Letroday 2.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LETRODAY 2.5 (LETRODAY 2.5)

Composition:

Active substance: letrozole;

One film-coated tablet contains 2.5 mg of letrozole;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); maize starch; colloidal anhydrous silicon dioxide; magnesium stearate; film coating: Opadry Yellow 03F520312 (hypromellose, iron oxide yellow (E 172), titanium dioxide (E 171), macrogol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, slightly biconvex, film-coated tablets of dark yellow color with bevelled edges, marked with "L2.5" on one side and smooth on the other.

Pharmacotherapeutic group.

Agents used in hormonal therapy. Hormone antagonists and related agents. Aromatase inhibitors. Letrozole.

ATC code L02BG04.

Pharmacological Properties.

Pharmacodynamics.

Letrozole is a non-steroidal aromatase inhibitor (an estrogen biosynthesis inhibitor) and an antineoplastic agent.

In cases where tumor tissue growth is dependent on estrogen, eliminating the estrogen-mediated stimulatory effect is essential for suppressing tumor growth. In postmenopausal women, estrogens are primarily produced via the enzyme aromatase, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) into estrone (E1) and estradiol (E2). Therefore, specific inhibition of the aromatase enzyme can achieve suppression of estrogen biosynthesis in peripheral tissues and in tumor tissue.

Letrozole inhibits aromatase by competitively binding to the heme subunit of cytochrome P450, a component of this enzyme, resulting in reduced estrogen biosynthesis in all tissues.

In healthy postmenopausal women, a single dose of letrozole at 0.1 mg, 0.5 mg, and 2.5 mg reduces serum levels of estrone and estradiol (compared to baseline levels) by 75–78% and 78%, respectively. Maximum reduction is achieved within 48–78 hours.

In postmenopausal women with advanced breast cancer, daily administration of letrozole at doses ranging from 0.1 to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75–95% of baseline levels. With doses of 0.5 mg and higher, concentrations of estrone and estrone sulfate often fall below the detection limit of the assay method used for hormone measurement. This indicates that these doses achieve more pronounced suppression of estrogen synthesis. Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is a highly specific inhibitor of aromatase activity. No impairment of adrenal steroid hormone synthesis has been observed. In postmenopausal patients treated with daily doses of 0.1–5 mg of letrozole, no clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH, or renin activity were detected. ACTH stimulation tests performed at 6 and 12 weeks of therapy with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not reveal any notable reduction in aldosterone or cortisol synthesis. Thus, there is no need to administer glucocorticoids or mineralocorticoids.

In healthy postmenopausal women, single doses of letrozole at 0.1 mg, 0.5 mg, and 2.5 mg did not alter plasma concentrations of androgens (androstenedione and testosterone). Similarly, in postmenopausal patients receiving daily doses of 0.1–5 mg of letrozole, no changes in plasma androstenedione levels were observed. This indicates that blockade of estrogen biosynthesis does not lead to accumulation of androgen precursors of estrogens. No changes in plasma concentrations of luteinizing hormone and follicle-stimulating hormone were observed in patients treated with letrozole, nor were there any changes in thyroid function as assessed by levels of thyroid-stimulating hormone, T4, and T3.

Pharmacokinetics.

Absorption. Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean bioavailability is 99.9%). Food slightly reduces the rate of absorption (mean time to reach maximum plasma concentration (tmax) is 1 hour when administered fasting and 2 hours when taken with food; mean maximum plasma concentration (Cmax) is 129 ± 20.3 nmol/L when fasting and 98.7 ± 18.6 nmol/L when taken with food). However, the extent of absorption (assessed by area under the concentration-time curve) is unchanged. These minor changes in absorption rate are considered clinically insignificant; therefore, letrozole can be administered independently of food intake.

Distribution. Plasma protein binding of letrozole is approximately 60% (primarily to albumin – 55%). Erythrocyte concentrations of letrozole are about 80% of its plasma levels. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of radioactivity in plasma was attributed to unchanged active substance. Therefore, the systemic effect of letrozole metabolites is negligible. Letrozole rapidly and widely distributes into tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 L/kg.

Metabolism and Elimination. Letrozole undergoes extensive metabolism, forming a pharmacologically inactive carbinol metabolite – the primary elimination pathway. Metabolic clearance (CLm) of letrozole is 2.1 L/h, which is lower than hepatic blood flow (approximately 90 L/h).

