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 of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, BENICAR HCT ® 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 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 BENICAR HCT ® as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system 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, BENICAR HCT ® should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress 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 means of reversing hypotension and/or substituting for disordered renal function.
There is no clinical experience with the use of BENICAR HCT ® in pregnant women. 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 maximum recommended human dose [MRHD] on a mg/m2 basis) or pregnant rats at oral doses up to 1625 mg/kg/day (280 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, 162.5 mg/kg/day, is about 28 times, on a mg/m2 basis, the MRHD of BENICAR HCT ® (40 mg olmesartan medoxomil /25 mg hydrochlorothiazide/day).
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- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with BENICAR HCT ®, as with any angiotensin receptor blocker. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (See DOSAGE AND ADMINISTRATION). When electrolyte and fluid imbalances have been corrected, therapy usually can be continued without difficulty. A transient hypotensive response is not a contraindication to further treatment.
Thiazides 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 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 generally should not be given with thiazides (see PRECAUTIONS: Drug Interactions; Hydrochlorothiazide, Lithium).
In a double-blind clinical trial of various doses of olmesartan medoxomil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.4 mEq/L) was 2.1%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%. In this trial, no patient discontinued due to increases or decreases in serum potassium.
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 important when the patient is vomiting excessively or receiving 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 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 Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil. In patients whose renal function may depend upon 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 olmesartan medoxomil. (See CLINICAL PHARMACOLOGY, Special Populations)
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
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.
Information for Patients
Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told also that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
Symptomatic Hypotension: A patient receiving BENICAR HCT ® should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, BENICAR HCT ® should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light-headedness and possible syncope.
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with hydrochlorothiazide, digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by those enzymes are not expected.
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, Or Narcotics – potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulin) – dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs – additive effect or potentiation.
Cholestyramine and Colestipol Resins – absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (e.g. Norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Non depolarizing (e.g. Tubocurarine) – possible increased responsiveness to the muscle relaxant.
Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparation with olmesartan medoxomil-hydrochlorothiazide.
Non-steroidal Anti-inflammatory Drugs – in some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when olmesartan medoxomil-hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies with olmesartan medoxomil-hydrochlorothiazide have been conducted.
Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5 was negative in the Salmonella-Escherichia coli /mammalian microsome reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5 and 10:12.5, for clastogenic activity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. A positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio. Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 3144 mg/kg.
No studies of impairment of fertility with olmesartan medoxomil-hydrochlorothiazide have been conducted.
Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and both tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney, and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
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, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and 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 Categories C (first trimester) and D (second and third trimesters)
(See WARNINGS: Fetal/Neonatal Morbidity and Mortality)
It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. 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.
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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of BENICAR HCT ® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.
Olmesartan and hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.