Ovupic

Yellow colored, circular shaped, biconvex, film-coated tablet.
Each film-coated tablet contains: Letrozole, USP 2.5 mg.

Aromatase Inhibitor.
Pharmacology: Pharmacodynamics: The elimination of Estrogen-mediated growth stimulation is a prerequisite for tumor response in cases where the growth of tumor tissue depends on the presence of Estrogens and endocrine therapy is used. In postmenopausal women, Estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to Estrone and Estradiol. The suppression of Estrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the aromatase cytochrome P450, resulting in a reduction of Estrogen biosynthesis in all tissues where present.
In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg and 2.5 mg Letrozole suppress serum estrone and estradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed plasma concentration of Estradiol, Estrone, and Estrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of Estrone and Estrone sulphate were below the limit of detection in the assays, indicating that higher Estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all these patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg, and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg, indicating that the blockade of Estrogen biosynthesis does not lead to accumulation of androgenic precursors. 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 test.
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median t_max 1 hour fasted versus 2 hours fed; and mean C_max 129±20.3 nmol/liter fasted versus 98.7±18.6 nmol/liter fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance, and therefore Letrozole may be taken without regard to mealtimes.
Distribution: Plasma protein binding of Letrozole is approximately 60%, mainly to albumin (55%). The concentration of Letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labelled Letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87±0.47 L/kg.
Biotransformation: Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of Letrozole (CL_m=2.1 L/h) but 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. In vitro, but their individual contributions to Letrozole clearance in vivo have not been established. In an interaction study coadministration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in Letrozole clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance.
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-labelled 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 two unidentified metabolites, and 6% to unchanged Letrozole.
Elimination: The apparent terminal elimination half-life in plasma is about 2 to 4 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 the 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.
Linearity/non-linearity: The pharmacokinetics of Letrozole were dose proportional after single oral doses up to 10 mg (dose range: 0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5 mg). After a 30 mg single oral dose there was a slightly dose over-proportional increase in AUC value. The dose over-proportionality is likely to be the result of a saturation of metabolic elimination processes. Steady levels were reached after 1 to 2 months at all dosage regimens tested (0.1-5.0 mg daily).
Special populations: Elderly: Age had no effect on the pharmacokinetics of Letrozole.
Renal impairment: In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of Letrozole or the urinary excretion of the glucuronide of its carbinol metabolite was found after a single dose of 2.5 mg. In addition to the previously mentioned study assessing the influence of renal impairment on Letrozole, a covariate analysis was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine clearance (ClCr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min] showed no statistically significant association between Letrozole plasma trough levels at steady-state (C_min). Furthermore, data of Study AR/BC2 and Study AR/BC3 in second-line metastatic breast cancer showed no evidence of an adverse effect of Letrozole on ClCr or an impairment of renal function.
Therefore, no dose adjustment is required for patients with renal impairment (ClCr ≥10 mL/min). Little information is available in patients with severe impairment of renal function (ClCr <10 mL/min).
Hepatic impairment: In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of Letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh C) to those in healthy volunteers (N=8), AUC and t_1/2 increased by 95 and 187%, respectively. Thus, Letrozole should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.
Extended adjuvant treatment of hormone-dependent early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy for 5 years.
First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer.
Advanced breast cancer after relapse or disease progression, in women with natural or artificially induced postmenopausal endocrine status, who have previously been treated with Anti-Estrogens.
Neoadjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery not indicated.
Efficacy has not been demonstrated in patients with hormone receptor negative breast cancer.

Adult and elderly patients: The recommended dose of Letrozole tablet is 2.5 mg once daily.
In patients with advanced or metastatic breast cancer, treatment with Letrozole tablets should continue until tumor progression is evident.
In the adjuvant and extended adjuvant setting, treatment with Letrozole tablets should continue for 5 years or until tumor relapse occurs, whichever is first.
In the neoadjuvant setting, treatment with Letrozole tablets could be continued for 4 to 8 months in order to establish optimal tumor reduction. If the response is not adequate, treatment with Letrozole tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.
Following standard adjuvant tamoxifen therapy, treatment with Letrozole tablets should continue for 5 years or until tumor relapse occurs, whichever comes first. In patients with metastatic disease, treatment with Letrozole tablets should continue until tumor progression is evident. Regular monitoring to observe progression during the pre- operative treatment period is recommended. No dose adjustment is required for elderly patients.
Pediatric population: Letrozole tablets are not recommended for use in children and adolescents. The safety and efficacy of Letrozole tablets in children and adolescents aged up to 17 years have not been established. Limited data are available and no recommendation on a posology can be made.
Renal impairment: No dosage adjustment of Letrozole tablets is required for patients with renal insufficiency with creatinine clearance ≥10 mL/min. Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 10 mL/min.
Hepatic impairment: No dosage adjustment of Letrozole tablets is required for patients with mild to moderate hepatic insufficiency (Child-Pugh grade A or B). Insufficient data are available for patients with severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision.
Method of administration: Letrozole tablets should be taken orally and can be taken with or without food.
A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5 mg recommended dose, over-proportionality in systemic exposure was observed.

