Femara 2.5mg Novartis supports breast cancer treatment (3 blisters x 10 tablets)

Dosage form Box of 3 blisters x 10 tablets
Specifications Letrozole

Ingredient

Composition information	Content
Letrozole	2.5mg

Uses

Indications

Femara drug indications for treatment in the following cases:

Supplemented treatment for women after menopause with early -stage breast cancer, a positive hormone receptor. Progressing in natural or artificial menopause women, previously treated with anti -estrogen drugs. Treatment continues after surgery to follow the standard therapy. In postmenopausal women, estrogen is mainly formed by the effects of aromatase enzyme is the adrenal and adrenal transformation of the adrenal gland - mainly Androstenedione and Testosterone - Oestrone (E1) and Oestradiol (E2). Therefore, the inhibition of estrogen biosynthesis in peripheral tissue and cancer tissue can be achieved due to specialized inhibition of enzyme aromatase.

Letrozole is an non -steroid AROMATASE inhibitor. This substance inhibits the enzyme aromatase by competing attaching to the hem of the enzyme cytochrome paso unit, resulting in a decrease in estrogen biosynthesis in all tissues.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg and 2.5 mg of Letrozole inhibit serum oesttrone from 75-78% and inhibit oestradiol 78% compared to the original level. The maximum inhibition is achieved from 48-78 hours.

In post-menopause patients with progressive breast cancer, the dose of 0.1-5 mg/day inhibits oestradiol, oestrone and oestrone sulphate levels in plasma from 75-95% compared to the original level in all treated patients. With a dose of 0.5 mg and higher, oestrone and oestrone sulphate concentrations are lower than the limits that can be detected in tests, showing that the inhibitor of estrogen is more achieved when using these doses. The inhibition of estrogen is maintained during the treatment period in all patients.

Letrozole is highly specific in inhibiting Aromatase activity. Not recorded the decrease in the adrenal steroids. Clinical changes have not been seen about clinical changes in concentrations of cortisol, aldosterone, 11-dyoxycortisol, 17-hydroxy-progesterone and acth in plasma, or the activity of lenin in plasma in menopause patients treated with the dose of Letrozole 0.1-5 mg/day.

ACTH stimulating test is performed after 6-12 weeks of treatment with a dose of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg and 5 mg, which shows any decline in production of aldosterone or cortisol. Therefore, there is no need to add glucocorticoid and mineral corticosteroids.

No change has been recorded in plasma androstenedone concentrations in healthy postmenopausal women after using single doses of 0.1 mg, 0.5 mg and 2.5 mg of letrozole or changes in androstenedione concentration in plasma in post -menopause patients with doses of 0.1 - 5 mg/day, indicates that the inhibition of estrogen -inhibitors leads to non -valuable estrogen biosum The precursor of Androgen. LH and FSH concentrations in plasma are not affected by Letrozole in patients, thyroid function is not affected when assessed by TSH, T4 and T3 tests.

complementary treatment

Big 1-98 study

Big-98 is a multi-centered random study with over 8,000 women after menopause with early-stage breast cancer with positive hormone receptors and has surgery to remove tumors, with one of the following treatment groups:

a. Tamoxifen for 5 years;

b. Femara for 5 years;

c. Tamoxifen for 2 years then use Femara for 3 years;

d. Femara for 2 years then used tamoxifen for 3 years. according to).

The main ending is still not sick (DFS), the end of the end is still alive (OS), still living without disease for a long time (DDFS), still living without systemic disease (SDFS), Breast Cancer Invasive and Time to Mobile.

Results after the average monitoring period 26 months

The data in Table 2 reflects the results of the main core analysis (PCA) including data from groups that do not switch to other treatment (groups A and B) and the withdrawn data to 30 days after switching to other treatment in two transfer groups (groups C and D).

This analysis is conducted when the average treatment time is 24 months and the average monitoring time is 26 months using Femara for 5 years better than using tamoxifen on all ending outputs except in general alive and breast cancer on both sides.

