Zircol

Each film-coated tablet contains Lercanidipine HCl 10 mg. Each film-coated tablet contains Lercanidipine HCl 20 mg equivalent to Zircol 18.8 mg. Zircol also contains the following excipients: Tablet Core: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone K30, magnesium stearate. Film-Coating: Hypromellose, talc, titanium dioxide (E171), macrogol 6000 and ferric oxide (E172).

Zircol is indicated for the treatment of mild to moderate essential hypertension. Some individuals, not adequately controlled on a single antihypertensive agent may benefit from the addition of Zircol with beta-adrenoceptor blocking drug, a diuretic or an angiotensin-converting enzyme inhibitor.

Recommended Dose: 10 mg orally once daily at least 15 min before meals. The dose may be increased to 20 mg depending on the individual patient's response.

Dose titration should be gradual because it may take about 2 weeks before the maximal antihypertensive effect is apparent. In severe hypertension, the dose titration period should be reduced.

Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the addition of Zircol to therapy with a β-adrenoceptor blocking drug (atenolol), a diuretic (hydrochlorothiazide) or an angiotensin-converting enzyme (ACE) inhibitor (captopril or enalapril). Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that efficacy will be improved by higher doses; whereas side effects may increase.

Elderly: Although the 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.

Renal or Hepatic Impairment: Special care should be exercised when treatment is commenced in patients with mild to moderate renal or hepatic dysfunction. Although the usual recommended dose schedule may be tolerated by these subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the dosage should be considered. Zircol is not recommended for use in patients with severe hepatic impairment or in patients with severe renal impairment (GFR <30 mL/min).

Hypersensitivity to Zircol, to any dihydropyridine or to any of the excipients of Zircol.

Patients with left ventricular outflow tract obstruction, untreated congestive cardiac failure, unstable angina pectoris, severe renal or hepatic impairment or within 1 month of a myocardial infarction. Co-administration with strong inhibitors of CYP3A4, cyclosporine and grapefruit juice.

Use in pregnancy & lactation: Data for Zircol provide no evidence of a teratogenic effect in the rat and the rabbit, and reproductive performance in the rat was unimpaired. Nevertheless, since there is no clinical experience with Zircol in pregnancy and lactation and other dihydropyridine compounds have been found teratogenic in animals, Zircol should not be administered during pregnancy or to women with childbearing potential unless effective contraception is used. Because of high lipophilicity of Zircol, distribution in milk may be expected. Therefore, it should not be administered to nursing mothers.

Zircol is used alone or in combination with an angiotensin-converting enzyme inhibitor to treat hypertension (high blood pressure), and chest pains associated with heart attack.

Zircol is known to be metabolized by the CYP3A4 enzyme and, therefore, inhibitors and inducers of CYP3A4 administered concurrently may interact with the metabolism and elimination of Zircol.

Co-prescription of Zircol with inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided.

An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of Zircol (a 15-fold increase of the AUC and an 8-fold increase in the C_max for the eutomer S-Zircol).

Cyclosporine and Zircol should not be administered together. Increased plasma levels of both Zircol and cyclosporine have been observed following concomitant administration. A study in young healthy volunteers has shown that when cyclosporine was administered 3 hrs after Zircol intake, the plasma levels of Zircol did not change, while the AUC of cyclosporine increased by 27%. However, the co-administration of Zircol with cyclosporine has caused a 3-fold increase of the plasma levels of Zircol and a 21% increase of the cyclosporine AUC. Zircol should not be taken with grapefruit juice.

As for other dihydropyridines, Zircol is sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect.

When concomitantly administered at a dose of 20 mg with midazolam orally to elderly volunteers, Zircol's absorption was increased (by approximately 40%) and the rate of absorption was decreased (T_max was delayed from 1.75-3 hrs). Midazolam concentrations were not modified. Caution should be exercised when Zircol is co-prescribed with other substrates of CYP3A4 eg, terfenadine, astemizole, class III anti-arrhythmic drugs eg, amiodarone, quinidine.

Co-administration of Zircol with CYP3A4 inducers eg, anticonvulsants (eg, phenytoin, 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.

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

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers with an age of 65±7 years (mean SD), has shown no clinically relevant modification of the pharmacokinetics of Zircol.

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

Co-administration of Zircol 20 mg in patients chronically treated with β-methyldigoxin showed no evidence of pharmacokinetic interaction. Healthy volunteers treated with digoxin following dosing with Zircol 20 mg given fasted showed a mean increase of 33% in digoxin C_max, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.

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

The co-administration of Zircol 20 mg to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin.

Zircol has been safely administered with diuretics and ACE inhibitors.

Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Incompatibilities: Not applicable.

Treatment with Zircol is generally well tolerated. In controlled clinical trials the most commonly observed side effects were related to the vasodilatory properties of Zircol: Flushing, peripheral oedema, tachycardia, palpitation, headache, dizziness, asthenia. Other adverse experiences which were not clearly drug related and which occurred in less than 1% of patients were: Fatigue, gastrointestinal disturbances such as dyspepsia, nausea, vomiting, epigastric pain and diarrhea, polyuria, rash, somnolence and myalgia.

Hypotension may occur in rare cases. Although not observed in clinical trials, gingival hyperplasia may rarely occur as reported following the use of other dihydropyridines. 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 Zircol has been observed. Zircol dose not appear to influence adversely blood sugar or serum lipid levels. 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.