Telmisartan Amlodipine Drug Information

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 .

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. The maximum recommended dose is Widaplik (40 mg/5 mg/2.5 mg) orally once daily.

• 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.

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 . Avoid use of aliskiren with Widaplik in patients with renal impairment (GFR <60 mL/min). 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 . 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.

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.

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.

Pregnancy Risk Summary Widaplik can cause fetal harm when administered to a pregnant woman. 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 ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin-aldosterone system from other antihypertensive agents. Studies in rats and rabbits showed fetotoxicity only at maternally toxic doses of telmisartan ( see Data ). When pregnancy is detected, discontinue Widaplik as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Telmisartan Use of drugs that act on the RAAS in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin-aldosterone system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking Widaplik during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.

If oligohydramnios is observed, discontinue Widaplik, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to Widaplik for hypotension, oliguria, and hyperkalemia.

If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Indapamide Diuretics are known to cross the placental barrier and appear in cord blood.

There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult. Data Animal Data No reproductive toxicity studies have been conducted with Widaplik. However, these studies have been conducted for telmisartan, amlodipine and indapamide alone.

Telmisartan No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m 2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain.

The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m 2 basis, the MHRD of telmisartan (80 mg/day). Amlodipine No evidence of teratogenicity or embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. Indapamide Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide.

Postnatal development in rats and mice was unaffected by pretreatment of parent animals during gestation.

Pediatric Use Safety and effectiveness of Widaplik in pediatric patients have not been established. Neonates with a history of in utero exposure to Widaplik If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

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 . 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 Anuria

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.