Table 2: The number of living is not infected and alive in general (PCA ITT group) with an average monitoring time of 26 months.

Femara

n = 4003

tamoxifen
n = 4007 Risk ratio
(95% CI) The value of (0.70, 0.93) 0.0030 extra) 265 318 0.82 (0.70, 0.97) 0.0204 1,06)

0.1546

still alive without systemic disease (Supporting) 323 383 0.83 (0.72, 0.97)

0.0172 172 Mangon (TD> 19 31 0.61 (0.35, 1,08) 0.0910 CI = Trusting interval

Use auxiliary therapy.

Analysis of single -therapy groups (MAA), which includes data on single therapy groups, only provide updated information in a long time appropriate about the effectiveness of the Femara monar therapy compared to Tamoxifen (Table 3). In 2005, based on PCA data presented in Table 2 and in the recommendation by the independent data control council, Tamoxifen mono therapeutic groups are known for drug names and patients allowed to switch to Femara.

26% of randomly selected patients have switched to Femara - including a very small number of patients switching to other Aromatase inhibitors. To find out the influence of this optional conversion, monitor the censorship of analysis on the conversion date of the option (in the group using Tamoxifen) summarized for MAA (Bȧng 4).

With an average 73 -month monitoring time and 60 -month average treatment time, the risk of DSF decreases significantly when using Femara compared to Tamoxifen (analysis of ITT: HR 0.88% CI 95% 0.78, 0.99; P = 0.03); Affirming the results of PCA 2005. Censorship analysis of DFS shows similar benefits (HR 0.85%; CI 95% 0.75, 0.96).

Similarly, updated analysis also confirms the superiority of Femara in reducing the risk of cases of non -disease without disease in the long run (HR 0.87% 0.76, 1.00) and increases the time until the distance of metastases (HR 0.85%; CI 95% 0.72, 1.00). Moreover, the number of survival in general is meaningful in ITT analysis. Censorship analysis of the number of vital in general shows significant greater benefits (HR 0.82% 0.70, 0.96) The advantage of the group using Femara.

Table 3: The number of living is not sick and alive in general (PCA ITT group) with an average tracking time of 73 months.

Femara

n = 2463

tamoxifen
n = 2459

Risk ratio
(95% CI) Value P 0.88 (0.78, 0.99)

0.03

time to the time of metastasis (extra conclusion) 257 298 0.85 (0.72, 1.00)

0.045 Support) 385

432

0.87 (0.76, 1.00) 0.049 1,02) 0.08

34 44 0.76 (0.49, 1.19) 0.2 The censorship of the number of vital is generally vital 338 338 0.82 (0.70,0.96) - Logany, stratified by randomly selected and used supplementary therapy.

The next treatment analysis (STA) is conducted with an average monitoring time of 48 months focusing on the second main question of the study. The main product for the STA is from the transfer group (or the mono therapeutic groups in the same time) + 30 days (STA-S) with the second spell-
The party applies to comparing each pair of groups at 2.5%. In addition, the exploration analysis is conducted from the random arrangement (STA-R) with an average tracking time of 67 months, with the results of each comparison summarized by risk ratios and 99%confidence range.

With an average 48 -month monitoring time, there are no significant differences in any conclusion from the transfer group in the next treatment analysis for single therapy (such as [using tamoxifen for 2 years then used] Femara for 3 years compared to using tamoxifen for 2 years, DFS HR 0.89; CL 97.5% 0.68, 1.15 and (using Femara for 2 years later than] Use Femara for more than 2 years, DFS HR 0.93; CT 97.5% 0.71, 1.22).

With an average 67 -month monitoring time in general, there are no significant differences in any conclusion from random options in the next treatment analysis (for example, using tamoxifen for 2 years and then using Femara for 3 years compared to using Femara for 5 years, DFS HR 1.10 Ci 99% 0.86, 1.41; DFS HR 0.96; CI 99% 0.74, 1.24). There is no evidence that the next combination of Femara and Tamoxifen is better when using only Femara for 5 years.

