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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. In clinical trials with losartan potassium-hydrochlorothiazide, no adverse experiences peculiar to this combination have been observed. Adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo.
In general, treatment with losartan potassium-hydrochlorothiazide was well tolerated. For the most part, adverse experiences 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 experiences 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, the following adverse experiences reported with losartan-hydrochlorothiazide occurred in ≥ 1 percent of patients, and more often on drug than placebo, regardless of drug relationship:
|Losartan Potassium- Hydrochlorothiazide (n=858)||Placebo (n=173)|
|Body as a Whole|
|Upper respiratory infection||6.1||4.6|
The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group in studies of essential hypertension: asthenia/fatigue, diarrhea, nausea, headache, bronchitis, pharyngitis.
Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients and somewhat more frequent in Blacks compared to non-Blacks for both the losartan-hydrochlorothiazide and the control groups.
A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.
Other adverse experiences that have been reported with losartan, without regard to causality, are listed below:
Body as a Whole: chest pain, facial edema, fever, orthostatic effects, syncope; Cardiovascular: angina pectoris, arrhythmias including atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia and ventricular fibrillation, CVA, hypotension, myocardial infarction, second degree AV block; Digestive: anorexia, constipation, dental pain, dry mouth, dyspepsia, flatulence, gastritis, vomiting; General disorders and administration site conditions: malaise; Hematologic: anemia; Metabolic: gout; Musculoskeletal: arm pain, arthralgia, arthritis, fibromyalgia, hip pain, joint swelling, knee pain, leg pain, muscle cramps, muscle weakness, musculoskeletal pain, myalgia, shoulder pain, stiffness; Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, insomnia, libido decreased, memory impairment, migraine, nervousness, panic disorder, paresthesia, peripheral neuropathy, sleep disorder, somnolence, tremor, vertigo; Respiratory: dyspnea, epistaxis, nasal congestion, pharyngeal discomfort, respiratory congestion, rhinitis, sinus disorder; Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, sweating, urticaria; Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity, taste perversion, tinnitus; Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.
Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole: weakness; Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation; Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema; Metabolic: hyperglycemia, glycosuria, hyperuricemia; Musculoskeletal: muscle spasm; Nervous System/Psychiatric: restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis; Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis; Special Senses: transient blurred vision, xanthopsia.
Persistent dry cough (with an incidence of a few percent) 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 below.
|† Demographics = (89% Caucasian, 64%
†† Demographics = (90% Caucasian, 51% female)
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 post-marketing experience.
Severe Hypertension: In a clinical study in patients with severe hypertension (SiDBP ≥ 110 mmHg), the overall pattern of adverse events reported through six weeks of follow-up was similar in patients treated with HYZAAR as initial therapy and in patients treated with losartan as initial therapy. There were no reported cases of syncope in either treatment group. There were 2 (0.6%) and 0 (0.0%) cases of hypotension reported in the group treated with HYZAAR and the group treated with losartan, respectively. There were 3 (0.8%) and 2 (1.2%) cases of increased serum creatinine ( > 0.5 mg/dL) in the group treated with HYZAAR and the group treated with losartan, respectively, during the same time period. (See CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Severe Hypertension.)
The following additional adverse reactions have been reported in post-marketing experience:
Digestive: Hepatitis has been reported rarely in patients treated with losartan.
Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported with losartan. Anaphylactic reactions have been reported.
Musculoskeletal: Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Respiratory: Dry cough (see above) has been reported with losartan.
Skin: Erythroderma has been reported with losartan.
Laboratory Test Findings
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of HYZAAR.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 0.6 and 0.8 percent, respectively, of patients with essential hypertension treated with HYZAAR alone. No patient discontinued taking HYZAAR due to increased BUN. One patient discontinued taking HYZAAR due to a minor increase in serum creatinine.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.14 grams percent and 0.72 volume percent, respectively) occurred frequently in patients treated with HYZAAR alone, but were rarely of clinical importance. No patients were discontinued due to anemia.
Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with HYZAAR alone, no patients were discontinued due to these laboratory adverse experiences.
Serum Electrolytes: See PRECAUTIONS.
Read the Hyzaar (losartan potassium-hydrochlorothiazide) Side Effects Center for a complete guide to possible side effects
No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. (See CLINICAL PHARMACOLOGY, Drug Interactions.) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium (see PATIENT INFORMATION, Potassium Supplements).
Lithium: As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Dual blockade of the renin-angiotensin-aldosterone system: It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher frequency of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent. Dual blockade (e.g., by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function.
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.
Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (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 preparations with HYZAAR.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) — The administration of a non-steroidal anti-inflammatory agent, including a selective cyclooxygenase-2 inhibitor, can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when HYZAAR and non-steroidal anti-inflammatory agents, including selective cyclooxygenase-2 inhibitors, are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
In patients receiving diuretic therapy, co-administration of NSAIDs with angiotensin receptor blockers, including losartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving hydrochlorothiazide, losartan, and NSAID therapy.
Read the Hyzaar Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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