Side Effects of Hyzaar (losartan and hydrochlorothiazide)

Hyzaar (losartan and hydrochlorothiazide) is a combination of an angiotensin receptor blocker (ARB) and a diuretic (water pill) used to treat high blood pressure (hypertension).

Angiotensin, formed in the blood by the action of angiotensin converting enzyme (ACE), is a powerful chemical that attaches to angiotensin receptors found in many tissues but primarily on smooth muscle cells surrounding blood vessels. Angiotensin's attachment to the receptors causes the muscles to contract and the blood vessels to narrow which leads to an increase in blood pressure (hypertension).

Losartan (more specifically, the chemical formed when the liver converts the inactive losartan into an active chemical) blocks the angiotensin receptor. By blocking the action of angiotensin, losartan relaxes the muscles, dilates blood vessels, and reduces blood pressure.

Hydrochlorothiazide (HCTZ) is used to treat high blood pressure and fluid accumulation. It works by blocking salt and fluid reabsorption in the kidneys, causing an increased amount of urine containing salt (diuresis). The mechanism of its action in lowering high blood pressure is not well understood.

The combination of losartan and HCTZ reduces blood pressure better than either drug alone. Losartan increases potassium levels while HCTZ reduces potassium levels; the combination of both drugs has less effect on potassium levels.

Common side effects of Hyzaar include

• nausea,
• vomiting,
• back pain,
• stomach upset,
• dizziness, and
• upper respiratory infection.

Serious side effects of Hyzaar include

• persistent cough,
• severe low blood pressure (hypotension),
• changes in electrolyte concentrations,
• impotence,
• angioedema,
• reduced kidney function in some patients, and rarely,
• rhabdomyolysis (muscle breakdown),
• hepatitis,
• reduced number of platelets, and
• pancreatitis.

Drug interactions of Hyzaar include other substances that increase blood potassium-such as potassium-sparing diuretics (for example, spironolactone, triamterene, and amiloride), potassium supplements, or salt substitutes containing potassium, because losartan may increase levels of blood potassium which can lead to serious heart problems (arrhythmias).

• Combining losartan or other ARBs with nonsteroidal anti-Inflammatory drugs (NSAIDs) in patients who are elderly, volume-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure.
• These effects usually are reversible.
• The antihypertensive effect of losartan may be reduced by aspirin and other NSAIDs such as ibuprofen, indomethacin, and naproxen. HCTZ reduces the elimination of lithium by the kidneys and can lead to lithium toxicity.
• NSAIDs, for example, ibuprofen, may reduce the blood pressure effects of hydrochlorothiazide.
• Blood sugar levels can be elevated by HCTZ, necessitating adjustment in the doses of medications that are used for treating diabetes.
• Combining HCTZ with corticosteroids may increase the risk for low levels of blood potassium and other electrolytes. Low blood potassium (hypokalemia) can increase the toxicity of digoxin.
• Cholestyramine and colestipol bind to hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 43%-85%.

When used in the second or third trimester of pregnancy ACE inhibitors and ARBs can cause injury and even death to the fetus. Hyzaar should not be used during pregnancy.

It is unknown if losartan is excreted in breast milk. Due to the possibility of harm to the nursing infant, if possible, losartan should be discontinued by women who are breastfeeding. HCTZ is excreted in breast milk. 

Common side effects of Hyzaar are:

• nausea,
• vomiting,
• back pain,
• stomach upset,
• dizziness, and
• upper respiratory infection.

Other important side effects that may be caused by Hyzaar include:

• persistent cough,
• severe hypotension,
• changes in electrolyte concentrations,
• impotence, and
• angioedema.

Hyzaar may reduce kidney function in some patients and should not be used by patients who have bilateral renal artery stenosis (narrowing of both arteries going to the kidneys). Rare cases of rhabdomyolysis (muscle breakdown), hepatitis, ,reduced number of platelets, and pancreatitis have been reported.

Clinical Trials Experience

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 Hyzaar 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, pharyngitis, sinus disorder, respiratory distress (including pneumonitis and pulmonary edema).
• Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhea, constipation, 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, myalgia, arthralgia.
• 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, edema/swelling, malaise, fever, weakness.
• Investigations: Liver function abnormalities.

Cough

• 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.

Table 1:

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Hyzaar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

• Digestive: Hepatitis has been reported rarely in patients treated with losartan.
• Hematologic: Thrombocytopenia.
• 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: rhabdomyolysis
• Skin: Erythroderma

Agents Increasing Serum Potassium

• Coadministration of losartan with other drugs that raise serum potassium may result in hyperkalemia. Monitor serum potassium in such patients.

Lithium

• Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of angiotensin II receptor antagonists or thiazide diuretics.
• Monitor lithium levels in patients receiving Hyzaar and lithium.

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors

Losartan Potassium

• In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration 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.

Hydrochlorothiazide

• The administration of a non-steroidal anti-inflammatory agent including a selective COX-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 COX-2 inhibitors are used concomitantly, observe closely to determine if the desired effect of the diuretic is obtained.
• In patients receiving diuretic therapy, coadministration 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.

Dual Blockade Of The Renin-Angiotensin System (RAS)

• Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
• The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years.
• Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end-stage renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group.
• Closely monitor blood pressure, renal function, and electrolytes in patients on Hyzaar and other agents that affect the RAS.
• Do not coadminister aliskiren with Hyzaar in patients with diabetes. Avoid use of aliskiren with Hyzaar in patients with renal impairment (GFR <60 mL/min).

The Use Of Hydrochlorothiazide With Other Drugs

When administered concurrently, the following drugs may interact with thiazide diuretics:

• Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.
• 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. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.