Safety data with an average 60 -month treatment time

In Big-98 research with an average treatment time of 60 months, the side effects observed that it is suitable for the safety records of the drug. Certain adverse reactions have also been determined for analysis first, based on pharmacological properties and known side effects of two drugs.

The adverse reactions have been analyzed regardless of the drug's relationship. Most adverse reactions are reported (about 75% of patients reported to have 1 or more adverse reactions) are level 1 and level 2 according to CTC standard version 2.0/CTCAE, version 3.0. When considering all levels of research and treatment, the events are observed in Femara with a higher rate than Tamoxifen for hypercesting blood cholesterol (52% compared to 29%), fracture (10.1% compared to 7.1%), myocardial infarction (1% compared to 0.5%), osteoporosis (5.1% compared to 2.7%) and joint pain (25.2% compared to 20.4%).

Compared to Femara observed that the Tamoxifen group has a higher rate of hot overflow (38% compared to 33%), night sweating (17% compared to 15%), vaginal bleeding (13% compared to 5.2%), constipation (2.9% compared to 2.0%), embolized embolism events (3.6% compared to 2.1%), increase in endometrial cancer (2.9% compared to 0.3%) Endometrial mail (1.8% compared to 0.3).

Supplementary treatment for early breast cancer, D2407 research

D2407 Research is a phase III study, knowing the name of the drug, random, multi -centrally designed to compare the effectiveness of complementary treatment of Letrozole with tamoxifen on bone density in bone (BMD), bone index and serum lipid index when fasting.

A total of 262 postmenopausal women with primary breast cancer sensitive to hormones that have been removed from a randomly selected tumor to use Letrozole 2.5 mg/day for 5 years, or tamoxifen 20mg/day for 2 years then use Letrozole 2.5 mg/day for 3 years.

The original purpose is to compare the effect on the lumbar spine BMD (L2 - L4) of Letrozole compared to Tamoxifen, which is evaluated according to the percentage of changes of the lumbar spine at 2 years compared to the original level.

After 24 months, BMD lumbar spine (L2 - L4) has an average decrease of 4.1% in the group using Letrozole compared to the average increase of 0.3% in the group using Tamoxifen (difference = 4.4%). After 2 years, the average difference in general about changing the lumbar spine between Letrozole and Tamoxifen is statistically significant with the advantage of Tamoxifen (P

Current data indicates that no patient has an ordinary BMD at the beginning (the point T is -1,9) becomes osteoporosis after 2 years and only one patient has bone deficiency at the beginning (point T is -1,9) progresses into osteoporosis during treatment (evaluation by central approval).

The results of the entire hip bone BMD are similar to the lumbar spine BMD. However, the differences are less published. After 2 years, a significant difference with the advantage of Tamoxifen was observed in the whole BMD safety group and all groups (p In the group using Tamoxifen, total total cholesterol levels decreased by 16% after 6 months compared to the original level; A similar decrease is also observed at the following visits to 24 months. In the Letrozole group, the average total cholesterol level is relatively stable over time, without significant increase in each visit. The differences between the two groups are statistically significant with the advantage of Tamoxifen at each time (p

Additional treatments

In a double, random, multicolored, placebuilding, placebuilding (CFEM345g MA-17) performed on more than 5,100 patients after menopause with positive breast cancer or patients with unknown breast cancer are those who still maintain non-disease-free condition after the completion of supplementary treatment with Tamoxifen (4.5 years to 6 years) is chosen in the use of Femara.

The main analysis was carried out with an average monitoring time of about 28 months (25% of patients were monitored by up to 38 months) showing that Femara significantly reduced the risk of relapse 42% compared to placebo (risk ratio 0.58; P = 0.00003). The analysis of the body sensitivity
receives the reliability of the data.

