Irbesartan and Hydrochlorothiazide (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of irbesartan and hydrochlorothiazide. 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.

The following have been very rarely reported with irbesartan and hydrochlorothiazide monotherapies: urticaria, jaundice, hepatitis, thrombocytopenia, and impaired renal function including renal failure.

The following have been reported with irbesartan monotherapy: tinnitus, hyperkalemia, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), anaphylactic reaction including anaphylactic shock, increased CPK and anemia.

The following have been reported with hydrochlorothiazide monotherapy: 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.

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 alone. No patient discontinued taking irbesartan and hydrochlorothiazide due to increased BUN. One patient discontinued taking irbesartan and hydrochlorothiazide 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 alone, one patient was discontinued due to elevated liver enzymes.

Serum Electrolytes: [see WARNINGS AND PRECAUTIONS (5.2, 5.6)].

7 DRUG INTERACTIONS

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 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 tablets 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 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 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Irbesartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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[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 system from other antihypertensive agents. When pregnancy is detected, discontinue irbesartan and hydrochlorothiazide as soon as possible.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes regardless of drug exposure. In the U.S. general population, the estimated background risk of major birth defects 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 preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum 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

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. 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 other symptoms of renal impairment. In neonates with a history of in utero exposure to irbesartan and hydrochlorothiazide, if oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

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 [see Warnings and Precautions (5.1)].

Data

Animal data

Irbesartan crosses the placenta in rats and rabbits. In female rats given irbesartan prior to mating through gestation and lactation at oral doses of 50, 180, or 650 mg/kg/day (1.6 to 21.1 times the maximum recommended human dose (MRHD) based on body surface area), fetuses examined on Gestation Day 20 showed increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla in all irbesartan-treated groups. Subcutaneous edema also occurred in fetuses at maternal doses ≥180 mg/kg/day (5.8 times the MRHD). These anomalies occurred when female rats received irbesartan from prior to mating through Day 20 of gestation but were not observed in pups postnatally in the same study, or when irbesartan was given to pregnant rats only during organogenesis (Gestation Day 6 through Gestation Day 15) at oral doses from 50 to 450 mg/kg/day (up to 14.6 times the MRHD). In addition, no adverse effects on kidney development were observed in pups from dams given irbesartan from Gestation Day 15 through Lactation Day 24 at doses of 50, 180, or 650 mg/kg/day (up to 21.1 times the MRHD). The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given oral doses of irbesartan of 30 mg/kg/day (1.9 times the MRHD based on body surface area) 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.

Radioactivity was present in the rat and rabbit fetuses during late gestation 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.

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