Nonsteroidal Aromatase Inhibitor – Inhibitor of Estrogen Biosynthesis – Antitumor Agent
Action And Clinical 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 their growth stimulus. 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.
In a controlled double-blind clinical trial, the overall objective tumor response rate (complete and partial response) was 23.6% in letrozole-treated patients compared to 16.4% in patients on 160 mg megestrol acetate. Treatment comparison of the response rate showed a statistically significant difference in favor of 2.5 mg letrozole (p=0.04).
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability=99.9%). Food slightly decreases the rate of absorption (median tmax 1 hour fasted vs 2 hours fed and mean Cmax 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 (Vdss=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 4-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 (Clm=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 4-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 And Clinical Uses: 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.
Contra-Indications: Premenopausal endocrine status, pregnancy, lactation.
Known or suspected hypersensitivity to letrozole, other aromatase inhibitors, or to the nonmedicinal ingredients (see Supplied).
Manufacturers’ Warnings In Clinical States: Occupational Hazards: Letrozole is unlikely to impair the ability of patients to drive or to operate machinery. However, in some cases, fatigue and dizziness have been observed with use. Patients should be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired.
Use with Other Anticancer Agents: 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 Â³0.003 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. These results indicate that no dosage adjustment is necessary for breast cancer patients with hepatic dysfunction. However, since letrozole elimination depends mainly on intrinsic metabolic clearance, caution is recommended.
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 CLcr (range 22.9 to 211.9 mL/min). No dosage adjustment is required in patients with CLcr ³10 mL/min. No data are available for patients with CLcr £9 mL/min.
Letrozole is weakly bound to plasma proteins; it is anticipated that it could be removed from blood by dialysis. 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.
In a large clinical trial there was no evidence of clinically relevant interactions in patients treated with letrozole receiving other commonly prescribed drugs (e.g., benzodiazepines; barbiturates; furosemide; NSAIDs such as diclofenac sodium, ibuprofen; omeprazole).
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and 2C19. Thus, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on the isoenzymes and whose therapeutic index is narrow.
Food Interactions : Food slightly decreases the rate of absorption (median tmax 1 hour fasted vs 2 hours fed and mean Cmax 129Â±20.3 nmol/L fasted vs 98.7Â±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 Reactions: In clinical trials, adverse experiences (AEs) were generally mild to moderate and rarely severe enough to require discontinuation of treatment. Many AEs were attributed either to the underlying disease or to the normal physiological consequences of estrogen deprivation (e.g., hot flushes, hair thinning).
Table I 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 2.0% (whether for letrozole or for megestrol acetate) in a controlled clinical trial with letrozole (2.5 mg daily) and megestrol acetate (160 mg daily) for up to 33 months.
Other adverse experiences considered to be possibly drug related and reported in at least 3 patients treated with letrozole, with a frequency below 2%, included weight loss and generalized edema.
There were no differences in the incidence and severity of adverse reactions in patients £55 years, 55 to 69 years, and ³70 years.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience with letrozole overdosage. No specific treatment for overdosage is known; treatment should be symptomatic and supportive.
Dosage And Administration: Adults and Geriatrics: 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 hepatic impairment or renal impairment (creatinine clearance ³ 10 mL/min).
Availability And Storage: Each dark yellow, round, slightly biconvex tablet with beveled-edge, bearing the imprint “FV” on one side and “CG” on the other, contains: letrozole 2.5 mg. Nonmedicinal ingredients: cellulose compounds, 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 below 30°C).
FEMARA® Novartis Pharmaceuticals Letrozole Nonsteroidal Aromatase Inhibitor – Inhibitor of Estrogen Biosynthesis – Antitumor Agent
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