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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 MICARDIS HCT as soon as possible.
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 initialization of treatment with MICARDIS HCT. Correct volume or salt depletion prior to administration of MICARDIS HCT.
Impaired Renal Function
Changes in renal function including acute renal failure can be caused by drugs that inhibit the reninangiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on MICARDIS HCT. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on MICARDIS HCT.
Electrolytes And Metabolic Disorders
Drugs, including telmisartan, that inhibit the renin-angiotensin system can cause hyperkalemia, particularly in patients with renal insufficiency, diabetes, or combination use with other angiotensin receptor blockers or ACE inhibitors and the concomitant use of other drugs that raise serum potassium levels [see DRUG INTERACTIONS].
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.
In controlled trials using the telmisartan/hydrochlorothiazide combination treatment, no patient administered 40 mg/12.5 mg, 80 mg/12.5 mg, or 80 mg/25 mg experienced a decrease in potassium ≥ 1.4 mEq/L, and no patient experienced hyperkalemia.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Because telmisartan decreases uric acid, telmisartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
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 [see CONTRAINDICATIONS].
Acute Myopia And Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angleclosure glaucoma may include a history of sulfonamide or penicillin allergy.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
The antihypertensive effects of hydrochlorothiazide may be enhanced in the postsympathectomy patient.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Advise female patients of childbearing age about the consequences of exposure to MICARDIS HCT during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see WARNINGS AND PRECAUTIONS].
Symptomatic Hypotension And Syncope
Advise patients that lightheadedness can occur, especially during the first days of therapy, and to report it to their healthcare provider. Inform patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Advise patients to contact their healthcare provider if syncope occurs [see WARNINGS AND PRECAUTIONS].
Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting the prescribing healthcare provider [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Acute Myopia And Secondary Angle-Closure Glaucoma
Advise patients to discontinue MICARDIS HCT and seek immediate medical attention if they experience symptoms of Acute Myopia or Secondary Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Telmisartan and Hydrochlorothiazide
No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide.
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 of telmisartan (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/m basis, 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).
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.
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.
There is no clinical experience with the use of telmisartan in pregnant women. 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 of up to 45 mg/kg/day. In rabbits, embryo lethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg on a mg/m² basis). In rats, maternally toxic (reduced body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (approximately 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 approximately 0.64 and 3.7 times, respectively, on a mg/m basis, the MRHD 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.
Use In Specific Populations
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 MICARDIS HCT 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 [see WARNINGS AND PRECAUTIONS].
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin 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 MICARDIS HCT, 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 MICARDIS HCT for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations].
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, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of MICARDIS HCT in pediatric patients have not been established.
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, support blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
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. 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.
Use In Patients With Hepatic Impairment
Patients with biliary obstructive disorders or hepatic insufficiency should initiate treatment under close medical supervision using the 40 mg/12.5 mg combination.
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 and higher blood levels.
Use In Patients With Renal Impairment
Safety and effectiveness of MICARDIS HCT in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. In patients with severe renal impairment, MICARDIS HCT tablets are not recommended. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/6/2017
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