Cardiovascular adverse reactions have been reported with letrozole treatment. In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, myocardial infarction during treatment and within 30 days of discontinuation of therapy occurred in 1% of patients treated with letrozole (n = 2,448) compared with 0.5% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of myocardial infarction was 1.7% versus 1.1%, respectively. Myocardial ischemia was reported in 0.2% of letrozole-treated patients compared with 0.4% of those who received tamoxifen, while angina requiring surgery occurred in 1.4% versus 1.3% of patients, respectively; chest pain (unspecified) occurred in less than 5% of patients treated with letrozole. Other cardiovascular events occurred in 4.9% of letrozole-treated patients during therapy, and in 7% of patients after 96 months of follow-up. When used as extended adjuvant treatment after completion of 5 years of tamoxifen therapy in a separate clinical trial, the incidence of cardiovascular ischemic events was comparable between patients who received letrozole (n = 2,563) compared with placebo (n = 2,573) (6.8% vs. 6.5%); cardiovascular events during treatment or within 30 days of stopping treatment occurred in 9.8% of letrozole-treated patients compared with 7% of those who received placebo, while the rate was 14.4% versus 9.8% after 62 months of follow-up. Chest pain occurred in 6% to 8% of patients receiving letrozole for advanced breast cancer (n = 814), while cardiovascular events such as angina, myocardial infarction, myocardial ischemia, and coronary heart disease occurred in less than or equal to 2% of patients. Palpitations and sinus tachycardia were reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experience.[29101]

In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, heart failure occurred in 1.1% of patients treated with letrozole (n = 2,448) compared with 0.6% of those who received tamoxifen (n = 2,447) during treatment and within 30 days of discontinuation of therapy; after a median of 96 months, the incidence of heart failure was 1.6% versus 1.4%, respectively. Edema was reported in 6.7% (grade 3 or 4, 0.1%) of patients in the letrozole arm compared with 6.5% (grade 3 or 4, less than 0.1%) of those who received tamoxifen. With extended adjuvant therapy with letrozole after completion of 5 years of tamoxifen therapy (n = 2,563), 18.4% (grade 3 or 4, 0.2%) of patients reported edema compared with 16.2% (grade 3 or 4, 0.2%) of those who received placebo. Peripheral edema occurred in 5% of patients receiving second-line therapy with letrozole for advanced breast cancer (n = 359) in another clinical trial. Heart failure was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.[29101]

Hypertension has been reported in 5% to 8% (grade 3 or 4, 1.2% or less) of patients treated with letrozole across clinical trials.[29101]

Hypercholesterolemia has occurred in patients treated with letrozole in clinical trials. In a large randomized clinical trial (BIG 1-98), hypercholesterolemia occurred in 52.3% (grade 3 or 4, 0.4%) of patients treated with letrozole (n = 2,448) compared with 28.6% (grade 3 or 4, 0.1%) of those who received tamoxifen (n = 2,447), requiring lipid-lowering medications in 29% versus 20% of patients, respectively. An increase of greater than or equal to 1.5 times the upper limit of normal (ULN) in total cholesterol (generally nonfasting) occurred in 8.4% of letrozole-treated patients who had a normal baseline total serum cholesterol compared with 3.9% of those in the tamoxifen arm. In an adjuvant safety study (n = 263), 12% of patients receiving letrozole had at least one total cholesterol value of a higher CTCAE grade than baseline compared with 4% of those treated with tamoxifen. In an open-label adjuvant clinical trial, hypercholesterolemia occurred in 7.6% (grade 3 or 4, 0.1%) of letrozole-treated patients (n = 2,049). In the extended adjuvant setting after a median follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or any lipid fraction (hypercholesterolemia: all grade, 15.6% vs. 15.5%; grade 3 or 4, less than 0.1% vs. 0.2%); general metabolic disorders including hypercholesterolemia occurred in 21.5% (grade 3 or 4, 0.9%) versus 20.9% (grade 3 or 4, 1.2%) of patients, respectively. Hypercholesterolemia occurred in 3% of patients receiving letrozole in the second-line advanced breast cancer setting in a separate clinical trial (n = 359).[29101]

