Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
In patients whose vascular tone and renal function depend predominantly on the activity of the RAAS (e.g. patients with congestive heart failure, severe renal impairment or renal artery stenosis), treatment with medicinal products that affect this system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with Edarbi.
Caution should be exercised in hypertensive patients with severe renal impairment, congestive heart failure or renal artery stenosis, as there is no experience of use of Edarbi in these patients (see sections 4.2 and 5.2).
Excessive blood pressure decreases in patients with ischaemic cardiomyopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). 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. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
There is currently no experience on the use of Edarbi in patients who have recently undergone kidney transplantation.
Edarbi has not been studied in patients with severe hepatic impairment and therefore its use is not recommended in this patient group (see sections 4.2 and 5.2).
In patients with marked volume- and/or salt-depletion (e.g. patients with vomiting, diarrhoea or taking high doses of diuretics) symptomatic hypotension could occur after initiation of treatment with Edarbi. Hypovolemia should be corrected prior to administration of Edarbi, or the treatment should start under close medical supervision, and consideration can be given to a starting dose of 20 mg.
Patients with primary hyperaldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the RAAS. Therefore, the use of Edarbi is not recommended in these patients.
Based on experience with the use of other medicinal products that affect the RAAS, concomitant use of Edarbi with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients (see section 4.5). In the elderly, in patients with renal insufficiency, in diabetic patients and/or in patients with other co-morbidities, the risk of hyperkalaemia, which may be fatal, is increased. Monitoring of potassium should be undertaken as appropriate.
Special caution is indicated in patients suffering from aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
As with other angiotensin II receptor antagonists the combination of lithium and Edarbi is not recommended (see section 4.5).
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of lithium and angiotensin-converting enzyme inhibitors. A similar effect may occur with angiotensin II receptor antagonists. Due to the lack of experience with concomitant use of azilsartan medoxomil and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
When angiotensin II receptor antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II receptor antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, adequate hydration and monitoring of renal function at the beginning of the treatment are recommended.
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of serum potassium should be undertaken as appropriate (see section 4.4).
Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
No clinically significant interactions have been reported in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlortalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, and warfarin. Following administration with a mixture of cytochrome P450 (CYP) probe substrates, no clinically significant drug interactions were observed with caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), or midazolam (CYP3A4).
Azilsartan medoxomil is rapidly hydrolysed to the active moiety azilsartan by esterases in the gastrointestinal tract and/or during drug absorption (see section 5.2). In vitro studies indicated that interactions based on esterase inhibition are unlikely.
The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4).
The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
There are no data from the use of azilsartan medoxomil in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there are no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken Angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).
Because no information is available regarding the use of azilsartan medoxomil during breastfeeding, Edarbi is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breast-feeding a newborn or preterm infant.
No data are available on the effect of azilsartan medoxomil on human fertility. Nonclinical studies demonstrated that azilsartan did not appear to affect male or female fertility in the rat (see section 5.3).
Azilsartan medoxomil has no or negligible influence on the ability to drive and use machines. However it should be taken into account that occasionally dizziness or tiredness may occur.
Edarbi at doses of 20, 40 or 80 mg has been evaluated for safety in clinical studies in patients treated for up to 56 weeks. In these clinical studies, adverse reactions associated with treatment with Edarbi were mostly mild or moderate, with an overall incidence similar to placebo. The most common adverse reaction was dizziness. The incidence of adverse reactions with this treatment was not affected by gender, age, or race. Adverse reactions were reported at a similar frequency for the Edarbi 20 mg dose as with the 40 and 80 mg doses in one placebo controlled study.
Adverse reactions based on pooled data (40 and 80 mg doses) are listed below according to system organ class and preferred terms. These are ranked by frequency, using the following convention: 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), including isolated reports. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Nervous system disorders | Common | Dizziness |
| Vascular disorders | Uncommon | Hypotension |
| Gastrointestinal disorders | Common Uncommon | Diarrhoea Nausea |
| Skin and subcutaneous tissue disorders | Uncommon Rare | Rash, pruritus Angioedema |
| Musculoskeletal and connective tissue disorders | Uncommon | Muscle spasms |
| General disorders and administration site conditions | Uncommon | Fatigue Peripheral oedema |
| Investigations | Common Uncommon | Blood creatine phosphokinase increased Blood creatinine increased Blood uric acid increased / Hyperuricemia |
When Edarbi was coadministered with chlortalidone, the frequencies of blood creatinine increased and hypotension were increased from uncommon to common.
When Edarbi was coadministered with amlodipine, the frequency of peripheral oedema was increased from uncommon to common, but was lower than amlodipine alone.
The incidence of elevations in serum creatinine following treatment with Edarbi was similar to placebo in the randomised placebo-controlled monotherapy studies. Coadministration of Edarbi with diuretics, such as chlortalidone, resulted in a greater incidence of creatinine elevations, an observation consistent with that of other angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. The elevations in serum creatinine during coadministration of Edarbi with diuretics were associated with larger blood pressure reductions compared with a single medicinal product. Many of these elevations were transient or nonprogressive while subjects continued to receive treatment. Following discontinuation of treatment, the majority of the elevations that had not resolved during treatment were reversible, with the creatinine levels of most subjects returning to baseline or nearbaseline values.
Small mean increases of serum uric acid were observed with Edarbi (10.8 μmol/l) compared with placebo (4.3 μmol/l).
Small decreases in hemoglobin and hematocrit (mean decreases of approximately 3 g/l and 1 volume percent, respectively) were observed in placebo-controlled monotherapy studies. This effect is also seen with other inhibitors of the RAAS.
A clinical study on the safety and efficacy of Edarbi in children and adolescents 6 to <18 years of age was conducted (see section 5.1). The overall safety profile of Edarbi in the paediatric population was consistent with the known safety profile in adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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