The statistically significant benefits of the number of patients who are still not infected (DFS) with the advantage of Letrozole have been recorded, regardless of lymphadenopathy - the risk ratio of 0.48 in patients without lymphadenopathy, P = 0.002, risk ratio of 0.61, P = 0.002 in patients with lymphadenopathy, the inspection committee of data and independent safety, people are not allowed to be transferred to the diseases in the use of the use of the drug in the group. Femara for up to 5 years when the study knew the drug name in 2003.

While updating, the final analysis was conducted in 2008, 1551 women (60% of them were suitable for switching) transferred from placebo to Femara for an average time of 31 months after completing the supplementary Tamoxifen therapy. The average time to use Femara is 40 months after transfer.

The final analysis is conducted with an average of 62 months of monitoring, which has confirmed the significant reduction in the risk of Femara's cancer recurrence compared to the placebo, although 60% of the appropriate patients in the group use the placebo to use Femara after the research has known the drug name.

In the Femara group, the average treatment time is 60 months in the placebo group, the average treatment time is 37 months. The DFS ratio after 4 years is determined according to the specified outline in the group using Femara in both analysis in 2004 and 2008, confirming the stability of data and the strong effect of long -term treatment with Femara. In the placebo group, the increase in the DFS ratio after 4 years in updated analysis clearly reflects the effect of 60% of patients switching to Femara.

This medication also explains the reason why the difference in treatment has decreased significantly.

In primitive analysis, for the end of the end, the number of survival in general (OS) has a total of 113 deaths that have been reported (51 for Femara, 62 for placebo). In general, there is no statistical significance between treatment for the number of vital (OS) (OS) (risk ratio 0.82, P = 0.29).

In patients with lymphadenopathy, Femara significantly reduces the risk of death due to all causes of about 40% (risk ratio 0.61, p = 0.035) while no difference is statistically significant in patients without lymphadenopathy (risk ratio: 1.36, p = 0.385), in patients using previous therapy or in patients who do not use previous therapy. Read more in Table 4, Table 5 and the results in the drug manual.

pharmacokinetic

absorption

Letrozole is absorbed quickly and completely from the digestive tract (absolute average bioavailability: 99.9%).

Food reduces the absorption rate (the time of achieving the highest concentration in plasma (Average TMAX: 1 hour of hunger compared to 2 hours after eating; and the highest concentration in plasma is average 129 ± 20.3 nmol/l at hunger compared to 98.7 ± 18.6 nmol/l after eating), but the absorption level (the area under the concentration curve - AUC) does not change.

secondary effect on absorption speed is not considered clinical significance, so Letrozole can be used without caring for meals.

distribution

Letrozole is associated with plasma proteins about 60%, mainly with albumin (55%). Letrozole concentration in red blood cells is about 80% compared to plasma concentrations.

After using 2.5 mg of Letrozole with 14C radioactive, about 82% of radioactive in plasma is a constant form of compound. Therefore, exposure to the body for metabolites is low. Letrozole is distributed quickly and strongly into the tissues. The apparent distribution volume in a stable state is about 1.87 +0.47 l/kg.

metabolism and elimination

The clearance of metabolism for carbinol metabolites without pharmacological activity is the main elimination sugar of Letrozole (ClM = 2.1 l/hour) but relatively slow when compared to the blood flow through the liver (about 90 l/h). The isenzyme 3A4 and 2A6 Cytochrome P450 are known to convert Letrozole into this transformation. The formation of small metabolites is not recognized and the excretion is directly through the kidney and stool only plays a small role in the entire Letrozole reversing.

Within 2 weeks after using 2.5 mg of Letrozole with radioactive C for healthy postmenopausal women, 88.2 ± 7.6% of radioactive is detected in urine and 3.8 ± 0.9% in fertilizer. At least 75% of radioactive is detected in urine up to 216 hours (84.7 ± 7.8% of the dose) is thought to be caused by glucuronide of carbinol metabolites, about 9% is due to two unplained metabolites and 6% due to the constant Letrozole.

