Brand
name:
LERKA (Lercanidipine, Zanidip)
(lercanidipine tablets)
Lercanidipine hydrochloride. : a dihydropyridine
derivative. It is a racemate due to the presence of a chiral carbon
atom at position
4 of the 1,4-dihydropyridine
ring.
Lercanidipine chemical structure
Chemical name: 3,5-pyridinedicarboxylic acid, 1,4- dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl
methyl ester hydrochloride. MW: 648.2 (free base: 611.7).
Lercanidipine hydrochloride (CAS: 132866-11-6) is a microcrystalline,
odourless, citrine powder, readily soluble in chloroform and methanol,
practically insoluble in water. Octanol:water partition coefficient
(LogP):
LERKA (Lercanidipine, Zanidip) tablets also contain lactose, microcrystalline cellulose,
sodium starch glycolate, povidone, magnesium stearate and the proprietary
film coating ingredient Opadry OY-SR-6497 as excipients.
Pharmacology Pharmacodynamic Properties
Lercanidipine is a calcium antagonist of the dihydropyridine group
and selectively inhibits the transmembrane influx of calcium into cardiac
and vascular smooth muscle, with a greater effect on vascular smooth
muscle than on cardiac smooth muscle. The antihypertensive action is
due to a direct relaxant effect on vascular smooth muscle which lowers
total peripheral resistance and hence blood pressure. Lercanidipine
has a prolonged antihypertensive activity because of its high membrane
partition coefficient. It is devoid of negative inotropic effects and
its vascular selectivity is due to its voltage-dependent calcium antagonist
activity. Since the vasodilatation induced by lercanidipine hydrochloride
is gradual in onset, acute hypotension with reflex tachycardia has
rarely been observed in hypertensive patients.
As for other asymmetric, 1,4-dihydropyridines, the antihypertensive
activity of lercanidipine is mainly due to the (S) - enantiomer.
No significant effects on ECG have been seen.
Clinical Trials
Placebo-controlled studies
Lercanidipine has been compared to placebo in four 4 to 16-week studies,
involving 671 patients with mild-moderate essential hypertension. All
studies used a 3-week placebo run-in period. Endpoints were diastolic
and systolic blood pressure 24 hours post dose. Both 10mg and 20mg
once daily significantly lowered diastolic and systolic blood pressure
compared to placebo, and the reduction in blood pressure was maintained
throughout the 24 hour dosing period.
Diastolic blood pressure changes observed after 4-week treatment with
10-20 mg QD lercanidipine ranged between 8 and 13 mmHg, as compared
to 3-6 mmHg induced by placebo.
Studies with 24-hour ambulatory blood pressure monitoring have documented
that the antihypertensive effect of lercanidipine is maintained throughout
the 24 hour dosing period, with limited variations between peak (5-7
hours post dosing) and trough blood pressure changes.
Active-controlled studies
Four clinical trials involving 538 patients with mild-moderate essential
hypertension have compared lercanidipine with nifedipine SR, atenolol,
hydrochlorothiazide and captopril. Trials included a 2-week washout
period followed by a 3-week placebo run-in, and 12-16 weeks of active
treatment. Diastolic and systolic blood pressure was measured 24 hours
post-dose. Lercanidipine was as effective as the comparator drugs,
and at least as well tolerated. 24-hour blood-pressure monitoring was
used in a comparative, cross-over trial of lercanidipine versus amlodipine
(n=16). The effect of lercanidipine paralleled that of amlodipine throughout
the 24 hour period.
Patients with Isolated Systolic Hypertension
The effect of lercanidipine 10-20mg daily on isolated systolic hypertension
was studied in a double-blind, randomised, placebo-controlled study
in 83 elderly patients (sitting SBP>160mm Hg and sitting DBP<95mm
Hg). The study consisted of 1 week wash-out, 3 weeks placebo run-in,
and 8 weeks of active treatment. Systolic and diastolic blood pressure
was measured 24 hours post dose. Lercanidipine 10 to 20 mg was efficacious
in lowering systolic blood pressure from the initial values of 172.6 ± 5.6
mmHg to 140.2 ± 8.7mmHg (mean±SD, per protocol population
in all patients completing the whole 8 weeks of double-blind treatment),
as compared to the changes in the placebo group (from 172.4±6.3
to 162.8±9.7 mmHg). Therefore,at study endpoint, patients treated
with lercanidipine experienced a significantly greater decrease (-22.6mm
Hg, p<0.001) in sitting systolic blood pressure in comparison to
placebo. The diastolic blood pressure was within normal range.
Long-term studies
In long term studies, 399 patients were followed for 12 months, with
dose titration allowed every 4 weeks, to 30mg daily. Development of
tolerance was not seen. The antihypertensive effect was maintained,
and the heart rate was not significantly affected. A further fall in
blood pressure was seen after the first and second month, with blood
pressure stabilising in the third month. The majority of patients remained
on 10mg once daily.
