IRBESARTAN AND HYDROCHLOROTHIAZIDE

Irbesartan and hydrochlorothiazide tablets are a combination of an angiotensin II receptor antagonist (AT 1 subtype), irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ). Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its empirical formula is C 25 H 28 N 6 O, and its structural formula is: Irbesartan, USP is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide, USP is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. Irbesartan and hydrochlorothiazide tablets, USP are available for oral administration in film-coated tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. All dosage strengths contain the following inactive ingredients: croscarmellose sodium, ferric oxide black, ferric oxide red, ferric oxide yellow, hypromellose, lactose monohydrate, lecithin, macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part.hydrolyzed, talc, and titanium dioxide. Chemical Structure Irbesartan Chemical Structure Hydrochlorothiazide

Irbesartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension. Irbesartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy. Irbesartan and hydrochlorothiazide tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of irbesartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 (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. The decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy. Data from Studies V and VI [see Clinical Studies (14.2) ] provide estimates of the probability of reaching a blood pressure goal with irbesartan and hydrochlorothiazide tablets compared to irbesartan or hydrochlorothiazide (HCTZ) monotherapy. The relationship between baseline blood pressure and achievement of a SeSBP <140 or <130 mmHg or SeDBP <90 or <80 mmHg in patients treated with irbesartan and hydrochlorothiazide tablets compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b. Figure 1a: Probability of Achieving SBP <140 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 1b: Probability of Achieving SBP <130 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 2a: Probability of Achieving DBP <90 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 2b: Probability of Achieving DBP <80 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* The above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 sitting systolic blood pressure ≤140 mmHg) for the treatment groups. The curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. For example, a patient with a blood pressure of 180/105 mmHg has about a 25% likelihood of achieving a goal of <140 mmHg (systolic) and 50% likelihood of achieving <90 mmHg (diastolic) on irbesartan alone (and lower still likelihoods on HCTZ alone). The likelihood of achieving these goals on irbesartan and hydrochlorothiazide tablets rises to about 40% (systolic) or 70% (diastolic). Irbesartan and hydrochlorothiazide tablets are a combination of irbesartan, an angiotensin II receptor antagonist, and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension: • In patients not adequately controlled with monotherapy. (1) • As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. (1) Irbesartan and Hydrochlorothiazide Figure 1A Irbesartan and Hydrochlorothiazide Figure 1B Irbesartan and Hydrochlorothiazide Figure 2A Irbesartan and Hydrochlorothiazide Figure 2B

General Considerations • Maximum effects within 2 to 4 weeks after dose change. (2.1) • Renal impairment: Not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min). (2.1 , 5.8) Hypertension • Initiate with 150 mg/12.5 mg. Titrate to 300 mg/12.5 mg then 300 mg/25 mg if needed. (2.2) • Replacement therapy: May be substituted for titrated components. (2.3) 2.1 General Considerations The side effects of irbesartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. [See Adverse Reactions (6) .] Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose. Irbesartan and hydrochlorothiazide tablets may be administered with or without food. Irbesartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents. Renal Impairment The usual regimens of therapy with irbesartan and hydrochlorothiazide tablets may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so irbesartan and hydrochlorothiazide tablets are not recommended. Hepatic Impairment No dosage adjustment is necessary in patients with hepatic impairment. 2.2 Add-On Therapy In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of irbesartan and hydrochlorothiazide tablets, in order of increasing mean effect, are (irbesartan and hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg. [See Clinical Studies (14.2) .] 2.3 Replacement Therapy Irbesartan and hydrochlorothiazide tablets may be substituted for the titrated components. 2.4 Initial Therapy The usual starting dose is irbesartan and hydrochlorothiazide tablets 150/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300/25 mg once daily as needed to control blood pressure [see Clinical Studies (14.2) ] . Irbesartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ] .

• Irbesartan and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product. • Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. • Do not coadminister aliskiren with irbesartan and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7) ] . • Hypersensitivity to any component of this product. (4) • Anuria. (4) • Hypersensitivity to sulfonamide-derived drugs. (4) • Do not coadminister aliskiren with irbesartan and hydrochlorothiazide tablets in patients with diabetes. (4)