Thromboembolic events have been reported with letrozole treatment. In a large randomized, double-blind clinical trial (BIG 1-98) of patients receiving adjuvant treatment for early breast cancer, cerebrovascular accident (CVA)/ transient ischemic attack (TIA) (stroke) during treatment and within 30 days of discontinuation of therapy occurred in 2.1% of patients treated with letrozole (n = 2,448) compared with 1.9% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of CVA/TIA was 3% versus 2.8%, respectively. A higher incidence of thromboembolic events (thromboembolism) was seen in patients treated with tamoxifen, both during study treatment (2.1% vs. 3.6%) and at a median follow-up of 96 months (3.2% vs. 4.6%). Peripheral thromboembolic events (including venous thrombosis, thrombo-phlebitis, portal vein thrombosis and pulmonary embolism) and cerebrovascular events (including TIA, thrombotic or hemorrhagic strokes and development of hemi-paresis) occurred in less than 2% of patients with advanced breast cancer who were treated with letrozole in a separate randomized trial (n = 455). Arterial thrombosis was reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.[29101]

Respiratory adverse reactions have been reported with letrozole therapy in clinical trials, including dyspnea (all grade, 5.5% to 18%; grade 3 or 4, 0.8%) and cough (grade 1 or 2, 5.2% to 13%). Chest wall pain occurred in 6% of patients treated with first-line letrozole for advanced breast cancer, and pleural effusion was reported in less than 5% of patients receiving second-line letrozole for advanced breast cancer.[29101]

Hyperbilirubinemia and jaundice were each identified in less than 5% of patients receiving adjuvant treatment with letrozole (n = 2,049) in a large randomized clinical trial. Additionally, elevated hepatic enzymes and hepatitis were reported in postmarketing experience with letrozole.[29101]

Gastrointestinal adverse reactions have been reported across clinical trials with letrozole, including weight gain (all grade, 2% to 12.9%; grade 3 or 4, less than or equal to 1.1%), nausea (all grade, 6.7% to 17%; grade 3 or 4, 0.1% to 0.3%), abdominal pain (less than or equal to 6%), weight loss (all grade, 5.7% to 7%; grade 3 or 4, less than or equal to 0.3%), diarrhea (all grade, 5% to 8%; grade 3 or 4, less than or equal to 0.5%), vomiting (all grade, 3.3% to 7%; grade 3 or 4, less than or equal to 0.1%), dyspepsia (less than or equal to 3%), constipation (all grade, 2% to 11.3%; grade 3 or 4, 0.1% to 0.2%), and anorexia (all grade, 0.8% to 5%; grade 3 or 4, less than 0.1%). In a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, stomatitis, appetite stimulation, xerostomia, dysgeusia, and polydipsia were also reported.[29101]

Decreases in bone mineral density (BMD) have been reported with letrozole treatment. In a study evaluating the safety of letrozole in the adjuvant setting (n = 263), a median decrease in lumbar spine (L2 to L4) BMD of 4.1% occurred at 24 months in the letrozole arm compared with 0.3% in the tamoxifen arm; no patients with a normal BMD at baseline because osteoporotic over the 2 years of the safety study, and 1 patient with osteopenia at baseline (T score, -1.9) developed osteoporosis during the treatment period. The results for total hip BMD were similar, although the differences between the 2 treatments were less pronounced (4% vs. 6%, respectively). Bone fractures occurred in 10.2% of patients treated with letrozole (n = 2,448) compared with 7.2% of those who received tamoxifen (n = 2,447) during treatment and within 30 days of discontinuation of therapy in a large randomized clinical trial (BIG 1-98); after a median of 96 months, the incidence of bone fractures was 14.7% versus 11.4%, respectively. The incidence of osteoporosis in the letrozole arm was 5.1% to 10.9% (grade 3 or 4, 0.2% to 0.4%) and osteopenia was 3.6% to 9.9% (grade 3 or 4, less than or equal to 0.2%). The incidence of bone fractures at any time after randomization in an extended adjuvant treatment trial was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% versus 7.8%, respectively. In the extended adjuvant study, clinical fractures occurred in 5.9% of patients who received letrozole (n = 2,563) compared with 5.5% of those who received placebo (n = 2,573). The overall incidence of osteoporosis was 6.9% in the letrozole arm, with 21.1% of patients treated with bisphosphonates; osteoporosis occurred in 5.5% of patients in the placebo arm, with bisphosphonates administered to 18.7%. Updated results from a BMD substudy in the extended adjuvant setting found that at 2 years, patients treated with letrozole had a median decrease from baseline of 3.8% in hip BMD compared to 2% in the placebo arm; changes from baseline in lumbar spine BMD in letrozole- and placebo-treated groups were not significantly different. In this substudy, new fractures occurred in 13.3% compared with 7.8% of patients, and new osteoporosis in 14.5% compared with 7.8% of patients, respectively. Fracture occurred in less than 5% of patients who received letrozole in the second-line advanced breast cancer setting (n = 359).[29101]