There is no clinical experience of overdosage only isolated cases of overdose with Letrozole have been reported. Each of these doses was well tolerated. There is no clinical evidence for a particular dose of Letrozole resulting in life-threatening symptoms.
There is no specific antidote to Letrozole. In general, supportive care, symptomatic treatment and frequent monitoring of vital signs are appropriate.

Hypersensitivity to the Letrozole.
Premenopausal endocrine status.
Pregnancy.
Breast-feeding.

Menopausal status: In patients whose menopausal status is unclear, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or Estradiol levels should be measured before initiating treatment with Letrozole. Only women of postmenopausal endocrine status should receive Letrozole.
Renal impairment: Letrozole has not been investigated in a sufficient number of patients with a creatinine clearance lower than 10 mL/min. The potential risk/benefit to such patients should be carefully considered before administration of Letrozole.
Hepatic impairment: In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal half-life were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision.
Bone effects: Letrozole is a potent Estrogen-lowering agent. Women with a history of osteoporosis and/or fractures, or who are at increased risk of osteoporosis, should have their bone mineral density formally assessed prior to the commencement of adjuvant and extended adjuvant treatment and monitored during and following treatment with Letrozole. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. In the adjuvant setting a sequential treatment schedule (Letrozole 2 years followed by tamoxifen 3 years) could also be considered depending on the patient's safety profile.
Tendonitis and tendon rupture: Tendonitis and tendon ruptures (rare) may occur. Close monitoring of the patients and appropriate measures (e.g., immobilization) must be initiated for the affected tendon.
Other warnings: Co-administration of Letrozole with Tamoxifen, other Anti-estrogens or Estrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of Letrozole.

Women of perimenopausal status or child-bearing potential: Letrozole should only be used in women with a clearly established postmenopausal status. As there are reports of women regaining ovarian function during treatment with Letrozole despite a clear postmenopausal status at start of therapy, the physician needs to discuss adequate contraception when necessary.
Pregnancy: Based on human experience in which there have been isolated cases of birth defects (labial fusion, ambiguous genitalia), Letrozole may cause congenital malformations when administered during pregnancy.
Letrozole is contraindicated during pregnancy.
Breast-feeding: It is unknown whether Letrozole and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
Letrozole is contraindicated during breast-feeding.
Fertility: The pharmacological action of Letrozole is to reduce Estrogen production by aromatase inhibition. In premenopausal women, the inhibition of Estrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.

Summary of the safety profile: The frequencies of adverse reactions for Letrozole are mainly based on data collected from clinical trials.
Up to approximately one third of the patients treated with Letrozole in the metastatic settings and approximately 80% of the patients in the adjuvant setting as well as in the extended adjuvant setting experienced adverse reactions. The majority of the adverse reactions occurred during the first few weeks of treatment.
The most frequently reported adverse reactions in clinical studies were hot flushes, hypercholesterolemia, arthralgia, fatigue, increased sweating and nausea.
Important additional adverse reactions that may occur with Letrozole are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events). The frequency category for these adverse reactions is described in Table 1.
Tabulated list of adverse reactions: The frequencies of adverse reactions for Letrozole are mainly based on data collected from clinical trials.
The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post-marketing experience with Letrozole tablets.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 1.)

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Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following tables provide information on significant differences in Letrozole versus tamoxifen monotherapy and in the Letrozole-tamoxifen sequential treatment therapy: See Tables 2 and 3.

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Click on icon to see table/diagram/image

Metabolism of Letrozole is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak, unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole. The effect of potent CYP450 inhibitors is unknown.
There is no clinical experience to date on the use of Letrozole in combination with Estrogens or other anticancer agents, other than Tamoxifen. Tamoxifen, other anti-estrogens or estrogen-containing therapies may diminish the pharmacological action of Letrozole. In addition, co-administration of Tamoxifen with Letrozole has been shown to substantially decrease plasma concentrations of Letrozole. Co-administration of Letrozole with Tamoxifen, other anti- estrogens or estrogens should be avoided.
In vitro, Letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving Letrozole concomitantly with medicinal products whose elimination is mainly dependent on these isoenzymes and whose therapeutic index is narrow (e.g. Phenytoin, Clopidogrel).

Store at temperatures not exceeding 30°C.

Cancer Hormone Therapy

L02BG04 - letrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.

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