In human microsomes with specific isozyme CYP, CYP3A4 convert Letrozole into carbinol metabolites, CYP2A6 convert Letrozole into both metabolites and derivatives of this substance. At the liver microsome, Letrozole inhibits strong CYP2A6 but the memory
CYP2C19 is only at an average level.

The last elimination of the plasma is about 2 days. After using 2.5 mg/day, the concentration in a stable state is reached within 2-6 weeks. Plasma concentrations in a stable state are about 7 times higher than the measured concentration after taking a single dose of 2.5 mg, while this concentration is 1.5-2 times higher than the values at a stable state predicted from the measured concentrations after using a single dose, showing the low linearly of Letrozole's lighter pharmacokinetics when taking the dose of 2.5 mg/day.

Because the concentrations in a stable state are maintained over time, it may be concluded that there is no continuous Letrozole accumulation.

Age does not affect the pharmacokinetics of Letrozole.

Before taking Femara 2.5mg Novartis supports breast cancer treatment (3 blisters x 10 tablets)

How to use

Oral drugs, can be used when hungry or full.

Dosage

adults, elderly patients

Femara dose is recommended for 2.5mg, 1 time/day. In supplementary and supplementary treatment, continue to use Femara for 5 years or until a tumor recurrence, depending on which event comes first. In patients with metastases, Femara should be further treated until the tumor's progression is clear. No dose adjustment in elderly patients.

Children

Do not use this drug for children.

Patients with liver failure or renal failure

No dose adjustments for patients with liver or renal failure (Creatinine clearance> 10 ml/minute). However, close monitoring of patients with severe liver failure (Child-Pough index type C).

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.

What to do when using overdose?

What to do when you forget a dose? However, if close to the next dose, skip the forgotten dose and take the next dose at the time as planned. Note that it should not be used double the prescribed dose.

Side Effects

In general, Femara is well tolerated through all studies such as a first and second -therapy for breast cancer, a supplementary treatment for early -stage breast cancer and long -term supplementary treatment for women who had previously had standard therapy with Tamoxifen.

About 1/3 patients are treated with Femara in the metastatic group and supplementary treatment, about 75% of patients in the supplementary group (both Femara and Tamoxifen groups, with an average treatment time of 60 months) and about 80% of patients in the prolonged supplementary group (both Femara and placebo groups, with an average treatment time of 60 months) meet adverse reactions.

In general, the adverse reactions are mainly mild or medium, and most are associated with the lack of estrogen.

The most common adverse reactions in clinical studies are hot, joint pain, nausea and fatigue. Many adverse reactions can be considered as common pharmacological consequences due to estrogen deficiency (for example, hot face, hair loss and vaginal bleeding).

The following side effects are listed in Table 1 reported from clinical trials and from after -sales experience with Femara.

Side reactions are classified as frequency, first are the most common, using the following conventions: very common (> 1/10), often encountered (1/100, 1/10,000, Table 1

Infection and parasite infection
rarely

Urinary tract infection

Pain caused by tumors (6)

leukopenia

Anorexia, increased appetite, increased blood cholesterol
Systemic edema

Depression
anxiety (1)

headache, dizziness
drowsy, insomnia, memory loss, then sensory disorder (2), then disorder, stroke, Calmic syndrome

cataracts, eye irritation, blurring

Brushing the chest drum, tachycardia

thrombosis (3), hypertension, chemical heart anemia (7.8).

Respiratory disorders, chest and mediastinum
rarely Difficulty breathing, ho

nausea, vomiting, indigestion, constipation, diarrhea
abdominal pain, stomatitis, dry mouth

Hepatitis energy

Skin disorders and subcutaneous tissue
often encounter
very rare

Hair loss, increased sweating, rash (4).