Musculoskeletal adverse reactions have been reported with letrozole therapy across clinical trials. In patients receiving letrozole as adjuvant (n = 4,497) or extended adjuvant (n = 2,563) therapy, these included arthralgia (all grade, 22% to 48.2%; grade 3 or 4, 1% to 3.9%), myalgia (all grade, 6.7% to 11.4%; grade 3 or 4, 0.3% to 0.8%), back pain (all grade, 5% to 10.3%; grade 3 or 4, 0.3% to 0.5%), bone pain (all grade, 5% to 6.7%; grade 3 or 4, 0.2% to 0.5%), pain in extremities (all grade, 4.2% to 8.2%; grade 3 or 4, 0.2% to 0.4%), arthritis (all grade, 6.7% or less; grade 3 or 4, 0.4% or less), musculoskeletal pain (all grade, 6% or less; grade 3 or 4, 0.3% or less), musculoskeletal stiffness (all grade, 5% or less; grade 3 or 4, 0.1% or less), and breast pain (all grade, 1.5% or less; grade 3 or 4, less than 0.1%). In patients receiving letrozole for advanced breast cancer (n = 814), pain (5%), bone pain (22%), musculoskeletal pain (21%), back pain (18%), arthralgia (8% to 16%), limb pain (10%), and breast pain (7%) were reported. Cancer pain was reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.[29101]

Psychiatric adverse reactions that have been reported with letrozole therapy in clinical trials include depression (all grade, 7.2% or less; grade 3 or 4, 0.8% or less), insomnia (all grade, 5.8% to 7.8%; grade 3 or 4, 0.3% or less), and anxiety (5% or less); psychiatric disorders in general (including insomnia) occurred in 12.5% (grade 3 or 4, 0.8%) of patients receiving extended adjuvant therapy with letrozole in a clinical trial. In a combined analysis of the first- and second-line metastatic trials and postmarketing experiences dysesthesia (including hypoesthesia/paresthesias), memory impairment, irritability, and nervousness were also reported.[29101]

Alopecia was reported in 3.4% to 6.2% (grade 3 to 4, less than or equal to 0.1%) of patients receiving adjuvant breast cancer treatment with letrozole in randomized clinical trials; radiation skin injury was also reported in less than or equal to 5.9% (grade 3 or 4, less than or equal to 0.5%) of letrozole-treated patients. In those receiving letrozole as second-line treatment for advanced breast cancer, rash (including erythematous rash (erythema), maculopapular rash, psoriaform rash, and vesicular rash) was reported in 5% and pruritus in 1% of patients; alopecia occurred in less than 5% of patients. Urticaria and xerosis were reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, while toxic epidermal necrolysis and erythema multiforme were both reported in postmarketing experience with letrozole.[29101]

Vaginal bleeding (all grade, 5.3% vs. 13.1%; grade 3 or 4, less than 0.1% vs. 0.3%), endometrial proliferation disorders (all grade, 0.3% to 0.6% vs. 1.8% to 3.5%; grade 3 or 4, 0% vs. 0.6%), ovarian cyst (all grade, 0.4% vs. 0.7%; grade 3 or 4, 0.2% vs. 0.2%), and other endometrial disorders (grade 1 or 2, less than 0.1% vs. 0.1%) occurred less frequently with letrozole (n = 2,448) compared with tamoxifen (n = 2,447) when administered as adjuvant therapy; there was also a higher incidence for tamoxifen regarding endometrial hyperplasia or cancer (0.3% vs. 2.9%). Vaginal irritation occurred more often in the letrozole arm (all grade, 4.6% vs. 3.1%; grade 3 or 4, less than 0.1% vs. less than 0.1%). Reproductive disorders occurred in 11.8% of patients who received extended adjuvant therapy with letrozole after completion of 5 years of tamoxifen (n = 2,563) compared with placebo (n = 2,573), including vaginal bleeding (all grade, 4.8% vs. 6.6%; grade 3 or 4, less than 0.1% vs. 0.2%) and vulvovaginal dryness (grade 1 or 2, 5.3% vs. 4.9%). A patient-reported measure that captured the impact of treatment on important symptoms associated with estrogen deficiency favored placebo for the sexual symptom domain. Vaginal discharge was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences.[29101]

In a large, randomized clinical trial of patients receiving adjuvant therapy for breast cancer (BIG 1-98), a new primary malignancy occurred during treatment and within 30 days of discontinuation of therapy in 2.2% of patients treated with letrozole (n = 2,448) compared with 3.2% of those who received tamoxifen (n = 2,447); after a median of 96 months, the incidence of new primary malignancy was 5.3% versus 6.1%, respectively. Endometrial hyperplasia/cancer occurred in 0.3% versus 2.9% of patients during letrozole or tamoxifen therapy, respectively, and in 0.4% versus 2.9% of patients, respectively, after 96 months of follow-up. Lymphedema has been reported in 7% to 7.8% (grade 3 or 4, 0.2% or less) of patients treated with letrozole.[29101]

