Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Novartis New Zealand Limited, 109 Carlton Gore Road, Newmarket, Auckland 1023, PO Box 99102, Newmarket, Auckland 1149, Telephone: 0800 354 335
Known hypersensitivity to isradipine, to other calcium channel blockers of the dihydropyridine type or to any of the excipients (see section 6.1 List of Excipients).
As with other calcium channel blockers of the dihydropyridine type, Dynacirc SRO should not be used in patients with any of the following conditions:
Individualized dosing of Dynacirc SRO is recommended for elderly patients and patients with hepatic impairment.
A cautious dosing regimen is recommended for patients with renal impairment or chronic heart failure.
Caution should be exercised when treating patients with confirmed or strongly suspected sick sinus syndrome who are not fitted with a pacemaker. Care is recommended when treating patients with low systolic blood pressure.
Extreme caution is advised when giving dihydropyridines to patients with severe aortic stenosis.
Angina pectoris may occur, predominantly in patients with pre-existing coronary artery disease. At the start of treatment or when dosage increments are made too quickly in patients with pre-existing angina pectoris, frequency, duration and severity of anginal attacks may be increased.
If hypersensitivity develops, Dynacirc SRO should be discontinued.
Concomitant administration with rifampicin or other enzyme-inducing drugs should be avoided (see section 4.5 Interactions with other medicines and other forms of interaction).
Concurrent administration of rifampicin greatly reduces the plasma concentrations of isradipine. Therefore, concomitant administration with rifampicin or other enzyme-inducing drugs (e.g. anticonvulsants such as carbamazepine, phenobarbital) should be avoided.
Based on a case report and on the known risks related to the co-administration of phenytoin with calcium channel blockers, concomitant administration with phenytoin should be avoided.
Increased plasma levels, and potentiation of drug activity and adverse effects (e.g. peripheral oedema), have been reported when dihydropyridines are administered concomitantly with cytochrome P450 3A inhibitors. There is little evidence for such interactions with isradipine, but caution should be exercised when coadministering Dynacirc with strong CYP3A inhibitors such as macrolide antibiotics (e.g. erythromycin, clarithromycin, troleandomycin), HIV protease inhibitors (e.g. ritonavir, indinavir, nelfinavir) or reverse transcriptase inhibitors (e.g. delavirdine), and azole antifungals (e.g. ketoconazole, itraconazole, voriconazole).
As with all antihypertensives, concomitant treatment with oral baclofen is likely to further increase a possible fall in blood pressure. It may therefore be necessary to monitor blood pressure and adjust the dosage of the antihypertensive medication accordingly.
Concurrent administration of cimetidine increases the bioavailability of isradipine by about 50% (see section 4.2 Dose and method of administration).
The peak plasma concentration of isradipine increases by about 20% during co-administration with diclofenac but this is not expected to be clinically significant, as steady state exposure remained unchanged.
The pharmacokinetics of isradipine are not modified by the concomitant administration of digoxin, propranolol, warfarin, hydrochlorothiazide or ciclosporin.
Isradipine does not seem to inhibit the cytochrome P450 enzymes, in particular CYP3A4, to a clinically significant extent.
Isradipine does not affect the pharmacokinetics of digoxin, warfarin, hydrochlorothiazide, diclofenac, theophylline, triazolam or ciclosporin.
Isradipine induces a small (27%) increase in the bioavailability (AUC) of propranolol. The clinical relevance is not known.
The concomitant intake of grapefruit juice may increase the bioavailability of isradipine.
There are no data supporting any special recommendations in women of child-bearing potential.
Animal studies do not show any harmful effects on fertility (see Section 5.3 Pre-clinical safety data).
There is limited information on the use of Dynacirc SRO in pregnant women. Data on a limited number of pregnant women exposed to Dynacirc in the third trimester indicate no adverse effects of isradipine on pregnancy or on the health of the fetus or neonate. Animal studies do not show any directly or indirectly harmful effects on pregnancy, embryofetal development, parturition or postnatal development at therapeutically relevant dose levels (see Section 5.3 Pre-clinical safety data). The oral use of Dynacirc in the third trimester has not been associated with any change in fetal heart rate or uteroplacental blood flow and the tocolytic effect seems to be weak.
The risk to the fetus/mother is unknown. Because animal reproductive toxicity studies are not always predictive of human response, isradipine should be used during pregnancy only if clinically indicated and only if the expected benefit outweighs the potential risk to the fetus.
There is limited information on the use of Dynacirc SRO in breast-feeding women. In a study in rats it was shown that small amounts of isradipine pass into the milk. Animal experiments have not shown isradipine to have any adverse effects when administered during lactation. It is unknown whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isradipine is administered to a breastfeeding woman.
There are no data on the effects of Dynacirc SRO on the ability to drive or use machines.As with other calcium channel blockers, syncope, dizziness, hypotension, visual disturbances and blurred vision are known adverse drug reactions associated with the use of Dynacirc. Patients should not drive a vehicle or operate a machine or perform tasks that require alertness if they experience these symptoms.
Most adverse reactions observed in clinical trials were mild, generally dose-dependent and related to the vasodilating properties of Dynacirc: dizziness, headache, flushing, tachycardia, palpitations and localised peripheral oedema of non-cardiac origin (local arterial dilatation seems to be involved rather than fluid retention). These tend to disappear or to decrease as treatment continues.
Improved tolerability could be achieved with SRO capsules, the incidence of dizziness, headache, flushing and oedema peripheral being lower than with the tablets.
Adverse drug reactions (Table 1) are listed according to system organ class in MedDRA. MedDRA version used is 15.1. Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports, not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1. Adverse reactions observed in clinical trials (occurring more frequently with isradipine than with placebo) and compiled from spontaneous reports are presented below according to system organ class:
Very rare: Thrombocytopenia, leukopenia, anaemia.
Very rare: Anaphylactic reactions
Very rare: Decreased appetite.
Very rare: Depression, anxiety, nervousness.
Not known: Insomnia.
Very common: Headache.
Common: Dizziness.
Very rare: Hypoaesthesia, paraesthesia, somnolence.
Not known: Transient ischemic attack, lethargy.
Not known: Syncope, stroke
Very rare: Visual impairment, vision blurred.
Common: Tachycardia, palpitations.
Very rare: Ventricular arrhythmia, myocardial infarction, cardiac failure, angina pectoris, atrial fibrillation, bradycardia.
Very common: Flushing.
Uncommon: Hypotension.
Common: Dyspnoea
Very rare: Cough.
Common: Abdominal discomfort.
Very rare: Vomiting, nausea, gingival hyperplasia.
Not known: Dry mouth, constipation, diarrhoea.
Very rare: Hepatitis.
Common: Rash.
Very rare: Dermatitis allergic, pruritus, hyperhidrosis , angioedema,and photosensitivity reaction.
Very rare: Arthralgia, back pain, muscle spasms, pain in extremity.
Common: Polyuria.
Very rare: Erectile dysfunction, gynecomastia.
Very common: Oedema peripheral
Common: Fatigue, malaise.
Very rare: Asthenia.
Not known: Chest pain.
Uncommon: Weight increased. Very rare: Liver functions test abnormal
Reporting of suspected adverse reactions-Reporting suspected adverse reactions after authorization of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via https://nzphvc.otago.ac.nz/reporting/
Not applicable.
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