telmisartan, amlodipine and indapamide

Brand names: WIDAPLIK

Boxed warning

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Widaplik as soon as possible [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]. Drugs that act directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]. WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue WIDAPLIK as soon as possible ( 5.1 , 8.1 ) • Drugs that act directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus ( 5.1 , 8.1 )

Warnings

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 ) 5.1 Fetal 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 ) ]. 5.2 Hypotension 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. 5.3 Electrolyte 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. 5.4 Impaired 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. 5.5 Acute 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. 5.6 Hyperuricemia Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide-like diuretics.

Contraindications

4 CONTRAINDICATIONS Do not use in patients with anuria, known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, indapamide, or to other sulfonamide-derived drugs, or to any other component of this product. Do not co-administer aliskiren with Widaplik in patients with diabetes [see Drug Interactions ( 7.1 )] . Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, amlodipine, indapamide, or to other sulfonamide-derived drugs, or to any other component of this product ( 4 ) Do not co-administer aliskiren with Widaplik in patients with diabetes ( 4 ) Anuria ( 4 )

Overdose

10 OVERDOSAGE Telmisartan Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. Amlodipine Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the MRHD on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption. Indapamide Symptoms of overdosage of indapamide include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed. If this occurs, support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.

Drug interactions

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 ) 7.1 Drug 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. 7.2 Drug 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. 7.3 Drug 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.

Uses

1 INDICATIONS AND USAGE Widaplik (telmisartan/amlodipine/indapamide) is indicated for the treatment of hypertension in adult patients, to lower blood pressure. Widaplik may be used as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including angiotensin II receptor blockers, dihydropyridine calcium channel blockers and thiazide-like diuretics. There are no controlled trials demonstrating risk reduction with Widaplik. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving the goal with a triple combination product compared with mono- or dual therapy when deciding whether to use Widaplik as initial therapy. Individual blood pressure goals may vary based upon the patient’s risk. WIDAPLIK is a combination tablet of telmisartan, an angiotensin II receptor blocker, amlodipine, a dihydropyridine calcium channel blocker and indapamide, a thiazide-like diuretic. Widaplik is indicated for the treatment of hypertension, including as initial treatment, to lower blood pressure. ( 1 ) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1 )

Dosage forms & strengths

TABLET
TELMISARTAN 40 mg/1 AMLODIPINE BESYLATE 5 mg/1 INDAPAMIDE 2.5 mg/1 TELMISARTAN 10 mg/1 AMLODIPINE BESYLATE 1.25 mg/1 INDAPAMIDE .625 mg/1 TELMISARTAN 20 mg/1 AMLODIPINE BESYLATE 2.5 mg/1 INDAPAMIDE 1.25 mg/1

2 DOSAGE AND ADMINISTRATION For initial treatment of hypertension, start with Widaplik (10 mg/ 1.25 mg/0.625 mg) or Widaplik (20 mg/2.5 mg/1.25 mg) orally once daily. Titrate up to a maximum dose of Widaplik (40 mg/5 mg/2.5 mg) orally once daily. ( 2.2 ) Dosage may be increased after 2 weeks to a maximum dose of 40 mg/5 mg/2.5 mg orally once daily to achieve more rapid control. ( 2.1 ) Almost all of the antihypertensive effect is apparent within 2 weeks of initiating treatment. ( 2.1 ) 2.1 General Considerations Dose orally once daily. Dosage must be individualized and may be increased after 2 weeks of treatment. Almost all the antihypertensive effect is apparent within 2 weeks of initiating treatment. Swallow tablets whole. Do not cut, crush, or chew tablets. Widaplik may be taken with or without food. Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with Widaplik [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage The recommended starting dosage is with Widaplik (10 mg/1.25 mg/0.625 mg) orally once daily or Widaplik (20 mg/2.5 mg/1.25 mg) orally once daily, based on anticipated need for blood pressure reduction. In elderly patients consider starting with Widaplik (10 mg/1.25 mg/0.625 mg) orally once daily [see Use in Specific Populations, Geriatric Use ( 8.5 )]. The maximum recommended dose is Widaplik (40 mg/5 mg/2.5 mg) orally once daily.

All identified pills

Side effects

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. 6.1 Clinical 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 patients who discontinued study medication due to an adverse event over the 12-week treatment period was 2.0% for Widaplik and 1.4%, 1.1%, and 1.4% for the telmisartan/indapamide, telmisartan/amlodipine, and amlodipine/indapamide groups, respectively. Most adverse reactions were generally mild to moderate in severity. Table 2: Adverse Reactions Reported in >2% of Patients Treated with Widaplik during the 12-Week Treatment Period of Study 2 Widaplik (n = 547) Telmisartan/ Indapamide (n = 275) Telmisartan/ Amlodipine (n = 282) Amlodipine/ Indapamide (n = 276) Symptomatic hypotension, n (%) 32 (5.9%) 11 (4.0%) 5 (1.8%) 4 (1.4%) Sodium <135 mmol/L at week 12, n (%) 40 (7.3%) 19 (6.9%) 9 (3.2%) 10 (3.6%) Potassium <3.5 mmol/L at week 12, n (%) 37 (6.8%) 13 (4.7%) 0 (0%) 35 (12.7%) 6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience with telmisartan, amlodipine or indapamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Telmisartan The most frequently reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioedema, urticaria, sweating increased, erythema, dyspepsia, diarrhea, pain, erectile dysfunction, abdominal pain, myalgia, eosinophilia, thrombocytopenia, anemia, and increased CPK, rhabdomyolysis, drug eruption (e.g., toxic skin eruption mostly reported as toxicoderma, rash, and urticaria). Amlodipine Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), extrapyramidal disorder. Indapamide Exacerbation of systemic lupus erythematous, choroidal effusion, acute myopia, and angle-closure glaucoma.

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