APROVASC Film-coated tablet Ref.[50621] Active ingredients: Amlodipine Irbesartan Irbesartan and Amlodipine

Special warnings

Hypotension – Patients with volume depletion

Symptomatic hypotension may occur in patients with sodium/volume depletion and in those under intensive treatment with diuretics and/or salt restriction, or in hemodialysis. The depletion of volume and/or sodium should be corrected before starting treatment with Aprovasc.

Hypoglycaemia

Irbesartan may induce hypoglycaemia, particularly in diabetic patients. In patients treated with insulin or antidiabetics an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required when indicated.

Fetal/neonatal morbidity and mortality

Although there is no experience with irbesartan in pregnant women, it has been reported that exposure to ACE inhibitors, administered to pregnant women during the second and third trimesters of pregnancy, may cause injuries and death to the fetus. Therefore, as any other drug acting directly on the renin-angiotensin-aldosterone system, Aprovasc should not be administered during pregnancy. If pregnancy is detected during treatment, Aprovasc should be discontinued as soon as possible.

Patients with heart failure

Patients with heart failure must be treated cautiously. In a long-term, placebocontrolled study (PRAISE-2) of amlodipine in patients with NYHA class III and IV heart failure of non-ischaemic origin, the use of amlodipine is associated with an increase in reports of pulmonary oedema despite no significant difference in the frequency of cases in which the heart failure worsened as compared to placebo (see Pharmacokinetics and Pharmacodynamics).

Hepatic impairment

For amlodipine: As with other calcium antagonists, the half-life of amlodipine is prolonged and the AUC values are greater in patients with impaired liver function and dose recommendations have not been established for this group. Therefore, amlodipine must be initiated at the lowest possible dose range and should be used with caution, both on initial treatment and when increasing the dose in these patients. A slow dose adjustment and careful monitoring in patients with severe liver failure may be necessary.

Hypertensive crisis

The safety and efficacy of Aprovasc in the treatment of hypertensive crisis has not been established.

General precautions

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The dual blockade of the renin-angiotensin-aldosterone system by combining Aprovasc with angiotensinconverting enzyme inhibitors (ACEIs) or with aliskiren is not recommended since there is an increased risk of hypotension, hyperkalemia and decreased renal function compared to monotherapy.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

The use of Aprovasc in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure (Glomerular Filtration Rate (GFR) <60 mL/min/1.73 m²).

The use of Aprovasc in combination with ACE-inhibitors is contraindicated in patients with diabetic nephropathy.

The use of Aprovasc in patients with psoriasis or with a history of psoriasis should be weighed carefully as it may exacerbate psoriasis.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovasc, a similar effect should be anticipated with angiotensin II receptor antagonists.

Renal impairment and kidney transplantation

When Aprovasc is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovasc in patients with a recent kidney transplantation.

Hypertensive patients with type 2 diabetes and renal disease

The effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see Pharmacodynamic properties).

Hyperkalaemia

As with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovasc, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see Interaction with other medicinal products and other forms of interaction).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovasc is not recommended.

General

Changes in the renal function of susceptible individuals can be expected as a consequence of the inhibition of the renin-angiotensin-aldosterone system. In patients whose renal function depends on the activity of the reninangiotensin-aldosterone system (hypertensive patients with renal artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment with other drugs that affect this system has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including irbesartan, cannot be excluded.

Geriatric use

In elderly patients with volume depletion (including those on therapy with diuretics), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, can cause a deterioration of renal function, including a possible acute renal failure. These effects are usually reversible. Renal function should be monitored in patients receiving periodic treatment with irbesartan and NSAIDs. The antihypertensive effect of angiotensin II receptor antagonists can be attenuated by NSAIDs including selective COX-2 inhibitors. Among patients who received irbesartan in clinical studies, no overall differences were observed in terms of efficacy and safety in older patients (65 years or older) or in younger patients.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

Lithium

The concomitant use of angiotensin II receptor blockers and calcium channel blockers may reduce renal lithium clearance and the increase of serum levels that may reach toxic levels. Hence, the combination of lithium and Aprovasc is not recommended.

For irbesartan and amlodipine combination: Based on a pharmacokinetic study where irbesartan and amlodipine were administered alone or in combination, there is no pharmacokinetic interaction between irbesartan and amlodipine.

No drug interaction studies have been conducted with Aprovasc and other medicinal products.

For Irbesartan

Based on in vitro information, no interactions are expected with drugs whose metabolism is dependent on CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4 cytochrome isoenzymes.

Irbesartan is primarily metabolized by CYP2C9, however, no significant interactions were observed during clinical interaction studies when irbesartan was administered concomitantly with warfarin (a drug metabolized by CYP2C9).

Diuretics and other antihypertensive agents

Other antihypertensive agents may increase the hypotensive effects of irbesartan; however irbesartan has been safely administered with other antihypertensive agents, such as betablockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovasc (see Special warnings and special precautions for use).

