Azilsartan medoxomil

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.

Caution should be exercised in hypertensive patients with severe renal impairment and end stage renal disease as there is no experience of use of Edarbi in these patients.

As there is limited experience of use of azilsartan medoxomil in patients with mild to moderate hepatic impairment close monitoring is recommended and consideration should be given to 20 mg as a starting dose.

Azilsartan medoxomil has not been studied in patients with severe hepatic impairment and therefore its use is not recommended in this patient group.

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.

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.

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.

Based on experience with the use of other medicinal products that affect the RAAS, concomitant use of azilsartan medoxomil 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. 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.

Patients with primary hyperaldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the RAAS. Therefore, the use of azilsartan medoxomil is not recommended in these patients.

Hemodialysis does not remove azilsartan from the systemic circulation.

For patients with possible depletion of intravascular volume or salt depletion (e.g. patients with vomiting, diarrhoea or taking high doses of diuretics), azilsartan medoxomil should be initiated under close medical supervision and consideration can be given to 20 mg as a starting dose.

Special caution is indicated in patients suffering from aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy.

The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy.

There are no data from the use of azilsartan medoxomil in pregnant women. Studies in animals have shown reproductive toxicity.

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).

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.

Because no information is available regarding the use of azilsartan medoxomil during breastfeeding, azilsartan medoxomil is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breast-feeding a newborn or preterm infant.

Fertility

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.

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.

Summary of the safety profile

Azilsartan medoxomil 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 azilsartan medoxomil 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 azilsartan medoxomil 20 mg dose as with the 40 and 80 mg doses in one placebo controlled study.

Tabulated list of adverse reactions

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.

Description of selected adverse reactions

When azilsartan medoxomil was coadministered with chlortalidone, the frequencies of blood creatinine increased and hypotension were increased from uncommon to common.

When azilsartan medoxomil was coadministered with amlodipine, the frequency of peripheral oedema was increased from uncommon to common, but was lower than amlodipine alone.

Investigations

Serum creatinine

The incidence of elevations in serum creatinine following treatment with azilsartan medoxomil was similar to placebo in the randomised placebo-controlled monotherapy studies. Coadministration of azilsartan medoxomil 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 coadminstiration of azilsartan medoxomil 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 near-baseline values.

Uric acid

Small mean increases of serum uric acid were observed with azilsartan medoxomil (10.8 μmol/l) compared with placebo (4.3 μmol/l).

Hemoglobin and hematocrit

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.

Paediatric population

A clinical study on the safety and efficacy of azilsartan medoxomil in children and adolescents 6 to <18 years of age was conducted. The overall safety profile of azilsartan medoxomil in the paediatric population was consistent with the known safety profile in adults.