Cataracts were reported in 2% (grade 3 or 4, 0.7%) of patients receiving adjuvant therapy for early breast cancer with letrozole (n = 2,448) compared with 2.2% (grade 3 or 4, 0.7%) of those who received tamoxifen (n = 2,447) in a large randomized clinical trial (BIG 1-98). Cataracts and ocular irritation were also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences, while blurred vision was observed in postmarketing experience with letrozole.[29101]

Moderate decreases in lymphocyte counts (lymphopenia) of uncertain clinical significance were observed in some patients treated with letrozole 2.5 mg daily; this decrease was transient in about half of those affected. Thrombocytopenia occurred in 2 patients treated with letrozole, although the relationship to the study drug was unclear. Leukopenia was also reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.[29101]

Infection was reported in 6.5% (grade 3 or 4, 1.6%) of patients receiving extended adjuvant treatment with letrozole after completion of 5 years of tamoxifen therapy (n = 2,563) compared with 6.3% (grade 3 or 4, 1.3%) of those who received placebo in a randomized clinical trial. In patients who received letrozole as first-line therapy for advanced breast cancer (n = 455), influenza was reported in 6% of patients compared with 4% of those who received tamoxifen; urinary tract infection occurred in 6% versus 3% of patients, respectively. Viral infections (not specified) were also reported in 6% of patients treated with letrozole as second-line therapy for advanced breast cancer (n = 359). Increased urinary frequency and fever were additionally reported in a combined analysis of the first- and second-line metastatic trials and postmarketing experiences with letrozole.[29101]

Spontaneous fetal abortion and congenital birth defects/teratogenesis have been reported in postmarketing experience with letrozole therapy.[29101]

Fatigue including lethargy, malaise, and asthenia occurred in 9.6% to 16.8% (grade 3 or 4, 0.2% to 0.4%) of letrozole-treated patients in 2 large randomized clinical trials of adjuvant therapy, while headache (all grade, 4.3% to 6.3%; grade 3 or 4, 0.1% to 0.3%) and dizziness (all grade, 3.4% to 4.6%; grade 3 or 4, 0.2% or less) were also reported with adjuvant letrozole therapy; less than 5% of patients treated with letrozole reported falls or vertigo. The incidence of asthenia was higher in the extended adjuvant clinical trial, occurring in 33.6% (grade 3 or 4, 0.6%) of patients treated with letrozole compared with 32.1% (grade 3 or 4, 0.3%) of those who received placebo; general disorders that included asthenia were reported in 45% (grade 3 or 4, 1.2%) and 42.4% (grade 3 or 4, 1.1%) of patients, respectively. In this trial, nervous system disorders occurred in 33.7% (grade 3 or 4, 2.5%) of patients in the letrozole arm compared with 31.8% (grade 3 or 4, 2.3%) of those who received placebo, and included headache (all grade, 20.1% vs. 19.7%; grade 3 or 4, 0.7% vs. 0.7%) and dizziness (all grade, 14.2% vs. 13.3%; grade 3 or 4, 0.4% vs. 0.2%). Fatigue/asthenia (4% to 13%), weakness (6%), headache (8% to 9%), vertigo (less than 5%), dizziness (3% or less), and somnolence (drowsiness) (3% or less) also occurred when letrozole was used to treat advanced breast cancer.[29101]

Hot flashes were reported in 33.5% of patients treated with letrozole (n = 2,448) compared with 38% of those who received tamoxifen (n = 2,447) as adjuvant therapy for early breast cancer in a large randomized clinical trial (BIG 1-98); night sweats occurred in 14.5% and 17.4% of patients, respectively. Compared to anastrozole as adjuvant therapy (all grade, 32.3%; grade 3 or 4, 0.4%), hot flashes occurred in 32.5% (grade 3 or 4, 0.8%) of those treated with letrozole. Vascular disorders occurred in 53.6% (grade 3 or 4, 2.3%) of patients receiving letrozole as extended adjuvant therapy after completion of 5 years of tamoxifen therapy compared with 47.8% (grade 3 or 4, 2.9%) of those who received placebo, including flushing (all grade, 49.7% vs. 43.3%; grade 3 or 4, 0.1% vs. 0%); hyperhidrosis was reported in 24.2% (grade 3 or 4, less than 0.1%) compared with 22.4% (grade 3 or 4, 0%), respectively. A patient-reported measure that captured the impact of letrozole treatment on important symptoms associated with estrogen deficiency favored placebo for vasomotor domains. Hot flashes also occurred in 6% to 19% of patients receiving letrozole for treatment of advanced breast cancer, while hyperhidrosis occurred in less than 5% of these patients.[29101]

