Irbesartan and Hydrochlorothiazide

1 INDICATIONS AND USAGE Irbesartan and hydrochlorothiazide is indicated for the treatment of hypertension. Irbesartan and hydrochlorothiazide may be used in patients whose blood pressure is not adequately controlled on monotherapy. Irbesartan and hydrochlorothiazide 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 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 compared to irbesartan or 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 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)* *For all probability curves, patients without blood pressure measurements at Week 7 (Study VI) and Week 8 (Study V) were counted as not reaching goal (intent-to-treat analysis). 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 rises to about 40% (systolic) or 70% (diastolic). Irbesartan and hydrochlorothiazide is 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 )

2 DOSAGE AND ADMINISTRATION 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 150/12.5 mg. Titrate to 300/12.5 mg then 300/25 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 may be administered with or without food. Irbesartan and hydrochlorothiazide may be administered with other antihypertensive agents. Renal Impairment : The usual regimens of therapy with irbesartan and hydrochlorothiazide 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, 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 may be substituted for the titrated components. 2.4 Initial Therapy The usual starting dose is irbesartan and hydrochlorothiazide 150 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2)] . Irbesartan and hydrochlorothiazide is not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ].

5 WARNINGS AND PRECAUTIONS • Hypotension: Correct volume-depletion prior to administration. (5.2) • Impaired renal function. (5.8) • Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus. (5.4) • Acute myopia and secondary angle-closure glaucoma. (5.9) 5.1 Fetal Toxicity Pregnancy Category D 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 irbesartan and hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1) ]. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. 5.2 Hypotension in Volume- or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with irbesartan and hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, e.g., in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of antihypertensive therapy. If hypotension occurs, 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 Hypersensitivity Reaction Hydrochlorothiazide : Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5.4 Systemic Lupus Erythematosus Hydrochlorothiazide : Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.5 Electrolyte and Metabolic Imbalances Irbesartan and Hydrochlorothiazide : In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 7.5% versus 6% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was <1% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to hydrochlorothiazide. Coadministration of irbesartan and hydrochlorothiazide with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. Hydrochlorothiazide : Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in …

4 CONTRAINDICATIONS • Irbesartan and hydrochlorothiazide is 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 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 in patients with diabetes. ( 4 )

7 DRUG INTERACTIONS • 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 Non-Steroidal 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. The antihypertensive effect of ARBs may be attenuated by NSAIDs. Therefore, monitor renal function and blood pressure periodically in patients receiving irbesartan and NSAID therapy. Hydrochlorothiazide Administration of a non-steroidal 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 and non-steroidal 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 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 in patients with diabetes. Avoid use of aliskiren with irbesartan and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min). 7.3 Agents Increasing Serum Potassium Coadministration of irbesartan and hydrochlorothiazide 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 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 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.

8.1 Pregnancy Pregnancy Category D 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 irbesartan and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue irbesartan and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to irbesartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ]. Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than the maximum recommended human dose (MRHD), fetuses showed increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also occurred in fetuses at doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant rats received irbesartan through Day 20 of gestation but not when drug was stopped on gestation Day 15. The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses [see Nonclinical Toxicology (13.2) ]. Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. When pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm. A development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan and hydrochlorothiazide. Although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos.

8.3 Nursing Mothers It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6 ADVERSE REACTIONS Most common adverse events (≥5% on irbesartan and hydrochlorothiazide and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 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 has been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with irbesartan and hydrochlorothiazide, 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 was 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 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 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, cardio-respiratory 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, somnole…