Source: FDA, National Drug Code (US) Revision Year: 2020
COZAAR is contraindicated:
COZAAR can cause fetal harm when administered to a pregnant woman. 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 COZAAR as soon as possible [see Use in Specific Populations (8.1)].
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with COZAAR. Correct volume or salt depletion prior to administration of COZAAR [see Dosage and Administration (2.1)].
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 COZAAR. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on COZAAR [see Drug Interactions (7.3) and Use in Specific Populations (8.7)].
Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of COZAAR may be required [see Adverse Reactions (6.1)].
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see Drug Interactions (7.1)].
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.
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.
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:
| Study 1* | HCTZ | Losartan | Lisinopril |
|---|---|---|---|
| Cough | 25% | 17% | 69% |
| Study 2† | Placebo | Losartan | Lisinopril |
| Cough | 35% | 29% | 62% |
* Demographics = (89% Caucasian, 64 % female)
† 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 postmarketing experience.
In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with COZAAR were similar to those reported previously for patients with hypertension.
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.
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.
Coadministration of losartan with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.
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.
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 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).
COZAAR can cause fetal harm when administered to a pregnant woman. 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. 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. When pregnancy is detected, discontinue COZAAR as soon as possible (see Clinical Considerations).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death.
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 COZAAR, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to COZAAR for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to COZAAR, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.
Losartan potassium was administered orally to rats during the period of late gestation through lactation (Gestation Day 15 through Lactation Day 20) at doses of 10, 25, and 100 mg/kg/day. Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.
It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Neonates with a history of in utero exposure to COZAAR: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Antihypertensive effects of COZAAR have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m² [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
Of the total number of patients receiving COZAAR in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients with renal insufficiency have elevated plasma concentrations of losartan and its active metabolite compared to subjects with normal renal function. No dose adjustment is necessary in patients with renal impairment unless a patient with renal impairment is also volume depleted [see Dosage and Administration (2.3), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
The recommended starting dose of COZAAR is 25 mg in patients with mild-to-moderate hepatic impairment. Following oral administration in patients with mild-to-moderate hepatic impairment, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and 1.7 times those seen in healthy volunteers. COZAAR has not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
In the LIFE study, Black patients with hypertension and left ventricular hypertrophy treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with COZAAR (both cotreated with hydrochlorothiazide in the majority of patients). The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on COZAAR. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients [see Clinical Studies (14.2)].
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