Femara®

Letrozole

Nonsteroidal Aromatase Inhibitor--Inhibitor of Estrogen Biosynthesis--Antitumor Agent

Novartis Pharmaceuticals

http://www.novartis.com/http://www.novartis.com/

Femara Monograph PDF download here.

 

CPS:PIS_m211600

Date of Preparation: May 16, 1997

Date of Revision: February 29, 2004

 

 

Pharmacology

Letrozole is a potent and highly specific nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.

     Letrozole exerts its antitumor effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens—primarily androstenedione and testosterone—to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.

     In healthy postmenopausal women, single oral doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum estrone by 75 to 78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48 to 78 hours.

     In postmenopausal women with advanced breast cancer, daily letrozole doses of 0.1 to 5 mg suppress estradiol, estrone and estrone sulfate plasma levels by 75 to 95% from baseline in all patients treated. With 0.5 mg doses and higher, many plasma levels of estrone and estrone sulfate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.

     Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes in the plasma levels of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH (adrenocorticotropic hormone) or in plasma renin activity were found in postmenopausal patients treated with 0.1 to 5 mg letrozole daily. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid or mineralocorticoid supplementation is not required.

     Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5 mg, or on plasma androstenedione concentrations among postmenopausal patients treated with daily doses of 0.1 to 5 mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T₄ and T₃ uptake.

 

Pharmacokinetics

Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability=99.9%). Food slightly decreases the rate of absorption (median t_max 1 hour fasted vs 2 hours fed and mean C_max 129±20.3 nmol/L fasted vs 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

Distribution: Letrozole is rapidly and extensively distributed into tissues (Vd_ss=1.87±0.47 L/kg). Plasma protein binding is approximately 60%, mainly to albumin. The letrozole concentration in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labeled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low.

Biotransformation and Elimination: Metabolic clearance to a pharmacologically inactive carbinol metabolite, CGP 44645, is the major elimination pathway of letrozole (Cl_m=2.1 L/h), but it is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labeled letrozole to healthy postmenopausal volunteers, 88.2±7.6% of the radioactivity was recovered in urine and 3.8±0.9% in feces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7±7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to 2 unidentified metabolites, and 6% to unchanged letrozole.

     The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

 

Indications

As first-line therapy in postmenopausal women with advanced breast cancer. Letrozole is also indicated for the hormonal treatment of advanced/metastatic breast cancer in women with natural or artificially induced postmenopausal status, who have disease progression following antiestrogen therapy.

 

Contraindications

Premenopausal endocrine status, pregnancy, lactation.

     Known or suspected hypersensitivity to letrozole, other aromatase inhibitors, or to the nonmedicinal ingredients (see Supplied).

 

Warnings

Occupational Hazards

Ability to drive and use machines: Since fatigue and dizziness have been observed with the use letrozole, and somnolence has been reported uncommonly, caution is advised when driving or using machines.

Use with Other Anticancer Agents: Coadministration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The clinical significance of this finding has not been explored in prospective clinical trials.

     There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.

Reproductive Toxicology: Letrozole was evaluated for maternal toxicity as well as embryotoxic, fetotoxic and teratogenic potential in female rats following oral administration of daily doses of 0.003, 0.01 or 0.03 mg/kg on gestation days 6 through 17. Oral administration of letrozole to pregnant rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg. Embryotoxicity and fetotoxicity were seen at doses ≥ 0.003 mg/kg, and there was an increase in the incidence of fetal malformation among the animals treated. However it is not known whether this was an indirect consequence of the pharmacological activity of letrozole (inhibition of estrogen biosynthesis) or a direct drug effect.

 

Precautions

Special Populations: Hepatic Impairment: In a single dose trial with 2.5 mg letrozole in volunteers with hepatic impairment, mean AUC values of the volunteers with moderate hepatic impairment was 37% higher than in normal subjects, but still within the range seen in subjects with normal hepatic function. In a study comparing the pharmacokinetics of letrozole after a single oral dose of 2.5 mg in 8 subjects with liver cirrhosis and severe nonmetastatic hepatic impairment (Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t_1/2 increased by 95% and 187%, respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. Long-term effects of this increased exposure have not been studied.