Musculoskeletal and connective tissue disorders

joint pain
muscle pain, bone pain, osteoporosis, fracture of osteoarthritis
trigger finger (trigger finger)

many times

Reproductive disorders and breast disorders
rarely

vaginal bleeding, vaginal discharge, vaginal dryness, breast pain

Tired
(5), Peripheral edema
Fever, dry mucosa, thirst

weight gain
weight loss

(2) includes abnormalities, reducing sensation.

(3) includes shallow and deep thrombosis.

(4) Including the Red Red Red Rite, Lumpy Ban, Psoriasis and Blister.

(5) includes weakness and discomfort.

(6) In case of metastases/supplementary treatment.

(7) In the case of complementary treatment and arrest for any cause, the following eight reactions have occurred in the group using Femara and the group using Tamoxifen in the corresponding site: thrombotic embolization (2.1% compared to 3.6%), angina (1.1% compared to 1.0%), myocardial infarction (1.0% compared to 0.5%) and Configure (0.8% compared to 0.5%).

(8) In the prolonged supplementary treatment regime, with an average treatment time of 60 months with Letrozole and 37 months with a placebo, the following side effects have been reported corresponding to Femara and placebo (excluding cases of femara switching to Femara): new or severe chest pain (1.4% compared to 1.0%); Chest pain requires surgery (0.8% compared to 0.6%); Myocardial infarction (1.0% compared to 0.7%), thrombotic embolism (0.9% compared to 0.3%); stroke/rays (1.5% compared to 0.8%).

(9) Based on after -sales experience. The microscopy of the patient's album use is unknown, so it is not possible to be sure the frequency of these reactions is not sure, so it is called 'unknown'.

*Notice the doctor with unexpected effects encountered when using the drug.

Warnings

Before using the drug you need to read the instructions carefully and refer to the information below.

Contraindicated

Femara drugs are contraindicated in the following cases:

Hypersensitivity to the active ingredient or any ingredient of excipients.

Caution when using

renal failure: Fermara has not been studied in patients with creatinine clearance

Hepatic failure: In patients with severe liver failure (Child-Pough index of type C), systemic exposure and the final half-life is approximately twice as much as a healthy volunteer. Therefore, these patients must be closely monitored.

Effects on bone: There is a report on osteoporosis or fracture when using Femara. So recommendations to monitor bone firmness during treatment.

Use drugs for women during pregnancy and lactation

Pregnant women

Contraindicated to use Femara during pregnancy.

Cases of only one birth defect (adhesive lips or large lips, unclear genitalia) have been reported in pregnant women using Femara.

Women are likely to be pregnant

Physicians need to discuss about the necessity of adequate contraception for pregnant women who include those who were previously, during and after menopause or new menopause until the postmenopause was completely defined.

breastfeeding women

Contraindicated to use Femara during breastfeeding.

The effect of the drug on driving, operating machinery

because of fatigue and dizziness have been recorded when using Femara and occasionally reporting about drowsiness, should be cautious when driving or using machinery.

Drug interaction

Clinical interactive studies with cimetidine and warfarin show that the use of Femara with these drugs does not cause significant drug interactions.

A review of the data of clinical trials shows that there is no evidence of other clinical interactions related to other prescribed drugs.

So far has no clinical experience in using Femara in combination with other anti -cancer drugs.

Letrozole inhibits in vitro, cytochrome p459.isozyme 2A6 and moderate inhibition for 2C19. CYP 2A6 does not play a major role in drug metabolism. In In vitro tests, Letrozole actually cannot inhibit the metabolism of diazepam (a substrate of CYP2C19) at a concentration of about 100 times higher than the observed concentration in plasma in a stable state. Therefore, it is not sure to occur clinically related interactions with CYP2C19. However, it is necessary to be cautious when using the drugs that tend to depend mainly on these isenzymes and the drug has a narrow treatment index.

Storage

Leave a cool place, avoid light, temperature below 30⁰C.

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