Pharmacokinetics
Absorption
Lercanidipine is completely absorbed after oral administration. Peak
plasma levels of 3.30ng/mL ± 2.09 s.d and 7.66 ng/mL ± 5.90
s.d occur 1.5-3 hours after dosing with 10mg and 20mg, respectively.
The absolute bioavailability of lercanidipine is about 10%, because
of high first pass metabolism. The bioavailability increases 4-fold
when lercanidipine is ingested up to 2 hours after a high fat meal,
and about 2-fold when taken immediately after a carbohydrate-rich meal.
Consequently, lercanidipine should be taken at least 15 minutes before
a meal.
With oral administration, lercanidipine exhibits non-linear kinetics.
After 10, 20 or 40mg, peak plasma concentrations observed were in the
ratio 1:3:8 and areas under plasma concentration-time curves in the
ratio 1:4:18, showing a progressive saturation of first pass metabolism.
Accordingly, bioavailability increases as dosage increases.The two
enantiomers of lercanidipine have a similar time to peak plasma concentration.
The peak plasma concentration and AUC are, on average,
1.2-fold higher for the (S) enantiomer. No in vivo interconversion
of enantiomers is observed.
Distribution
Distribution of lercanidipine from plasma to tissues and organs is
rapid and extensive. Serum protein binding exceeds 98%. The free fraction
of lercanidipine may be increased in patients with renal or hepatic
impairment as plasma protein levels are decreased in these disease
states.
Metabolism : As for other dihydropyridine derivatives, lercanidipine
is extensively metabolised by CYP3A4. It is predominantly converted
to inactive metabolites;
no parent drug is found in the urine or faeces. About 50% of the dose
is excreted in the urine.
Elimination
The mean terminal elimination half-life of S- and R-lercanidipine
enantiomers is 5.8 ± 2.5 and 7.7 ± 3.8 hours, respectively.
No accumulation was seen upon repeated administration. The therapeutic
activity of lercanidipine lasts for 24 hours, due to its high binding
to lipid membranes.
In elderly patients, the pharmacokinetics of lercanidipine is similar
to that observed in the general population.
A study in patients with mild hepatic impairment (Child-Pugh class
A) showed that the pharmacokinetic behaviour of the drug is similar
to that observed in the general population. No studies have been undertaken
in patients with moderate or severe hepatic impairment.In patients
with severe renal dysfunction (creatinine clearance < 12mL/min)
or dialysis-dependent patients, plasma levels were increased by about
70%. As a consequence, the drug should be contraindicated in severe
renal impairment.LERKA (Lercanidipine, Zanidip) is indicated for the
treatment of mild to moderate hypertension.
Contraindications
* Hypersensitivity to any dihydropyridine or any ingredient of LERKA (Lercanidipine, Zanidip);
* Severe renal impairment (creatinine clearance < 12 mL/min).
* Concomitant treatment of LERKA (Lercanidipine, Zanidip) with cyclosporin should be avoided
Precautions :
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 should
be required in such patients.
Outflow obstruction (aortic stenosis)
Lercanidipine should be administered with caution in patients with
left ventricular outflow obstruction (aortic stenosis).
Congestive heart failure
In general calcium channel blockers should be used with caution in
patients with heart failure. Although animal data and acute haemodynamic
evaluation in patients with preserved left ventricular function have
not demonstrated that lercanidipine exerts a direct negative inotropic
effect, safety in patients with congestive heart failure has not been
established. Therefore, as for other calcium channel blockers, lercanidipine
should be used with caution in such patients, especially if untreated.
Unstable angina pectoris or within one month of a myocardial infarction
Rarely patients have developed documented increased frequency, duration
and/or severity of angina on starting calcium channel blocker therapy
or at the time of dosage increase (particularly those with severe obstructive
coronary artery disease). The mechanism of this effect has not been
elucidated, however the possibility of an exacerbation of angina and/or
cardiac ischaemia exists. It is therefore suggested that the use of
calcium channel blockers is not advisable in patients with unstable
angina pectoris or recent myocardial infarction.
Carcinogenesis, mutagenesis, impairment of fertility
No evidence for genotoxic activity was observed with lercanidipine
in in vitro
Use in pregnancy: Category C
There is no clinical experience with lercanidipine in pregnancy, but
other dihydropyridine compounds have been found to cause irreversible
malformations in animals. Therefore, lercanidipine should not be administered
during pregnancy or to women with child-bearing potential unless effective
contraception is used.
