WIDAPLIK telmisartan, amlodipine and indapamide 40 mg; 5 mg; 2.5 mg Tablet, 30-count

5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Electrolyte and Glucose Imbalances: Monitor serum electrolytes and glucose ( 5.3 ) Impaired Renal Function: Monitor renal function ( 5.4 ) Acute angle closure glaucoma can develop ( 5.5 ) Hyperuricemia may occur ( 5.6 )

5.1Fetal Toxicity Use of drugs that act on the renin-angiotensin-aldosterone 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 Widaplik as soon as possible [see Use in Specific Populations ( 8.1 ) ].

5.2Hypotension Widaplik can cause symptomatic hypotension. Patients with hypovolemia, salt depletion, or aortic stenosis are at increased risk. Monitor blood pressure and adjust dose as needed. Hypotension leading to worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Widaplik because of the amlodipine component, particularly in patients with severe obstructive coronary artery disease.

5.3Electrolyte and Glucose Imbalances Thiazide-like diuretics can cause hyponatremia, hypomagnesemia and hypokalemia and can also alter serum glucose and affect insulin requirements. Drugs that inhibit the renin angiotensin-aldosterone system can cause hyperkalemia. Patients with renal impairment or heart failure are at increased risk for hyperkalemia. Monitor serum electrolytes and glucose periodically.

5.4Impaired Renal Function Inhibiting the renin-angiotensin-aldosterone system or diuresis can precipitate renal dysfunction, oliguria and acute renal failure. Patients with severe congestive heart failure or renal dysfunction are at increased risk [see Clinical Pharmacology ( 12.3 ) ]. Monitor renal function periodically and adjust dose as needed.

5.5Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion Sulfonamide or sulfonamide-derivative drugs, like indapamide, can cause an idiosyncratic reaction resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. Symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated, the angle-closure glaucoma may result in permanent visual field loss.

The primary treatment is to discontinue Widaplik as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.6Hyperuricemia Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide-like diuretics.

6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: • Fetal toxicity [see Warnings and Precautions ( 5.1 )] • Hypotension [see Warnings and Precautions ( 5.2 )] • Electrolyte and Glucose Imbalances [see Warnings and Precautions ( 5.3 )] • Impaired Renal Function [see Warnings and Precautions ( 5.4 )] • Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion [see Warnings and Precautions ( 5.5 )] • Hyperuricemia [see Warnings and Precautions ( 5.6 )] The most common adverse reaction is symptomatic hypotension.

Low sodium and potassium values were recorded more often with Widaplik compared to placebo ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Widaplik Safety data were obtained from two randomized controlled studies that included 1,680 randomized patients with hypertension of whom 782 received Widaplik. Given the well-established safety profiles of the component medicines, only serious adverse events and the following adverse events of special interest were recorded: symptomatic hypotension, abnormal laboratory findings (sodium, potassium, uric acid, glucose, lipids, creatinine, eGFR), headache, peripheral edema, or other reason for discontinuation of study medication.

Study 1 In Study 1 (NCT04518306), 295 adult patients who were not receiving antihypertensive treatment for two weeks with baseline home systolic blood pressure 130-154 mmHg were randomized in a 2:2:1 ratio to Widaplik (10 mg/1.25 mg/0.625 mg), Widaplik (20 mg/2.5 mg/1.25 mg), or placebo. The study was 4 weeks in duration and randomized 232 patients to Widaplik and 63 to placebo. The proportion of patients who discontinued study medication due to an adverse event was 0% for Widaplik (10 mg/1.25 mg/0.625 mg), 5.1% for Widaplik (20 mg/2.5 mg/1.25 mg), and 1.6% for placebo.

Symptomatic hypotension, hyponatremia, and hypokalemia were more common with Widaplik than placebo (see Table 1). Most cases were mild to moderate in severity. Table 1: Adverse Reactions Reported in >2% of Patients Treated with Widaplik during the 4-Week Placebo-Controlled Treatment Period of Study 1 Widaplik (10 mg/1.25 mg/0.625 mg) (n=113) Widaplik (20 mg/2.5 mg/1.25 mg) (n=118) Placebo (n=62) Symptomatic hypotension n (%) 4 (3.5%) 6 (5.1%) 0 (0%) Sodium <135 mmol/L at week 4, n (%) 4 (3.5%) 1 (0.8%) 0 (0%) Potassium <3.5 mmol/L at week 4, n (%) 4 (3.5%) 6 (5.1%) 1 (1.6%) Study 2 Study 2 (NCT04518293) enrolled 2,242 patients on 0-3 antihypertensive medications at the screening visit.

After a 4-week active run-in period during which all patients were initially switched to Widaplik (20 mg/2.5 mg/1.25 mg), patients then entered a double-blind period where they were randomized 2:1:1:1 to either continue on Widaplik (20 mg/2.5 mg/1.25 mg) or switch to telmisartan/amlodipine (TA) 20 mg/2.5 mg, telmisartan/indapamide (TI) 20 mg/1.25 mg, or amlodipine/indapamide (AI) 2.5 mg/1.25 mg. After 6 weeks in the double-blind period, doses were doubled in all treatment groups and treatment was continued for an additional 6 weeks.

The study randomized 551 patients to Widaplik and 834 to one of the two-drug combinations. During the 4-week active run-in period on Widaplik, 3.2% of patients had symptomatic hypotension. During the run-in period, 3.2% of patients discontinued study medication due to an adverse event, including 0.8% of patients who discontinued due to symptomatic hypotension.

Because of this run-in design, the proportion of patients with adverse reactions described below is lower than expected in practice (see Table 2). The proportion of p…

7 DRUG INTERACTIONS NSAIDs: Increased risk of renal impairment and loss of anti-hypertensive effect ( 7.1 ) If simvastatin is co-administered with Widaplik, do not exceed doses greater than 20 mg daily of simvastatin ( 7.2 ) Do not co-administer aliskiren with Widaplik in patients with diabetes ( 7.1 )

7.1Drug Interactions with Telmisartan Aliskiren and other renin-angiotensin-aldosterone system (RAAS) inhibitors: Do not co-administer aliskiren with Widaplik in patients with diabetes. Most patients receiving the combination of two RAAS inhibitors do not obtain any additional benefit compared to monotherapy [see Contraindications ( 4 )] . Avoid use of aliskiren with Widaplik in patients with renal impairment (GFR <60 mL/min) [see Warnings and Precautions ( 5.4 )].

Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Monitor digoxin levels when initiating, adjusting, and discontinuing Widaplik to keep the digoxin level within the therapeutic range. Lithium: Increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan.

Monitor serum lithium levels during concomitant use [see Drug Interactions with Indapamide ( 7.3 )] . Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible. Monitor renal function periodically in patients receiving Widaplik and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.2Drug Interactions with Amlodipine Impact of other drugs on amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when Widaplik is co-administered with CYP3A inhibitors to determine the need for dose adjustment. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine.

Blood pressure should be closely monitored when Widaplik is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with Widaplik. Impact of amlodipine on other drugs Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin.

Limit the dose of simvastatin in patients on Widaplik to 20 mg daily. Immunosuppressants: Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus and dose adjustment when appropriate is recommended.

7.3Drug Interactions with Indapamide Lithium: In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy. Norepinephrine: Indapamide, like thiazide diuretics, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.