It has been demonstrated that CYP3A4 and CYP2A6 isoenzymes of cytochrome P450 are capable of converting letrozole into its metabolite. Formation of small amounts of other, as yet unidentified metabolites, as well as excretion of unchanged drug in urine and feces, plays only a minor role in the overall elimination of letrozole.

Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of radioactivity was recovered in urine and 3.8 ± 0.9% in feces. At least 75% of urinary radioactivity detected within 216 hours (84.7 ± 7.8% of the administered dose) was attributed to glucuronide conjugates of the carbinol metabolite, nearly 9% to two other unidentified metabolites, and 6% to unchanged letrozole.

The apparent terminal half-life (t1/2) in plasma is approximately 2–4 days. After daily administration of 2.5 mg, steady-state concentration is reached within 2–6 weeks, at which point it is approximately 7 times higher than after a single dose of the same amount. Concurrently, steady-state concentrations are 1.5–2 times higher than those predicted based on calculations from single-dose data. This indicates that the pharmacokinetics of letrozole exhibit slightly nonlinear characteristics with daily dosing at 2.5 mg. Since steady-state concentrations are maintained over prolonged treatment periods, accumulation of letrozole does not occur.

Linearity/Nonlinearity. Letrozole pharmacokinetics were dose-proportional after single oral doses up to 10 mg (dose range 0.01–30 mg) and after daily doses up to 1.0 mg (dose range 0.1–5 mg). After a single oral dose of 30 mg, a slight but more than proportional increase in AUC was observed. With daily doses of 2.5 mg and 5 mg, AUC increased approximately 3.8- and 12-fold, respectively, compared to a 2.5- and 5-fold increase expected from linearity relative to the 1.0 mg/day dose. Thus, the recommended dose of 2.5 mg/day may represent a threshold dose at which nonlinearity becomes apparent, while at 5 mg/day nonlinearity becomes more pronounced. This dose non-proportionality is likely due to saturation of metabolic elimination processes. Steady-state concentrations were achieved within 1–2 months with all studied dosing regimens (0.1–5.0 mg daily).

Pharmacokinetics in Specific Patient Populations. In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 mL/min), no change in letrozole pharmacokinetics was observed after a single 2.5 mg dose. Furthermore, in this study, the impact of impaired renal function on letrozole was evaluated using an analysis of covariance based on data from two pivotal studies (AR/BC2 and AR/BC3). Calculated creatinine clearance (range in AR/BC2: 19–187 mL/min; in AR/BC3: 10–180 mL/min) showed no statistically significant correlation with minimum plasma concentrations of letrozole at steady state (Cmin). Moreover, data from the AR/BC2 and AR/BC3 studies on second-line treatment of metastatic breast cancer demonstrated no negative impact of letrozole on creatinine clearance or worsening of renal function.

Therefore, dose adjustment is not required in patients with impaired renal function (creatinine clearance ≥ 10 mL/min). Information regarding patients with severe renal impairment (creatinine clearance < 10 mL/min) is limited.

In a similar study conducted in subjects with varying degrees of hepatic function, it was established that in patients with moderate hepatic impairment (Child-Pugh class B), mean AUC values were 37% higher than in healthy volunteers but remained within the range observed in patients without hepatic dysfunction. In a pharmacokinetic study of a single dose in 8 patients with liver cirrhosis and severe hepatic impairment (Child-Pugh class C), AUC increased by 95% and t½ by 187% compared to healthy volunteers. Thus, higher letrozole levels are expected in patients with breast cancer and severe hepatic impairment compared to those without severe liver dysfunction. Therefore, Letrodei 2.5 should be used with caution in patients with severe hepatic impairment, considering the individual benefit-risk ratio. Although dose reduction is not justified, as no increase in toxicity has been observed in patients receiving daily doses of 5–10 mg/day, such patients require close monitoring. Additionally, no impact of renal impairment (calculated creatinine clearance 20–50 mL/min) or hepatic impairment on plasma letrozole concentrations was observed in 359 patients with advanced breast cancer. Letrozole pharmacokinetics are independent of age.

Clinical characteristics.

Indications.

• Adjuvant therapy of early-stage hormone receptor-positive invasive breast cancer in postmenopausal women.
• Extended adjuvant therapy of early-stage invasive breast cancer in postmenopausal women who have completed standard 5-year adjuvant therapy with tamoxifen.
• First-line therapy of hormone-dependent advanced breast cancer in postmenopausal women.
• Treatment of advanced breast cancer in postmenopausal women (naturally or artificially induced) following recurrence or disease progression after prior antiestrogen therapy.
• Neoadjuvant therapy in postmenopausal women with hormone receptor-positive, HER-2-negative breast cancer who are not candidates for chemotherapy and for whom immediate surgical intervention is not indicated.