     These results indicate that no dosage adjustment is necessary for breast cancer patients with mild to moderate hepatic dysfunction. However, since letrozole elimination depends mainly on intrinsic metabolic clearance, caution is recommended. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe nonmetastatic hepatic impairment. Therefore, such patients should be kept under close supervision for adverse events.

Renal Impairment: Pharmacokinetics of a single 2.5 mg letrozole dose were unchanged in a study in postmenopausal women with varying degrees of renal function (24-hour creatinine clearance=9 to 116 mL/min). In a study in 364 patients with advanced breast cancer there was no significant association between letrozole plasma levels and calculated CL_cr (range 22.9 to 211.9 mL/min). No dosage adjustment is required in patients with CL_cr≥ 10 mL/min. No data are available for patients with CL_cr≤ 9 mL/min. The potential risks and benefits to such patients should be considered carefully before prescribing letrozole.

Geriatrics

There have been no age-related effects observed on the pharmacokinetics of letrozole.

 

Drug Interactions

Clinical trials of interaction with letrozole and cimetidine or warfarin indicate that coadministration does not result in clinically significant drug interactions.

     A review of the clinical trial database indicated no evidence of other clinically relevant interactions with other commonly prescribed drugs.

     In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and moderately 2C19. CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady-state. Thus clinically relevant interactions with CYP2C19 are unlikely to occur. However, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

Food Interactions: Food slightly decreases the rate of absorption (median t_max 1 hour fasted vs 2 hours fed and mean C_max 129±20.3 nmol/L fasted vs 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

Drug/Laboratory Test Interactions: No clinically significant changes in the results of clinical laboratory tests have been observed.

 

Adverse Effects

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer. Approximately one third of patients treated with letrozole can be expected to experience adverse reactions. The most frequently reported adverse reactions in the clinical trials were hot flushes, nausea and fatigue (see  Table 1 and  Table 2). Many adverse reactions can be attributed to the normal physiological consequences of estrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding). The adverse drug reactions reported from clinical trials are summarized in  Table 1 and  Table 2 for first-line and second-line treatment with letrozole, respectively.

First-line Therapy: Overall, 455 postmenopausal patients with locally advanced or metastatic breast cancer were treated with letrozole in a well-controlled clinical trial and the median time of exposure was 11 months. The incidence of adverse experiences was similar for letrozole and tamoxifen. The most frequently reported adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse experiences other than progression of tumor occurred in 10/455 (2%) of patients on letrozole and in 15/455 (3%) of patients on tamoxifen.

      Table 1 shows the frequency of adverse events considered possibly related to trial drug that have been reported with an incidence of more than 2% (whether for letrozole or for tamoxifen) in a well-controlled clinical study with letrozole (2.5 mg daily) and tamoxifen (20 mg daily).

CPS:Femara_t1Click here for Table 1

Table 1: Femara

Frequency of Adverse Events (Experience >2%)

 

Adverse Event System Organ Class/Preferred Term	Femara N=455 (%)	Tamoxifen N=455 (%)
Gastrointestinal Disorders
Nausea	6.6	6.4
Constipation	2.4	1.3
Vomiting	2.2	1.5
General Disorders and Administration Site Conditions
Fatigue	2.6	2.4
Metabolism and Nutrition Disorders
Appetite Decreased	1.6	3.3
Appetite Increased	1.8	2.0
Nervous System Disorders
Headache	2.2	2.4
Skin and Subcutaneous Tissue Disorders
Alopecia	5.5	3.3
Sweating Increased	2.0	2.9
Vascular Disorders
Hot Flushes	16.7	14.3
Thromboembolic Events	1.5	1.9

 

Second-line Therapy:  Table 2 shows in decreasing order of frequency the AEs—considered possibly related to trial drug according to the investigator—that have been reported with an incidence of more than 1.0% (for letrozole) in a controlled clinical trial with letrozole (2.5 mg daily) and megestrol acetate (160 mg daily) for up to 33 months.