• Most common adverse events (≥5% on irbesartan and hydrochlorothiazide tablets and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Irbesartan and Hydrochlorothiazide Irbesartan and hydrochlorothiazide tablets have been evaluated for safety in 1,694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with irbesartan and hydrochlorothiazide tablets, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo. In general, treatment with irbesartan and hydrochlorothiazide tablets were well tolerated. For the most part, adverse events have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of irbesartan and hydrochlorothiazide tablets therapy due to clinical adverse events was required in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy. In these double-blind controlled clinical trials, the following adverse events reported with irbesartan and hydrochlorothiazide tablets occurred in ≥1% of patients, and more often on the irbesartan and hydrochlorothiazide combination than on placebo, regardless of drug relationship: Irbesartan/HCTZ (n=898) (%) Placebo (n=236) (%) Irbesartan (n=400) (%) HCTZ (n=380) (%) Body as a Whole Chest Pain 2 1 2 2 Fatigue 6 3 4 3 Influenza 3 1 2 2 Cardiovascular Edema 3 3 2 2 Tachycardia 1 0 1 1 Gastrointestinal Abdominal Pain 2 1 2 2 Dyspepsia/heartburn 2 1 0 2 Nausea/vomiting 3 0 2 2 Immunology Allergy 1 0 1 1 Musculoskeletal Musculoskeletal Pain 6 5 6 10 Nervous System Dizziness 8 4 6 5 Dizziness Orthostatic 1 0 1 1 Renal/Genitourinary Abnormality Urination 2 1 1 2 The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp. Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients. Adverse events in Studies V and VI were similar to those described above in Studies I through IV. Irbesartan Other adverse events that have been reported with irbesartan, without regard to causality, are listed below: Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: prostate disorder Respiratory: cough, upper respiratory infection, epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis Hydrochlorothiazide Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body as a Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Initial Therapy In the moderate hypertension Study V (mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse events reported for patients treated with irbesartan and hydrochlorothiazide tablets were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy. There were no reported events of syncope in the irbesartan and hydrochlorothiazide tablets treatment group and there was one reported event in the HCTZ treatment group. The incidences of prespecified adverse events on irbesartan and hydrochlorothiazide tablets, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%, and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia. The rates of discontinuation due to adverse events on irbesartan and hydrochlorothiazide tablets, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%. In the severe hypertension (SeDBP ≥110 mmHg) Study VI, the overall pattern of adverse events reported through 7 weeks of follow-up was similar in patients treated with irbesartan and hydrochlorothiazide tablets as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the prespecified adverse events on irbesartan and hydrochlorothiazide tablets and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates of discontinuation due to adverse events were 2.1% and 2.2%. [See Clinical Studies (14.2) .] 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of irbesartan and hydrochlorothiazide tablets. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to irbesartan and hydrochlorothiazide tablets. Irbesartan and hydrochlorothiazide Blood and lymphatic system: Thrombocytopenia Hepatobiliary: Hepatitis, Jaundice Renal and urinary : Impaired renal function including renal failure Skin and subcutaneous tissue: Urticaria Irbesartan Blood and lymphatic system: Anemia Ear and labyrinth: Tinnitus Gastrointestinal: Intestinal angioedema Skin and subcutaneous tissue: Angioedema (involving swelling of the face, lips, pharynx, and/or tongue) Immune system: Anaphylactic reaction including anaphylactic shock Investigations: Increased CPK (Creatine Phosphokinase) Metabolism and nutrition: Hyperkalemia, Hypoglycemia in diabetic patients Hydrochlorothiazide Eye: acute angle-closure glaucoma, acute myopia, and choroidal effusion Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. 6.3 Laboratory Abnormalities In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of irbesartan and hydrochlorothiazide tablets. Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% and 1.1%, respectively, of patients with essential hypertension treated with irbesartan and hydrochlorothiazide tablets alone. No patient discontinued taking irbesartan and hydrochlorothiazide tablets due to increased BUN. One patient discontinued taking irbesartan and hydrochlorothiazide tablets due to a minor increase in serum creatinine. Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with irbesartan and hydrochlorothiazide tablets alone, one patient was discontinued due to elevated liver enzymes. Serum Electrolytes: [See Warnings and Precautions (5.2 , 5.6) .]

• NSAIDs and selective COX-2 inhibitors: Can reduce diuretic, natriuretic of diuretic, may lead to increased risk of renal impairment and reduced antihypertensive effect. Monitor renal function periodically. ( 7 ) • Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. ( 7 ) • Antidiabetic drugs: Dosage adjustment of antidiabetic may be required. ( 7 ) • Cholestyramine and colestipol: Reduced absorption of thiazides. ( 7 ) • Lithium: Increases in serum lithium concentrations and lithium toxicity. ( 7 ) • Carbamazepine: Increased risk of hyponatremia. ( 7 ) 7.1 Nonsteroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) Irbesartan In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, monitor renal function and blood pressure periodically in patients receiving irbesartan and NSAID therapy. Hydrochlorothiazide Administration of a nonsteroidal anti-inflammatory agent, including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when irbesartan and hydrochlorothiazide tablets and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. 7.2 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on irbesartan and hydrochlorothiazide tablets and other agents that affect the RAS. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Do not coadminister aliskiren with irbesartan and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with irbesartan and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min). 7.3 Agents Increasing Serum Potassium Coadministration of irbesartan and hydrochlorothiazide tablets with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. 7.4 Antidiabetic Drugs (oral agents and insulin) Dosage adjustment of the antidiabetic drug may be required when coadministered with hydrochlorothiazide. 7.5 Cholestyramine and Colestipol Resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of hydrochlorothiazide and the resin such that irbesartan and hydrochlorothiazide tablets is administered at least 4 hours before or 4 to 6 hours after the administration of the resin. 7.6 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan or thiazide diuretics. Monitor lithium levels in patients receiving irbesartan and hydrochlorothiazide tablets and lithium. 7.7 Carbamazepine Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Monitor electrolytes during concomitant use.

16.2 Storage Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].