Side Effects of Cozaar (losartan)

Cozaar (losartan) is an angiotensin receptor blocker (ARB) used to treat high blood pressure (hypertension), reducing the risk of stroke in patients with hypertension, and left ventricular hypertrophy (overdeveloped heart muscle), and treating people with type 2 diabetes, and hypertensive patients with diabetic nephropathy (kidney disease). Cozaar may be used alone or in combination with other drugs. 

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 of blood vessels. Angiotensin's attachment to the receptors causes the muscle cells to contract and the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension).

Cozaar (more specifically, the chemical formed when the liver converts the inactive losartan into its active form) blocks the angiotensin receptor. By blocking the action of angiotensin, Cozaar relaxes muscle cells and dilates blood vessels thereby reducing blood pressure.

Common side effects of Cozaar include

• chest pain,
• diarrhea,
• dizziness,
• fatigue,
• insomnia,
• low blood sugar (hypoglycemia),
• muscle cramps,
• nasal congestion,
• urinary tract infections (UTIs), and
• weakness.

Serious side effects of Cozaar include

• persistent cough,
• increased serum potassium (hyperkalemia),
• impotence (erectile dysfunction, ED),
• reduced kidney function in some patients, and rarely,
• muscle breakdown (rhabdomyolysis).

Drug interactions of Cozaar include other drugs or substances that increase blood-such as potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium because it may lead to dangerous increases in serum potassium which can lead to serious heart problems (arrhythmias).

• Combining Cozaar or other ARBs with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure.
• The antihypertensive effect of Cozaar may be reduced by aspirin and other NSAIDs such as ibuprofen, indomethacin, and naproxen.
• Combining ARBs, ACE inhibitors, or aliskiren increases risk of hypotension (low blood pressure), hyperkalemia, and reduces kidney function compared to each drug used alone and there is no additional benefit on preventing end stage kidney disease or death.
• Aliskiren and Cozaar should not be combined in patients with diabetes or with renal impairment.
• Increases in blood lithium levels and lithium toxicity have occurred when lithium and ARBs or hydrochlorothiazide were combined. 

When used in the second or third trimester of pregnancy, ARBs can cause injury and even death to a fetus. Cozaar should not be used during pregnancy. When pregnancy is first detected, Cozaar should be stopped. 

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

Side effects include:

• Chest pain
• Diarrhea
• Dizziness
• Fatigue
• Insomnia
• Low blood sugar (hypoglycemia)
• Muscle cramps
• Nasal congestion
• Urinary tract infections (UTIs)
• Weakness

Losartan also may cause:

• A persistent cough
• An increase serum potassium (hyperkalemia)
• Impotence (erectile dysfunction, ED)

Losartan 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) 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.

Hypertension

Cozaar has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year.

Treatment with Cozaar was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with Cozaar and 3.7% of patients given placebo.

In 4 clinical trials involving over 1000 patients on various doses (10-150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with Cozaar and more commonly than placebo were:

• dizziness (3% vs. 2%),
• upper respiratory infection (8% vs. 7%),
• nasal congestion (2% vs. 1%), and
• back pain (2% vs. 1%).

The following less common adverse reactions have been reported:

• Blood and lymphatic system disorders: Anemia.
• Psychiatric disorders: Depression.
• Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine.
• Ear and labyrinth disorders: Vertigo, tinnitus.
• Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA.
• Respiratory, thoracic and mediastinal disorders: Dyspnea.
• Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting.
• Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity.
• Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.
• Reproductive system and breast disorders: Impotence.
• General disorders and administration site conditions: Edema.

Cough

• 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 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.

Hypertensive Patients With Left Ventricular Hypertrophy

• In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with Cozaar were similar to those reported previously for patients with hypertension.

Nephropathy In Type 2 Diabetic Patients

• In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 1513 patients treated with Cozaar or placebo, the overall incidences of reported adverse events were similar for the two groups.
• Discontinuations of Cozaar because of side effects were similar to placebo (19% for Cozaar, 24% for placebo).
• The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with Cozaar and occurring with ≥2% difference in the losartan group vs. placebo on a background of conventional antihypertensive therapy, were
  • asthenia/fatigue,
  • chest pain,
  • hypotension,
  • orthostatic hypotension,
  • diarrhea,
  • anemia,
  • hyperkalemia,
  • hypoglycemia,
  • back pain,
  • muscular weakness, and
  • urinary tract infection.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience with Cozaar. 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.
• General Disorders and Administration Site Conditions: Malaise.
• 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. Anaphylactic reactions have been reported.
• Metabolic and Nutrition: Hyponatremia.
• Musculoskeletal: Rhabdomyolysis.
• Nervous system disorders: Dysgeusia.
• Skin: Erythroderma.

Agents Increasing Serum Potassium

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

Lithium

• Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

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, 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.

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.
• In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Cozaar and other agents that affect the RAS.
• Do not coadminister aliskiren with Cozaar in patients with diabetes.
• Avoid use of aliskiren with Cozaar in patients with renal impairment (GFR <60 mL/min).