In animal studies, pregnant rats given lercanidipine orally at doses
= 2.5 mg/kg/day, beginning prior to mating, or 12 mg/kg/day, beginning
from early gestation, showed signs of distocia and had a increased
incidence of still births and a lower neonatal survival index. The
no-effect dose for effects on parturition and neonatal survival was
0.5 mg/kg/day (associated with lercanidipine concentration (AUC) about
50% of the expected human AUC) when dosing started before pregnancy
or 2.5 mg/kg/day (about 3 times the human AUC) when dosing started
during early gestation. Administration with lercanidipine at doses
of 2.5 mg/kg/day during gestation also caused a higher incidence of
fetal visceral abnormalities (mono/bilateral renal pelvic and/or ureteric
dilatation) and skeletal abnormalities (mainly delayed ossification)
at all dose levels. A no-effect dose was not established. The effects
of lercanidipine during pregnancy have not been investigated adequately
in a non-rodent species.
Use in Lactation
There is no clinical experience with lercanidipine in lactation. Distribution
into milk may be expected, due to the high lipophilicity of lercanidipine.
Therefore, lercanidipine should not be administered to lactating women.
Use in the Elderly
Although the pharmacokinetic data and clinical experience suggest
that no adjustment of the daily dose is required, special care should
be exercised when initiating treatment in the elderly.
Use in Children
Due to lack of clinical experience, lercanidipine is not recommended
for use in patients under the age of 18.
Use in Hepatic Impairment
The pharmacokinetics of lercanidipine in patients with mild hepatic
impairment are similar to those observed in the general population.
However, there are no studies in patients with moderate hepatic impairment
and dosage recommendations have not been established. Lercanidipine
should therefore be used with caution in this patient group and careful
monitoring undertaken during treatment, since the bioavailability and
hypotensive effect may be increased. The use of lercanidipine in patients
with moderate hepatic impairments should only be undertaken if the
benefits are considered to outweigh the risks. Lercanidipine is contraindicated,
in patients with severe hepatic disease.
Use in Renal Impairment
Although the pharmacokinetics of lercanidipine in patients with mild
to moderate renal impairment are similar to those observed in the general
population, special care should be exercised when commencing the treatment
in such patients. The usual recommended dose of 10mg daily may be tolerated;
however, an increase to 20mg daily should be approached with caution.
Interaction with other Drugs
Lercanidipine has been safely administered with diuretics and ACE
inhibitors. It may also be administered safely with beta-blockers which
are eliminated unchanged (such as atenolol).
Inhibitors or inducers of Cytochrome CYP3A4
Since the main metabolic pathway of lercanidipine involves the enzyme
CYP3A4, drugs that inhibit or induce this enzyme have the potential
to alter the plasma concentration of the compound.
Therefore, inhibitors of CYP3A4 (such as ketoconazole, itraconazole,
erythromycin, ritonavir and fluoxetine) may increase the plasma concentration
of lercanidipine, and such combinations should be used with caution.
An interaction study with fluoxetine in volunteers over the age of
65 years, showed no clinically relevant changes to the pharmacokinetics
of lercanidipine.
When co-administered with CYP3A4 inducers, such as anticonvulsants
(eg, phenytoin, carbamazepine) and rifampicin, the antihypertensive
effect of lercanidipine may be reduced and, therefore, blood pressure
should be monitored when the co-administration is foreseen.
CYP3A4 and CYP2D6 substrates
The potential for in vivo inhibition of CYP3A4 by lercanidipine is
negligible, as confirmed by an interaction study with midazolam in
healthy volunteers. After repeated co-administration with lercanidipine,
midazolam (a probe for CYP3A4 activity) was found to be essentially
bioequivalent to the drug administered alone. However, unless specific
data are available, caution should also be exercised when lercanidipine
is co-prescribed with other substrates of CYP3A4 which have a narrow
therapeutic index, such as cyclosporin, and class III antiarrhythmic
drugs (e.g. amiodarone and quinidine).
Co-administration of lercanidipine with cyclosporin resulted in a
3 fold increase in the plasma levels of lercanidipine and a 21% increase
in the bioavailability of cyclosporin. However, when cyclosporin was
administered 3 hours after lercanidipine, while the bioavailability
of cyclosporin increased by 27%. Therefore, cyclosporin and lercanidipine
should not be administered together.
Moreover, interaction studies in humans have shown that lercanidipine
did not modify the plasma levels of metoprolol, (a typical substrate
of CYP2D6). Therefore, at therapeutic doses it is unlikely that lercanidipine
will inhibit the biotransformation of drugs
These findings confirm that the inhibition of cytochrome P450 isoenzymes
observed in vitro with lercanidipine is devoid of any clinical significance
. In vitro experiments with human liver microsomes demonstrated that
lercanidipine inhibits CYP3A4 and CYP2D6 (IC50 of 2.6 µm and
0.8 µm, respectively). The IC50 concentrations for CYP3A4 and
CYP2D6 are 160 and 40 fold higher, respectively, than those reached
at peak in the plasma after a 20mg dose.