Irbesartan does not affect the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).

The pharmacokinetics of Irbesartan is not affected by concomitant administration of nifedipine or hydrochlorothiazide.

The combination of APROVASC with medications containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate (GFR) <60 mL/min/1.73 m²) and is not recommended in other patients.

Angiotensin-converting enzyme (ACE) inhibitors

The use of Aprovasc in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Repaglinide

Irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartan increased the C_max and the AUC of repaglinide (OATP1B1 substrate) 1.8 fold and 1.3 fold respectively when administered 1 hour before repaglinide. In another study, no relevant pharmacokinetic interaction was reported when two drugs were administered together. Therefore, it may be necessary to adjust the dose in antidiabetic treatment such as repaglinide (see General precautions).

Based on the experience with the use of other medications that affect the renin-angiotensin system, the concomitant use of Irbesartan with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medications that may increase kalaemia with irbesartan can cause an increase in serum potassium, sometimes severe, and requires close monitoring of serum potassium.

Non-steroidal anti-inflammatory drugs

When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and nonselective NSAIDs), attenuation of the antihypertensive effect may occur. As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see Special warnings and precautions for use). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

For Amlodipine

Amlodipine has been safely administered concomitantly with thiazide diuretics, beta blockers, alpha blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, nonsteroidal anti-inflammatory drugs, and oral hypoglycemic drugs. Data obtained from in vitro studies with human plasma show that amlodipine has no effect on protein binding of the medications studied (digoxin, phenytoin, warfarin or indomethacin).

Cimetidine

Co-administration of amlodipine with cimetidine did not alter amlodipine pharmacokinetics.

Grapefruit juice

The administration of amlodipine with grapefruit or grapefruit juice is not recommended as in some patients, its bioavailability may increase, resulting in an increase in the blood pressure lowering effects.

Sildenafil

When using amlodipine and sildenafil in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin

Simultaneous administration of multiple doses of 10 mg of amlodipine with 80 mg of atorvastatin showed no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin

Simultaneous administration of amlodipine with digoxin did not modify serum digoxin levels or digoxin renal clearance in healthy volunteers.

Warfarin

Simultaneous administration of amlodipine did not significantly modify the effect of warfarin on prothrombin time.

Effects of other medicinal products on amlodipine

CYP3A4 Inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in elderly subjects. Clinical monitoring and dose adjustment may be necessary.

Inducers of CYP3A4

Concomitant administration of inducers known as CYP3A4 may cause variations in plasma concentrations of amlodipine. Amlodipine should be used with caution when administered with CYP3A4 inducers. Blood pressure should be monitored and the dose considered should be adjusted during and after concomitant medication, particularly with potent CYP3A4 inducers (for example, rifampicin, hypericum perforatum).

Dantrolene (infusion)

In animals, fatal ventricular fibrillation and cardiovascular collapse have been observed in association with hyperkalaemia after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalaemia, it is recommended that concomitant administration of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine are added to the blood pressure lowering effects of other medicinal products with antihypertensive properties.

Tacrolimus

There is a risk of an increase in tacrolimus blood levels when it is administered together with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid tacrolimus toxicity, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and adjustment of the dose of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase the exposure of mTOR inhibitors.

Cyclosporine

No studies have been conducted on the pharmacological interaction between cyclosporine and amlodipine in healthy volunteers or other populations, except kidney transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in kidney transplant patients being treated with amlodipine, and cyclosporine doses should be reduced where necessary.

Simvastatin

Concomitant administration of multiple doses of 10 mg of amlodipine with 80 mg of simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients taking amlodipine to 20 mg per day.

Aluminium/magnesium (antacid)

The simultaneous administration of an antacid with aluminium/magnesium with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Laboratory test abnormalities

There were no clinically significant changes in laboratory parameters in controlled clinical studies with irbesartan in hypertensive patients. No special control of laboratory parameters is required in patients with essential hypertension receiving the treatment.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Aprovasc is contraindicated during pregnancy. Aprovasc should not be used in women of childbearing potential unless effective contraceptive measures are being used. If pregnancy occurs during treatment with Aprovasc, this should be discontinued as soon as possible (see Contraindications and Warnings).

Lactation

Aprovasc is contraindicated during lactation (see Contraindications).

Fetal/neonatal morbidity and mortality

Although there is no experience with irbesartan in pregnant women, it has been reported that exposure of the pregnancy product to ACE inhibitors, administered to pregnant women during the second and third quarters of pregnancy, causes injuries and death of the fetus. Therefore, as any other drug acting directly on the renin-angiotensin-aldosterone system, Aprovasc should not be administered during pregnancy. When pregnancy is detected during treatment, Aprovasc should be discontinued as soon as possible.