CPS:Femara_t2Click here for Table 2

Table 2: Femara

Frequency of Adverse Events (Experience >2%)

 

Adverse Experience	Femara  % (N=174)	Megestrol Acetate % (N=189)
Headache	6.9	4.8
Nausea	6.3	4.2
Peripheral edema	6.3	3.7
Fatigue	5.2	6.3
Hot flushes	5.2	3.7
Hair thinning	3.4	1.1
Rasha	3.4	0.5
Vomiting	2.9	1.6
Dyspepsia	2.9	1.6
Weight increase	2.3	8.5
Musculoskeletal painb	2.3	1.1
Anorexia	2.3	1.1
Vaginal bleeding	1.7	3.2
Leukorrhea	1.7	2.6
Constipation	1.7	2.1
Dizziness	1.1	3.7
Increased appetite	1.1	3.7
Increased sweating	1.1	2.1

 

 ^a Including: erythematous rash, maculopapular rash.

 ^b Including: arm pain, back pain, leg pain, skeletal pain.

 

 

     There were no differences in the incidence and severity of adverse reactions in patients ≤  55 years, 55 to 69 years, and ≥  70 years.

     Other adverse reactions, ranked according to frequency: uncommon ≥ 0.1% to <1%; rare ≥ 0.01% to <0.1%; very rare <0.01%, including isolated reports, included the following:

Infections and infestations

Uncommon: Urinary tract infection.

Neoplasms benign and malignant (including cysts and polyps)

Uncommon: Tumor pain.

 

Blood and lymphatic system disorders

Uncommon: Leukopenia.

 

Metabolism and nutrition disorders

Uncommon: Hypercholesterolemia, general edema.

Psychiatric disorders

Uncommon: Depression, anxiety{*Including nervousness, irritability.}.

 

Nervous system disorders

Uncommon: Somnolence, insomnia, memory impairment, dysesthesia{*Including paresthesia, hypoesthesia.}, taste disturbance.

Rare:    Cerebrovascular accident.

 

Eye disorders

Uncommon: Cataract, eye irritation.

 

Cardiac disorders

Uncommon: Palpitations, tachycardia.

Vascular disorders

Uncommon: Thrombophlebitis{*Including superficial and deep thrombophlebitis.}, hypertension.

Rare:    Pulmonary embolism, arterial thrombosis, cerebrovascular infarction.

 

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnea.

 

Gastrointestinal disorders

Uncommon: Abdominal pain, stomatitis, dry mouth.

 

Skin and subcutaneous tissue disorders

Uncommon: Pruritis, dry skin, urticaria.

Renal and urinary disorders

Uncommon: Increased urinary frequency.

Reproductive system and breast disorders

Uncommon: Vaginal discharge, vaginal dryness, breast pain.

General disorders and administration site conditions

Uncommon: Pyrexia, mucosal dryness, thirst.

Investigations

Uncommon: Weight loss, increase in aminotransferases.

 

Overdose

 

 

Symptoms

Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse events were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single dose studies the highest dose used was 30 mg, which was well tolerated; in multiple dose trials, the largest dose of 10 mg was well tolerated.

 

 

Treatment

See Symptoms.

 

Dosage

Adults and Elderly Patients: The recommended dose is one 2.5 mg tablet once daily. Treatment should continue until further tumor progression is evident. No dose adjustment is required for elderly patients.

Patients with Hepatic and/or Renal Impairment: No dosage adjustment is required for patients with renal impairment (creatinine clearance ≥ 10 mL/min) or moderate hepatic impairment. Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe nonmetastatic hepatic impairment. Therefore, patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision for adverse events (see Precautions).

 

Supplied

Each dark yellow, round, slightly biconvex tablet with beveled edges, bearing the imprint “FV” on one side and “CG” on the other, contains: letrozole 2.5 mg. Nonmedicinal ingredients: cellulose compounds (microcrystalline cellulose and methylhydroxypropylcellulose), cornstarch, iron oxide, lactose, magnesium stearate, polyethylene glycol, sodium starch glycolate, silicon dioxide, talc and titanium dioxide. Blister packages of 30. Protect from heat (store at room temperature 15 to 30°C). Protect from moisture.