Fetal Toxicity 

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 candesartan cilexetil and hydrochlorothiazide tablets 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. 

  


In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin 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 candesartan cilexetil and hydrochlorothiazide tablets, 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 candesartan cilexetil and hydrochlorothiazide tablets for hypotension, oliguria, and hyperkalemia. (see PRECAUTIONS, Pediatric Use.)  
  
There was no evidence of teratogenicity or other adverse effects on embryo-fetal development when pregnant mice, rats or rabbits were treated orally with candesartan cilexetil alone or in combination with hydrochlorothiazide. For mice, the maximum dose of candesartan cilexetil was 1000 mg/kg/day (about 150 times the maximum recommended daily human dose [MRHD]1). For rats, the maximum dose of candesartan cilexetil was 100 mg/kg/day (about 31 times the MRHD1). For rabbits, the maximum dose of candesartan cilexetil was 1 mg/kg/day (a maternally toxic dose that is about half the MRHD1). In each of these studies, hydrochlorothiazide was tested at the same dose level (10 mg/kg/day, about 4, 8, and 15 times the MRHD1 in mouse, rats, and rabbit, respectively). There was no evidence of harm to the rat or mouse fetus or embryo in studies in which hydrochlorothiazide was administered alone to the pregnant rat or mouse at doses of up to 1000 and 3000 mg/kg/day, respectively.

  


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.  
______________________________  
1 Doses compared on the basis of body surface area. MRHD considered to be 32 mg for candesartan cilexetil and 12.5 mg for hydrochlorothiazide.  
  
Hypotension   
Candesartan cilexetil and hydrochlorothiazide can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil and hydrochlorothiazide or volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil and hydrochlorothiazide tablets.   
In patients with heart failure, candesartan cilexetil and hydrochlorothiazide may cause excessive hypotension, which may lead to oliguria, azotemia, and (rarely) with acute renal failure and death (see WARNINGS, Impaired Renal Function). In such patients, candesartan cilexetil and hydrochlorothiazide therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of candesartan or diuretic is increased. 

Impaired Renal Function   
Monitor renal function periodically in patients treated with candesartan cilexetil and hydrochlorothiazide. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin 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 heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on candesartan cilexetil and hydrochlorothiazide. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil and hydrochlorothiazide. 

Potassium Abnormalities   
Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.   
In clinical trials of various doses of candesartan cilexetil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 2.5% versus 2.1% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% versus 1.0% for placebo. No patient receiving candesartan cilexetil and hydrochlorothiazide 16 mg/12.5 mg or 32 mg/12.5 mg was discontinued due to increases or decreases in serum potassium. 

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 angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. 

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.