Special precautions related to the carcinogenic, mutagenic and teratogenic effects, and effects on fertility

Irbesartan

No evidence of carcinogenicity was observed when Irbesartan was administered at doses up to 500/1000 mg/kg/day in rats (males/females, respectively) and 1000 mg/kg/day in mice for two years. These doses produced a systemic exposure 4-25 times (rats) and 4-6 times (mice) greater than exposure in humans who received 300 mg daily.

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, mammalian V79 premature gene-mutation test). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro human lymphocyte assay; in vivo mouse micronucleus study).

Fertility and reproduction were not affected in studies of male and female rats, even with doses that cause some parental toxicity (up to 650 mg/kg/day). No significant effects on the number of corpora lutea, implants or live fetuses were observed. Irbesartan did not affect the survival, development, or reproduction of the offspring.

Transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema) were observed in rat fetuses at doses of 50 mg/kg/day or higher, which resolved after birth. In rabbits, maternal mortality, abortion and early resorption were observed at doses of 30 mg/kg/day. No other teratogenic effects were observed in rats or rabbits.

Amlodipine

Carcinogenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats, double* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenesis: Mutagenicity studies did not reveal any effect related to amlodipine at either the gene or chromosome levels.

Infertility: There was no effect on fertility in rats treated with amlodipine (males for 64 days and females 14 days before mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m² basis).

In another study in rats in which the male rats were treated with amlodipine besylate for 30 days at a dose comparable to the dose in humans based on mg/kg, a reduction in plasma follicle-stimulating hormone and testosterone levels was seen, in addition to a reduction in the density of spermatozoids and in the number of mature spermatids and Sertoli cells.

^* Based on a 50 kg patient.

For irbesartan

The effect of irbesartan on the ability to drive and use machines has not been investigated. Based on its pharmacodynamic properties, it is unlikely that irbesartan will have an effect on the ability to drive or operate machines. However, it should be taken into account that patients being treated for hypertension may occasionally experience dizziness or tiredness.

For amlodipine

Amlodipine may have a mild or moderate effect on the ability to drive and use machines. If patients taking amlodipine experience dizziness, headache, fatigue or nausea, the reaction speed may be affected. Caution is advised especially when starting treatment.

Adverse events

Since clinical studies are conducted under broadly variable conditions, the incidence of adverse reactions observed in drug clinical studies cannot be directly compared to clinical studies with other medications and may not reflect the rates observed in practice.

For irbesartan

Irbesartan safety has been evaluated in clinical studies with approximately 5000 subjects, including 1300 hypertensive patients treated for 6 months and more than 400 patients treated for 1 year or more. In general, adverse events in patients receiving irbesartan were mild and transient and were not related to the dose. The incidence of adverse events was not related to age, gender, or race.

In placebo-controlled clinical trials, including 1965 patients treated with irbesartan (usual treatment duration of 1 to 3 months), the discontinuation of treatment due to any clinical or laboratory adverse event was 3.3 percent for patients treated with Irbesartan and 4.5 percent for patients treated with placebo (p=0.029).

Adverse events that have been reported in clinical studies or post-marketing with irbesartan are categorized below according to the system organ class and frequency (see Table 3).

The following CIOMS frequency rating is used, when applicable: 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), unknown: cannot be estimated from available data.

The frequencies of adverse reactions from the post-marketing experience are unknown, because these reactions are reported voluntarily from a population of uncertain size.

Table 3. Adverse Events Reported in Clinical Trials with Irbesartan or in Post-marketing Reports:

^a Including all adverse events, probably or possibly related, or indefinite relationship to the therapy, whatever its incidence in patients treated with placebo
^b Including all adverse events, probably or possibly related, or indefinite relationship to the therapy, occurring with a frequency of 0.5% to <1% and in a similar or slightly higher incidence in patients treated with irbesartan compared to patients treated with placebo (none of them significantly different in statistical terms between the 2 treatment groups)

Terms marked with a star (*) refer to the adverse reactions that were additionally reported in >2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo.

For amlodipine

Adverse events reported in clinical studies with amlodipine are categorized below according to system organ class and frequency (see Table 4).

The following CIOMS frequency rating is used, when applicable: 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), unknown: cannot be estimated from available data.

Table 4. Adverse Events Reported in Clinical Trials with Amlodipine:

In clinical studies comparing the fixed-dose combination irbesartan/amlodipine to either irbesartan or amlodipine monotherapy, the types and incidences of treatment-emergent adverse events (TEAEs) possibly related to study treatment were similar to those observed in earlier monotherapy clinical trials and postmarketing reports. The most frequently reported adverse event was peripheral edema, mainly associated with amlodipine (see Table 5).

The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).

Table 5. Treatment-Emergent Adverse Events Considered Possibly Related to Study Drug in Irbesartan/Amlodipine Clinical Studies (I-ADD, I-COMBINE and I-COMBO):