The efficacy of the drug has not been demonstrated in patients with hormone receptor-negative breast cancer.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Endocrine status characteristic of the premenopausal period.
• Pregnancy and breastfeeding.
• Women of reproductive age.

Interaction with other medicinal products and other forms of interaction.

Letrozole is partially metabolized via CYP2A6 and CYP3A4. Therefore, medicinal products affecting CYP3A4 and CYP2A6 enzyme activity may influence the systemic elimination of letrozole. The metabolism of letrozole appears to have low affinity for CYP3A4, as this enzyme does not become saturated at concentrations 150 times higher than the plasma concentrations of letrozole observed at steady state under typical clinical conditions.

To date, there is no clinical experience with the use of letrozole in combination with estrogens or other anticancer agents except tamoxifen. Tamoxifen, other antiestrogens, or estrogen-containing medicinal products may counteract the pharmacological effect of letrozole. Moreover, it has been demonstrated that concomitant administration of tamoxifen and letrozole significantly reduces plasma concentrations of letrozole. Concomitant use of letrozole with tamoxifen, other estrogen antagonists, or estrogens should be avoided.

MEDICINAL PRODUCTS THAT MAY INCREASE SERUM CONCENTRATIONS OF LETROZOLE

Inhibitors of CYP3A4 and CYP2A6 activity may reduce the metabolism of letrozole and thereby increase plasma concentrations of letrozole. Concomitant administration of medicinal products that strongly inhibit these enzymes (potent CYP3A4 inhibitors include, but are not limited to: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g., methoxsalen)) may increase exposure to letrozole. Therefore, caution is recommended in patients who require concomitant potent inhibitors of CYP3A4 and CYP2A6.

MEDICINAL PRODUCTS THAT MAY DECREASE SERUM CONCENTRATIONS OF LETROZOLE

Inducers of CYP3A4 activity may enhance the metabolism of letrozole and thereby reduce plasma concentrations of letrozole. Concomitant administration of medicinal products that induce CYP3A4 (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s wort) may reduce the AUC of letrozole. Therefore, caution is recommended in patients who require concomitant potent inducers of CYP3A4. Inducers of CYP2A6 are unknown.

Concomitant administration of letrozole (2.5 mg) and tamoxifen 20 mg once daily resulted in an average 38% reduction in plasma levels of letrozole. Clinical experience from second-line breast cancer treatment studies indicates that the therapeutic effect of letrozole and the frequency of adverse reactions were not increased when letrozole was administered immediately after tamoxifen. The mechanism of this interaction is unknown.

MEDICINAL PRODUCTS WHOSE SYSTEMIC SERUM CONCENTRATIONS MAY BE ALTERED BY LETROZOLE

In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and moderately CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when administering letrozole concomitantly with medicinal products whose elimination primarily depends on CYP2C19 and which have a narrow therapeutic index (e.g., phenytoin, clopidogrel). A substrate with a narrow therapeutic index for CYP2A6 is unknown.

Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate of CYP2C9 with a narrow therapeutic index, commonly used as a concomitant medication in the target population for letrozole) showed that co-administration of letrozole with these medicinal products does not result in clinically significant drug interactions.

A review of the database from these clinical studies revealed no evidence of other clinically significant interactions with commonly prescribed medicinal products.

Special precautions for use

There is no evidence to support the efficacy of letrozole in men with breast cancer, and therefore its use in male patients is not recommended.

Renal impairment

There are no data on the use of letrozole in patients with creatinine clearance < 10 mL/min. The benefit-risk ratio should be carefully considered before initiating treatment in such patients.

Cholesterol

Serum cholesterol monitoring should be considered. In an adjuvant treatment trial, hypercholesterolemia was reported in 52.3% of patients receiving letrozole and in 28.6% of those receiving tamoxifen. According to the grading criteria for adverse reactions, grade 3–4 hypercholesterolemia was reported in 0.4% of patients in the letrozole group and in 0.1% in the tamoxifen group. Additionally, in adjuvant therapy, an increase ≥1.5 × ULN in total cholesterol (usually non-fasting) was observed in patients receiving letrozole monotherapy who had normal baseline serum total cholesterol levels (i.e., ≤1.5 × ULN) in 151/1843 (8.2%) in the letrozole group versus 57/1840 (3.2%) in the tamoxifen group. Hypolipidemic therapy was required in 25% of patients receiving letrozole and in 16% of those receiving tamoxifen.

