Tribenzor (Page 4 of 8)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Tribenzor 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 Tribenzor as soon as possible. Consider alternative antihypertensive therapy during pregnancy.

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 birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–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

Olmesartan medoxomil

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 gestation. 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 olmesartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function [see Use in Specific Populations (8.4)].

Hydrochlorothiazide

Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of preeclampsia, these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided.

Data

Animal Data

No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. However, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together.

Olmesartan medoxomil.

No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

Olmesartan medoxomil and Hydrochlorothiazide.

No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the MRHD on a mg/m2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 times the MRHD on a mg/m2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m2 basis, the MRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.)

Amlodipine.

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis (calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose.

Hydrochlorothiazide.

No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD), on gestation days 6 through 15.

8.2 Lactation

Risk Summary

There is limited information regarding the presence Tribenzor in human milk, the effects on the breastfed infant, or the effects on milk production. Amlodipine and hydrochlorothiazide are present in human milk. Olmesartan is present in rat milk [see Data]. Because of the potential for adverse effects on the nursing infant, advise a nursing woman that breastfeeding is not recommended during treatment with Tribenzor.

Data

Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [14 C] olmesartan medoxomil to lactating rats.

8.4 Pediatric Use

The safety and effectiveness of Tribenzor in pediatric patients have not been established.

8.5 Geriatric Use

Tribenzor. In a controlled clinical trial, 123 hypertensive patients treated with Tribenzor were ≥65 years of age and 18 patients were ≥75 years of age. No overall differences in the efficacy or safety of Tribenzor were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out. The recommended initial dose of amlodipine in patients ≥ 75 years of age is 2.5 mg, a dose not available with Tribenzor.

8. 6 Hepatic Impairment

There are no studies of Tribenzor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with Tribenzor [see Warnings and Precautions ( 5.5)] .

Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½ ) is 56 hours in patients with severely impaired hepatic function.

Olmesartan medoxomil. Increases in AUC0- and peak plasma concentration (Cmax ) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.

Hydrochlorothiazide. In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

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