Hypercalcemia was reported in less than 5% of patients treated with letrozole as second-line therapy for advanced breast cancer.[29101]

Renal disorders were reported in 5.1% of patients treated with letrozole as extended adjuvant therapy after 5 years of tamoxifen therapy (n = 2,563) compared with 3.9% of those who received placebo (n = 2,573); renal failure (unspecified), or grade 3 or 4 renal disorders, occurred in 0.5% versus 0.2% of patients, respectively.[29101]

Carpal tunnel syndrome and trigger finger have each been reported in postmarketing experience with letrozole therapy.[29101]

Anaphylactoid reactions, hypersensitivity reactions, and angioedema have all been reported in postmarketing experience with letrozole therapy.[29101]

Use letrozole with caution in patients with pre-existing cirrhotic hepatic disease; a dose reduction may be necessary. Exposure to letrozole was approximately doubled in subjects with biliary cirrhosis and severe hepatic impairment compared with healthy volunteers with normal liver function; the effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.[29101]

Use letrozole with caution in patients with pre-existing osteoporosis, as use of letrozole has been associated with decreases in bone mineral density (BMD). Consider monitoring patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with letrozole. Adjuvant treatment with letrozole resulted in a significantly larger decrease in lumbar spine (L2 to L4) BMD compared to tamoxifen in a safety study. The incidence of fractures and osteoporosis was also greater in the letrozole group compared with the tamoxifen group in the adjuvant treatment trial (BIG 1-98). In a separate BMD sub-study of the extended adjuvant trial (MA-17B), there was not a significant difference in the change from baseline in lumbar spine BMD in letrozole and placebo treated groups. However, the incidence of bone fractures and new osteoporosis was greater in patients treated with letrozole compared with placebo.[29101]

Use letrozole with caution in patients with pre-existing hypercholesterolemia; consider monitoring serum cholesterol levels during treatment. Hypercholesterolemia requiring lipid lowering therapy was reported more often in patients treated with letrozole compared with tamoxifen in the adjuvant therapy trial (BIG 1-98). An increase of greater than or equal to 1.5 times the upper limit of normal (ULN) in total cholesterol was also observed more often in letrozole-treated patients who had baseline total serum cholesterol within the normal range compared with those who received tamoxifen.[29101]

The safety and effectiveness of letrozole in children has not been established; however, letrozole has been used for 1 to 2 years to increase height in male children and adolescents with either idiopathic short stature or constitutional delayed puberty. In animal studies, letrozole administration for 12 weeks at exposures similar to the AUC in adult patients receiving the FDA-approved dose of 2.5 mg per day resulted in adverse skeletal / growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis in young (postnatal day 7) rats. Additionally, decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. These changes were not reversible at clinically relevant exposures within 42 months of discontinuation.[33752] [33753] [29101]

Treatment with letrozole is contraindicated for use during pregnancy. Letrozole has been prescribed off-label as a fertility treatment because it suppresses estrogen and can promote ovulation; while the outcomes of pregnancies in one cohort study demonstrate a similar rate of miscarriage and ectopic pregnancy in women who took letrozole versus other drugs for ovarian stimulation,[31753] pregnancy should be avoided by females of reproductive potential during letrozole treatment and for at least 3 weeks after the last dose. Although there are no adequately controlled studies in pregnant women, letrozole can cause fetal harm or death when administered during pregnancy based on postmarketing reports, animal studies, and its mechanism of action. Women who are pregnant or who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. In postmarketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. Daily administration of letrozole to rats during organogenesis at doses approximately 0.01 times the maximum recommended human dose on a mg/m² basis resulted in embryofetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was also teratogenic to rats at the same dose, causing fetal domed head and cervical/centrum vertebral fusion. In rabbits, the same dose level resulted in intrauterine mortality, increased resorption, increased postimplantation loss, and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.[29101]

Counsel patients about the reproductive risk and contraception requirements during letrozole treatment. Letrozole can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 weeks after treatment with letrozole. Females of reproductive potential should undergo pregnancy testing prior to initiation of letrozole. Women who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of letrozole on human fertility, male and female infertility has been observed in animal studies.[29101]

Due to the potential for serious adverse reactions in nursing infants from letrozole, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether letrozole is present in human milk, although many drugs are excreted in human milk.[29101]