Hepatic impairment

In patients with severe hepatic impairment (Child-Pugh class C), the AUC and t½ of letrozole are approximately twice as long as in healthy individuals. These patients require closer monitoring.

Bone effects

Since letrozole is a potent agent that reduces estrogen concentrations, a decrease in bone mineral density can be expected. In women with osteoporosis or at risk of developing it, bone mineral density should be assessed using bone densitometry (e.g., DEXA scan) at the beginning of treatment. In the adjuvant setting, sequential treatment strategies (e.g., letrozole for 2 years followed by tamoxifen for 3 years) should also be considered based on the patient’s safety profile.

If necessary, treatment for osteoporosis should be initiated, and patients should be closely monitored during letrozole therapy.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (rare) may occur during letrozole treatment. In cases of tendon involvement, appropriate measures (including immobilization) should be taken and patients should be carefully monitored.

Menopausal status

In patients with uncertain menopausal status, levels of LH, FSH, and/or estradiol should be determined before initiating letrozole therapy. Letrozole should only be administered to women with a confirmed postmenopausal endocrine status.

Laboratory test abnormalities

No dose-dependent effects of letrozole on hematological or biochemical parameters have been observed. Moderate decreases in lymphocyte count of uncertain clinical significance were observed in some patients receiving letrozole 2.5 mg. This lymphocyte reduction was transient in approximately half of affected patients. Thrombocytopenia developed in two patients receiving letrozole; a causal relationship with the investigational drug was not established. Discontinuation of the study drug due to laboratory abnormalities, whether drug-related or not, occurred rarely.

Other precautions

Concomitant use of letrozole with tamoxifen, other estrogen antagonists, or estrogen-containing medicinal products should be avoided, as these substances may counteract the pharmacological effect of letrozole.

The product contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Perimenopausal women or women of reproductive potential

Letrozole should only be used in women with a clearly established postmenopausal status. Post-marketing reports have documented spontaneous abortions and congenital anomalies in newborns whose mothers were exposed to letrozole. Due to reports of ovarian function recovery in women during letrozole treatment, despite a confirmed postmenopausal status at the start of therapy, physicians should discuss appropriate contraceptive methods with patients when necessary.

Pregnancy

Based on human experience, including individual cases of congenital malformations (e.g., cleft lip, ambiguous external genitalia), letrozole is known to cause developmental fetal abnormalities when used during pregnancy. Animal studies have demonstrated reproductive toxicity. Letrozole is contraindicated during pregnancy.

Breastfeeding

It is unknown whether letrozole and its metabolites are excreted in human breast milk. The risk to the newborn infant cannot be excluded.

Letrozole is contraindicated during breastfeeding.

Fertility

The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a compensatory increase in gonadotropin levels (LH, FSH). The rise in FSH may stimulate follicular growth and potentially induce ovulation.

Ability to influence reaction speed when driving or operating machinery

Letrozole has a minor influence on the ability to drive or operate machinery. Since fatigue and dizziness may occur during treatment with letrozole, and somnolence in some cases, caution is recommended when driving or operating machinery.

Method of Administration and Dosage

Adult Patients, including Elderly Patients

The recommended dose of letrozole is 2.5 mg once daily. Dose adjustment is not required for elderly patients.

In patients with advanced or metastatic breast cancer, treatment with letrozole should be continued until tumor progression becomes evident.

Adjuvant or extended adjuvant therapy with letrozole should be administered for up to 5 years or until tumor progression, whichever occurs first.

In adjuvant treatment, a sequential treatment regimen may also be considered (letrozole for 2 years followed by tamoxifen for 3 years).

Neoadjuvant therapy with letrozole may last for 4–8 months to achieve optimal tumor size reduction. If the treatment response is inadequate, letrozole therapy should be discontinued and planned surgical intervention initiated and/or further treatment options discussed with the patient.

Dose adjustment of the drug is not required for elderly patients.

Children.
The drug is not used in children. Safety and efficacy of letrozole in pediatric patients have not been established. Available data are limited; therefore, dosage recommendations cannot be provided.

Renal or Hepatic Impairment

Dose adjustment of letrozole is not required in patients with renal impairment (creatinine clearance ≥ 10 mL/min) or mild to moderate hepatic impairment (Child-Pugh class A or B). Limited data are available for patients with severe renal impairment (creatinine clearance < 10 mL/min) or severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.