Beta-blockers
When lercanidipine was administered with metoprolol, a beta-blocker
eliminated mainly by the liver, the bioavailability of metoprolol was
not changed, while that of lercanidipine was reduced by 50%. Therefore,
when co-administered with metoprolol, it may be necessary to increase
the dose of lercanidipine. It is anticipated that a similar effect
may occur with propranolol.
Cardiac glycosides
Co-administration of lercanidipine in patients chronically treated
with beta-methyldigoxin (a pro-drug of digoxin) showed no evidence
of a pharmacokinetic interaction. However, patients on concomitant
digoxin treatment should be closely monitored.
Concomitant administration of cimetidine 400mg BD does not cause significant
changes in the plasma levels of lercanidipine: AUC and Cmax were increased
by a mean of 11%. However, at higher doses caution is required since
the bioavailability and the hypotensive effect of lercanidipine may
be increased.
Simvastatin
Co-administration of a 20 mg dose of lercanidipine with 40 mg simvastatin
resulted in no increase in the bioavailability of lercanidipine, however
a 56% increase was observed for simvastatin and a 28% increase for
its active metabolite ß-hydroxyacid. It is unlikely that these
changes are clinically relevant. However, it is recommended that when
required lercanidipine be administered in the morning and simvastatin
in the evening.
Warfarin
Co-administration of 20 mg lercanidipine with warfarin, in healthy
volunteers, did not alter the pharmacokinetics of lercanidipine.
The metabolism of dihydropyridines can be inhibited by grapefruit
juice, leading to increased plasma concentration and hypotensive effect.
Alcohol should be avoided while taking lercanidipine since it may
potentiate the effect of vasodilating antihypertensive drugs.
Adverse Reactions
Treatment with lercanidipine is generally well tolerated. In nine
placebo-controlled clinical trials with a treatment duration lasting
at least 4 weeks, 582 patients were initially treated with lercanidipine,
and 292 patients received placebo. Most of the events reported in the
studies were related to the vasodilatory effects of lercanidipine,
and were classified mild-moderate in severity.
Table 1 lists, according to organ system, adverse events that were
reported in placebo controlled trials in hypertensive patients with
lercanidipine tablets at an incidence greater than or equal to 1% in
at least one of the active treatment groups.
2.5 mg
QD up to 40 mg QD, and with treatment duration ranging from single
dose up to more than 1 year. Adverse experiences which were not clearly
drug related and which occurred in <1% but = 0.1% of patients
are summarized according to organ system.
Cardiovascular: palpitations/tachycardia.Central and Peripheral nervous
system: dizziness, vertigo.
Gastrointestinal: nausea, dyspepsia, abdominal pain, diarrhoea.
Psychiatric: somnolence.
General: flushing, asthenia (including fatigue and muscle weakness).The
following events have been rarely reported:
Cardiovascular: hypotension, orthostatic hypotension, periorbital
oedema, anginal pain, myocardial infarction, cardiac failure.
Serious adverse events have been reported in clinical trials in less
than 0.002% of the patients. The remaining adverse events have been
reported as mild to moderate in intensity.
Laboratory tests
There were reports of isolated and reversible increases in serum levels
of hepatic transaminases; no other clinically significant pattern of
laboratory test abnormalities related to lercanidipine has been observed.
Lercanidipine does not effect blood sugar or lipid levels.
Dosage and Administration
The recommended dose is 10mg once daily, at least 15 minutes before
a meal. The dose may be increased to 20mg once daily depending on the
individual response. Dose titration should be gradual, as it may take
about 2 weeks for the maximal hypertensive effect to be apparent. Titration
may proceed more rapidly, however, if clinically warranted, provided
the patient is assessed frequently. Since it is unlikely that increasing
the dose beyond 20mg will further improve the efficacy, and may be
associated with side effects, doses above 20 mg are not recommended.
Some individuals not adequately controlled on a single antihypertensive
agent may benefit from the addition of LERKA (Lercanidipine, Zanidip) at the same doses used
in monotherapy to the existing regimen with a beta-blocker, a diuretic
or an ACE-inhibitor.
Use in elderly, children, hepatic and renal impairment: see precautions.
Overdosage
There is no experience with lercanidipine overdosage. As with other
dihydropyridines, overdosage might be expected to cause excessive peripheral
vasodilation with marked hypotension and reflex tachycardia. In case
of severe hypotension, bradycardia and unconsciousness, cardiovascular
and respiratory monitoring will be required, and supportive treatment
may be necessary. Since lercanidipine is highly lipophilic, dialysis
is unlikely to be effective.
