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 congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on losartan potassium and hydrochlorothiazide tablets. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on losartan potassium and hydrochlorothiazide tablets [see Drug Interactions (7.3) and Use in Specific Populations (8.8)].
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.
In double-blind clinical trials of various doses of losartan potassium and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 6.7% versus 3.5% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% versus 0% for placebo.
Losartan potassium and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Losartan potassium and hydrochlorothiazide tablets also contain losartan which can cause hyperkalemia. Monitor serum electrolytes periodically [see Drug Interactions (7.1)].
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see Drug Interactions (7.1)].
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.
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.
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Losartan potassium-hydrochlorothiazide has been evaluated for safety in 858 patients treated for essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. Most adverse reactions have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse events was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively.
In these double-blind controlled clinical trials, adverse reactions occurring in greater than 2% of subjects treated with losartan-hydrochlorothiazide and at a greater rate than placebo were: back pain (2.1% vs 0.6%), dizziness (5.7% vs 2.9%), and upper respiratory infection (6.1% vs 4.6%).
The following additional adverse reactions have been reported in clinical trials with losartan potassium and hydrochlorothiazide tablets and/or the individual components:
Blood and the lymphatic system disorders: Anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.
Metabolism and nutrition disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance including hyponatremia and hypokalemia.
Psychiatric disorders: Insomnia, restlessness.
Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias.
Eye disorders: Xanthopsia, transient blurred vision.
Cardiac disorders: Palpitation, tachycardia.
Vascular disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis, cutaneous vasculitis).
Respiratory, thoracic and mediastinal disorders: Nasal congestion.
Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, nausea, vomiting, pancreatitis, sialoadenitis.
Hepato-biliary disorders: Jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Rash, pruritus, purpura, toxic epidermal necrolysis, urticaria, photosensitivity, cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm.
Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure.
Reproductive system and breast disorders: Erectile dysfunction/impotence.
General disorders and administration site conditions: Chest pain, malaise, weakness.
Investigations: Liver function abnormalities.
Persistent dry cough has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below.
These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.
Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.
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