Method of Administration

Letrozole should be taken orally, independently of food intake, as food does not affect the extent of drug absorption.

A missed dose should be taken as soon as the patient remembers. However, if the patient remembers close to the time of the next scheduled dose (within 2–3 hours), the missed dose should be skipped and the patient should continue with the next dose according to the regular schedule.

A double dose should not be taken, as supratherapeutic daily doses exceeding the recommended 2.5 mg dose have been associated with disproportionate systemic exposure.

Children.

The drug is not used in children, as its efficacy and safety have not been studied in this patient population within clinical trials.

Overdose.

Isolated cases of letrozole overdose have been reported.

There is no specific antidote for overdose; treatment should be symptomatic and supportive.

Undesirable effects

Overview of safety profile

The frequency of adverse reactions for letrozole was primarily determined based on data obtained from clinical trials.

Letrozole was generally well tolerated in all studies as first- and second-line therapy in the treatment of advanced breast cancer, as adjuvant therapy for early-stage breast cancer, and as extended adjuvant therapy for breast cancer in women who had previously received standard adjuvant therapy with tamoxifen. Adverse reactions were observed in nearly 1/3 of patients treated with letrozole in metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen, with a median treatment duration of 60 months), and nearly 80% of patients in the extended adjuvant therapy setting (both letrozole and placebo, with a median treatment duration of 60 months).

The observed adverse reactions were predominantly mild or moderately severe and in most cases were related to estrogen deficiency. The most commonly reported adverse reactions in clinical trial reports were hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Other important potential adverse reactions that may occur during treatment with letrozole include musculoskeletal disorders such as osteoporosis and/or bone fractures, and cardiovascular disorders (including cerebrovascular and thromboembolic events). Many adverse effects may be attributable to the natural pharmacological consequences of estrogen deficiency (e.g., hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred during the first few weeks of treatment. Frequency categories for these adverse reactions are described in Table 1.

Adverse reactions are listed by frequency, with the most common listed first. The following frequency categories were used to assess the incidence of various adverse reactions: 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); frequency not known (cannot be estimated from available data).

Table 1

(1) only in the treatment of metastatic disease

Some adverse reactions were reported at significantly different frequencies under adjuvant treatment conditions.

Table 2

Adjuvant therapy with letrozole compared to tamoxifen monotherapy: adverse events with significantly different frequencies

Note. During treatment – includes 30 days after the last dose. At any time – includes the follow-up period after completion or discontinuation of investigational treatment.

The difference is based on risk ratios and 95% confidence intervals.

Table 3

Sequential treatment compared to letrozole monotherapy: adverse events with significantly different frequencies

* Significantly lower than in the letrozole monotherapy group.

** Significantly higher than in the letrozole monotherapy group.

Note: The reporting period includes the treatment period or 30 days after discontinuation of treatment.

Description of selected adverse reactions

Cardiac adverse reactions

In the adjuvant treatment setting, in addition to the data presented in Table 2, the following adverse events were reported for letrozole and tamoxifen, respectively (with a median treatment duration of 60 months plus 30 days): angina requiring surgical intervention (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); arterial hypertension (5.6% vs. 5.7%); cerebrovascular disorders/transient ischemic attack (2.1% vs. 1.9%).

In the extended adjuvant treatment setting, the following adverse events were reported for letrozole (median treatment duration 5 years) and placebo (median duration of exposure 3 years), respectively: angina requiring surgical intervention (0.8% vs. 0.6%); newly diagnosed angina or worsening of existing angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic events* (0.9% vs. 0.3%); stroke/transient ischemic attack* (1.5% vs. 0.8%).

The incidence of events marked with * was statistically significantly different between the two treatment groups.

Musculoskeletal adverse reactions

Safety data for the musculoskeletal system obtained in the adjuvant treatment setting are presented in Table 2.

In the extended adjuvant treatment setting, bone fractures or osteoporosis were observed in a statistically significantly higher number of patients in the letrozole treatment group (bone fractures – 10.4% and osteoporosis – 12.2%) compared to patients in the placebo group (5.8% and 6.4%, respectively). Median treatment duration was 5 years for letrozole compared to 3 years for placebo.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the appropriate system.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, protected from light and out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Ugiea Pharma Specialities Limited.

Manufacturer's address and location of its business operations.

Survey No. 550, 551 and 552, Koltur Village, Shamirpet Mandal, Medchal-Malkajgiri, Medchal District, Telangana, 500101, India.