue, bone disorders

Uncommon: muscle cramps

Renal and urinary disorders

Uncommon: renal dysfunction, renal failure, proteinuria

Rare: oliguria

Reproductive system and breast disorders

Uncommon: impotence

Rare: gynaecomastia

General disorders and administration site conditions

Very common: asthenia

Common: fatigue

Uncommon: malaise, fever

Investigations

Common: hyperkalaemia, increases in serum creatinine

Uncommon: increases in blood urea, hyponatremia

Rare: elevation of liver enzymes, elevation of serum bilirubin.

Lercanidipine alone

The adverse drug reactions most commonly reported in clinical trials and in the post-marketing experience are peripheral oedema, headache, flushing, tachycardia and palpitations.

Immune system disorders

Rare: hypersensitivity

Nervous system disorders

Common: headache

Uncommon: dizziness

Rare: somnolence, syncope

Cardiac disorders

Common: tachycardia, palpitations

Rare: angina pectoris

Vascular disorders

Common: flushing

Uncommon: hypotension Gastrointestinal disorders:

Uncommon: nausea, dyspepsia, abdominal pain upper

Rare: vomiting, diarrhoea

Not known: gingival hypertrophy¹, peritoneal cloudy effluent¹

Hepatobiliary disorders

Not known: serum transaminase increased1

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Rare: urticaria

Not known: angioedema¹

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

Renal and urinary disorders

Uncommon: polyuria

Rare: pollakiuria

General disorders and administration site conditions

Common: oedema peripheral

Uncommon: asthenia, fatigue

Rare: chest pain

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

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. Lercanidipine does not appear to have any adverse effect on blood sugar or serum lipid levels.