WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue Edarbyclor as soon as possible [see Warnings and Precautions (5.1) ]. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ]. WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue EDARBYCLOR as soon as possible (5.1) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1)
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as volume- and/or salt-depleted patients, Edarbyclor can cause excessive hypotension. Correct volume or salt depletion prior to administration of Edarbyclor ( 5.2 ) • In patients with renal artery stenosis, Edarbyclor may cause renal failure ( 5.3 ) • Monitor renal function in patients with renal impairment. Consider discontinuing Edarbyclor with progressive renal impairment ( 5.3 ) 5.1 Fetal Toxicity Azilsartanmedoxomil Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbyclor as soon as possible [see Use in Specific Populations (8.1) ]. Chlorthalidone Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia. 5.2 Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbyclor. Such patients are probably not good candidates to start therapy with more than one drug; therefore, correct volume prior to administration of Edarbyclor. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.3 Impaired Renal Function Edarbyclor Monitor for worsening renal function in patients with renal impairment. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident. Azilsartanmedoxomil As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbyclor. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbyclor [see Drug Interactions (7) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results are expected. Chlorthalidone In patients with renal disease, chlorthalidone may precipitate azotemia. If progressive renal impairment becomes evident, as indicated by increased blood urea nitrogen, consider withholding or discontinuing diuretic therapy. 5.4 Hypokalemia Chlorthalidone Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Co-administration of digitalis may exacerbate the adverse effects of hypokalemia. Edarbyclor attenuates chlorthalidone-associated hypokalemia. In patients with normal potassium levels at baseline, 1.7% of Edarbyclor-treated patients, 0.9% of azilsartan medoxomil-treated patients, and 13.4% of chlorthalidone-treated patients shifted to low potassium values (less than 3.4 mmol/L). 5.5 Hyperuricemia Chlorthalidone Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.
6 ADVERSE REACTIONS The following potential adverse reactions with Edarbyclor, azilsartan medoxomil, or chlorthalidone and similar agents are included in more detail in the Warnings and Precautions section of the label: • Fetal toxicity [see Warnings and Precautions (5.1) ] • Hypotension in Volume- or Salt-Depleted Patients [see Warnings and Precautions (5.2) ] • Impaired Renal Function [see Warnings and Precautions (5.3) ] • Hypokalemia [see Warnings and Precautions (5.4) ] • Hyperuricemia [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence ≥2%) are dizziness and fatigue ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Edarbyclor has been evaluated for safety in more than 3900 patients with hypertension; more than 700 patients were treated for at least 6 months and more than 280 for at least 1 year. Adverse reactions have generally been mild and transient in nature. Common adverse reactions that occurred in the 8-week factorial design trial in at least 2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone are presented in Table 1. Table 1. Adverse Reactions Occurring at an Incidence of ≥2% of Edarbyclor-treated Patients and > Azilsartan medoxomil or Chlorthalidone Preferred Term Azilsartanmedoxomil 20, 40, 80 mg (N=470) Chlorthalidone 12.5, 25 mg (N=316) Edarbyclor 40 / 12.5, 40 / 25 mg (N=302) Dizziness 1.7% 1.9% 8.9% Fatigue 0.6% 1.3% 2.0% Hypotension and syncope were reported in 1.7% and 0.3%, respectively, of patients treated with Edarbyclor. Study discontinuation because of adverse reactions occurred in 8.3% of patients treated with the recommended doses of Edarbyclor compared with 3.2% of patients treated with azilsartan medoxomil and 3.2% of patients treated with chlorthalidone. The most common reasons for discontinuation of therapy with Edarbyclor were serum creatinine increased (3.6%) and dizziness (2.3%). The adverse reaction profile obtained from 52 weeks of open-label combination therapy with azilsartan medoxomil plus chlorthalidone or Edarbyclor was similar to that observed during the double-blind, active controlled trials. In 3 double-blind, active controlled, titration studies, in which Edarbyclor was titrated to higher doses in a step-wise manner, adverse reactions and discontinuations for adverse events were less frequent than in the fixed-dose factorial trial. Azilsartanmedoxomil A total of 4814 patients were evaluated for safety when treated with azilsartan medoxomil at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months, of these, 588 were treated for at least 1 year. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race. Adverse reactions with a plausible relationship to treatment that have been reported with an incidence of ≥0.3% and greater than placebo in more than 3300 patients treated with azilsartan medoxomil in controlled trials are listed below: Gastrointestinal Disorders: diarrhea, nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Chlorthalidone The following adverse reactions have been observed in clinical trials of chlorthalidone: rash, headache, dizziness, GI upset, and elevations of uric acid and cholesterol. Clinical Laboratory Findings with Edarbyclor In the factorial design trial, clinically relevant changes in standard laboratory parameters were uncommon with administration of the recommended doses of Edarbyclor. Renal parameters: Increased blood creatinine is a known pharmacologic effect of renin-angiotensin aldosterone system (RAAS) blockers, such as ARBs and ACE inhibitors, and is related to the magnitude of blood pressure reduction. The incidence of consecutive increases of creatinine ≥50% from baseline and >ULN was 2.0% in patients treated with the recommended doses of Edarbyclor compared with 0.4% and 0.3% with azilsartan medoxomil and chlorthalidone, respectively. Elevations of creatinine were typically transient, or non-progressive and reversible, and associated with large blood pressure reductions. Mean increases in blood urea nitrogen (BUN) were observed with Edarbyclor (5.3 mg/dL) compared with azilsartan medoxomil (1.5 mg/dL) and with chlorthalidone (2.5 mg/dL).