Isradipine

(BAN, USAN, rINN)
Isradipine Chemical formula
Synonyms: Isradipiini; Isradipin; Isradipinas; Isradipino; Isradipinum; Izradypina; PN-200-110. Isopropyl methyl 4-(2,1,3-benzoxadiazol-4-yl)1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate.
Cyrillic synonym: Израдипин.

💊 Chemical information

Chemical formula: C19H21N3O5 = 371.4.
CAS — 75695-93-1.
ATC — C08CA03.
ATC Vet — QC08CA03.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Isradipine). A yellow crystalline powder. Practically insoluble in water; freely soluble in acetone; soluble in methyl alcohol. Protect from light.

USP 31

(Isradipine). A yellow fine crystalline powder. Protect from light.

Stability.

An oral preparation of isradipine 1 mg/mL, prepared using the powder from capsules of isradipine suspended in syrup, 1 was stable when stored at 4° for up to 35 days after preparation. 1. MacDonald JL, et al. Stability of isradipine in an extemporaneously compounded oral liquid. Am J Hosp Pharm 1994; 51: 2409–11.

💊 Adverse Effects, Treatment, and Precautions

As for dihydropyridine calcium-channel blockers.
Flushing, palpitation, and oedema were more common in patients receiving isradipine, while headache, dizziness, and dyspnoea were reported in both groups with similar frequency. In another study,2 spontaneously reported adverse effects occurred less frequently in patients taking isradipine (18.4% of 103 patients) than in those taking amlodipine (33.3% of 102 patients). In particular, ankle oedema was less frequent, severe, and prolonged with isradipine than with amlodipine. A multicentre study3 comparing isradipine and enalapril antihypertensive therapy reported adverse effects in 51% of 71 patients taking isradipine and 45% of 64 patients taking enalapril. The commonest side-effects with isradipine were dizziness (14%), oedema (10%), fatigue (9%), headache (9%), and pruritus (7%).
1. Carlsen JE, Køber L. Blood pressure lowering effect and adverse events during treatment of arterial hypertension with isradipine and hydrochlorothiazide. Drug Invest 1990; 2: 10–16
2. Hermans L, et al. At equipotent doses, isradipine is better tolerated than amlodipine in patients with mild-to-moderate hypertension: a double-blind, randomized, parallel-group study. Br J Clin Pharmacol 1994; 38: 335–40
3. Johnson BF, et al. A multicenter comparison of adverse reaction profiles of isradipine and enalapril at equipotent doses in patients with essential hypertension. J Clin Pharmacol 1995; 35: 484–92.

💊 Interactions

As for dihydropyridine calcium-channel blockers. Cimetidine increases the bioavailability of isradipine and the dose of isradipine should be reduced by 50% in patients receiving both drugs.

💊 Pharmacokinetics

Isradipine is almost completely absorbed from the gastrointestinal tract after oral doses but undergoes extensive first-pass metabolism; the bioavailability is reported to be 15 to 24%. Peak plasma concentrations occur about 2 hours after oral dosage. It is about 95% bound to plasma proteins. Isradipine is extensively metabolised in the liver, at least partly by the cytochrome P450 isoenzyme CYP3A4. About 70% of an oral dose is reported to be excreted as metabolites in urine, the remainder in faeces. The terminal elimination half-life is often stated to be about 8 hours although a value of less than 4 hours has also been reported.
The mean terminal elimination half-life at steady state was 3.8 hours, suggesting that duration of action is likely to be short and that isradipine would need to be given at least twice daily. There was considerable interindividual variation in the pharmacokinetics. In an earlier study2 in healthy subjects the effective half-life of isradipine was calculated to be 8.8 hours, but radiolabelled isradipine was used and the assay method might have been less specific for unchanged drug.
1. Shenfield GM, et al. The pharmacokinetics of isradipine in hypertensive subjects. Eur J Clin Pharmacol 1990; 38: 209–11
2. Tse FLS, Jaffe JM. Pharmacokinetics of PN 200-110 (isradipine), a new calcium antagonist, after oral administration in man. Eur J Clin Pharmacol 1987; 32: 361–5.

Hepatic impairment.

Systemic availability after a radiolabelled oral dose of isradipine 5 mg was no different at 15.6% in 7 patients with non-cirrhotic chronic liver disease from the value of 16.5% in 8 healthy subjects.1 However, in 8 patients with cirrhosis of the liver availability was markedly increased to a mean of 36.9%; this was associated with decreased clearance (1.6 litres/minute, compared with 9.9 in controls). Terminal halflife, as measured after intravenous dosage, was greater at 11.9 hours in cirrhotic patients than the 5.1 hours seen in controls.
1. Cotting J, et al. Pharmacokinetics of isradipine in patients with chronic liver disease. Eur J Clin Pharmacol 1990; 38: 599–603.

💊 Uses and Administration

Isradipine is a dihydropyridine calcium-channel blocker with actions similar to those of nifedipine. It is used in the treatment of hypertension. The usual initial dose of isradipine is 2.5 mg by mouth twice daily increased if necessary after 3 to 4 weeks to 5 mg twice daily. Some patients may require 10 mg twice daily. In elderly patients an initial dose of 1.25 mg twice daily may be preferable; a maintenance dose of 2.5 or 5 mg once daily may sometimes be sufficient. A reduced dose should also be considered in patients with hepatic or renal impairment (see below). The dose of isradipine should be reduced in patients who are also taking cimetidine (see Interactions, above). A modified-release preparation allowing once-daily dosing is available in some countries.
1. Fitton A, Benfield P. Isradipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1990; 40: 31–74
2. Walton T, Symes LR. Felodipine and isradipine: new calciumchannel blocking agents for the treatment of hypertension. Clin Pharm 1993; 12: 261–75
3. Brogden RN, Sorkin EM. Isradipine: an update of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of mild to moderate hypertension. Drugs 1995; 49: 618–49.

Administration in hepatic or renal impairment.

In patients with hepatic or renal impairment UK licensed product information recommends an initial dose of isradipine of 1.25 mg twice daily. The dose may be increased as required, but a maintenance dose of 2.5 or 5 mg once daily may be sufficient in some patients.

💊 Preparations

BP 2008: Isradipine Tablets; USP 31: Isradipine Capsules.

Proprietary Preparations

Arg.: Dynacirc†; Austria: Lomir; Belg.: Lomir; Braz.: Lomir; Chile: Dynacirc†; Cz.: Lomir; Denm.: Lomir; Fin.: Lomir; Fr.: Icaz; Ger.: Lomir; Vascal; Gr.: Lomir; Hong Kong: Dynacirc; Hung.: Lomir; Ital.: Clivoten; Esradin; Lomir; Malaysia: Dynacirc; Mex.: Dynacirc; Neth.: Lomir; Norw.: Lomir; NZ: Dynacirc; Philipp.: Icaz; Pol.: Lomir; Port.: Dilatol; Lomir; Rus.: Lomir (Ломир); S.Afr.: Dynacirc; Singapore: Dynacirc; Spain: Lomir; Swed.: Lomir; Switz.: Lomir; Thai.: Dynacirc; Turk.: Dynacirc; UK: Prescal; USA: Dynacirc; Venez.: Dynacirc†.
Published May 02, 2019.