Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS HCT (telmisartan/hydrochlorothiazide) tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS HCT tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, MICARDIS HCT tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

A developmental toxicity study was performed in rats with telmisartan/hydrochlorothiazide doses of 3.2/1.0, 15/4.7, 50/15.6, and 0/15.6 mg/kg/day. Although the two higher dose combinations appeared to be more toxic (significant decrease in body weight gain) to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos.

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 [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m² basis]. 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/m² 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. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. 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/m² basis, the maximum recommended human dose of telmisartan (80 mg/day).

Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Hypotension in Volume-Depleted Patients

Initiation of antihypertensive therapy in patients whose renin-angiotensin system are activated such as patients who are intravascular volume- or sodium-depleted, e.g., in patients treated vigorously with diuretics, should only be approached cautiously. These conditions should be corrected prior to administration of MICARDIS HCT. Treatment should be started under close medical supervision (see DOSAGE AND ADMINISTRATION). If hypotension occurs, the patients 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.

Hydrochlorothiazide

Hepatic Impairment: Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Hypersensitivity Reaction: 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.

Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Lithium Interaction: Lithium generally should not be given with thiazides (see PRECAUTIONS: DRUG INTERACTIONS, Hydrochlorothiazide, Lithium).

Serum Electrolytes

Telmisartan & Hydrochlorothiazide

In controlled trials using the telmisartan/hydrochlorothiazide combination treatment, no patient administered 40/12.5 mg, 80/12.5 mg or 80/25 mg had a decrease in potassium 1.4 mEq/L, and no patient experienced hyperkalemia. No discontinuations due to hypokalemia occurred during treatment with the telmisartan/hydrochlorothiazide combination. The absence of significant changes in serum potassium levels may be due to the opposing mechanisms of action of telmisartan and hydrochlorothiazide on potassium excretion on the kidney.

Hydrochlorothiazide

Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient experiences excessive vomiting or receives parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the post sympathectomy patient.

If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Hepatic Function

Telmisartan

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS® HCT tablets should therefore be used with caution in these patients.

Impaired Renal Function

Telmisartan

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of telmisartan in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Telmisartan & Hydrochlorothiazide

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide.

Telmisartan

There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m² basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan > 100 times and > 25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m²basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, in the Mouse Lymphoma Cell (mutagenicity) assay, and in the Aspergillus nidulans non-disjunction assay.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

Nursing Mothers

It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In the controlled clinical trials (n=1017), approximately 20% of patients treated with telmisartan/hydrochlorothiazide were 65 years of age or older, and 5% were 75 years of age or older. No overall differences in effectiveness and safety of telmisartan/hydrochlorothiazide were observed in these patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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