Letrozole Mylan 2.5 mg film-coated tablets

4.8     Undesirable effects

 

Tabulated listing 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:

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥10%, common ≥1% to <10%, uncommon ≥0.1% to <1%, rare ≥0.01% to <0.1%, very rare <0.01%, not known (cannot be estimated from the available data).

 

¹ Adverse drug reactions reported only in the metastatic setting

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

Table 8       Disease-free and overall survival (Modified ITT population)

Median follow-up 28 months1

Median follow-up 62 months1

10.     DATE OF REVISION OF THE TEXT

 

AugustSeptember 2017

Section 2,
added subtitle "Excipient with known effect"
"lactose (as lactose monohydate)" changed to "lactose monohydrate"

Section 4.2, the following text added to Method of administration:
The 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 (see section 5.2).

Section 4.3, lactose warning changed to:
As the tablets contain lactose, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Section 4.8. the following side effects are added:
Nervous system disorders
Uncommon - carpal tunnel syndrome

Musculoskeletal and connective tissue disorders
Not known - Trigger finger

Table 2, "Adjuvant lLetrozole  monotherapy versus tamoxifen monotherapy – adverse events with significant differences" updated

Table 3, "Sequential treatment versus lLetrozole monotherapy – adverse events with significant differences" updated

How to report side effects section added.

Section 5.1:
Table 5, "Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up of 96 months (ITT population)" updated.

Table 6, "Sequential treatments analysis of disease-free survival with letrozole as initial endocrine agent (STA switch population)" updated.

Table 7, "Sequential Treatments Analyses from randomisation (STA-R) of disease-free survival (ITT STA-R population)" updated

Section 5.2, the following section added:
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).

the following text added to "Special population"
In addition to the above 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 (Cmin). Futhermore, 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).

Section 5.3, the following text added:
Oral administration of letrozole to female rats resulted in decreases in mating and pregnancy ratios and increases in pre-implantation loss.

In a 104-week mouse carcinogenicity study, no treatment-related tumors were noted in male mice. In female mice, a generally dose-related increase in the incidence of benign ovarian granulosa theca cell tumours was observed at all doses of letrozole tested. These tumours were considered to be related to the pharmacological inhibition of oestrogen synthesis and may be due to increased LH resulting from the decrease in circulating oestrogen.

Section 10. Date changed to May 2015


(internal ref: IT/H/0177/IB/012   PR 478687)

4.1 Therapeutic indications
 Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.
 Extended adjuvant treatment of hormone-dependent 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-oestrogens.
 Neo-adjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery not indicated.

4.2 Posology and method of administration

Posology

Adult and elderly patients
The recommended dose of Letrozole Mylan is 2.5 mg once daily. No dose adjustment is required for elderly patients.

In patients with advanced or metastatic breast cancer, treatment with Letrozole Mylan should continue until tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with Letrozole Mylan should continue for 5 years or until tumour relapse occurs, whichever is first. In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3 years) could also be considered (see sections 4.4 and 5.1).

In the neoadjuvant setting, treatment with Letrozole could be continued for 4 to 8 months in order to establish optimal tumour reduction. If the response is not adequate, treatment with Letrozole should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Paediatric population
Letrozole is not recommended for use in children and adolescents. The safety and efficacy of Letrozole 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.
Children

Patients with hepatic and/or Renal impairment
No dosage adjustment of Letrozole Mylan is required for patients with renal insufficiency with creatinine clearance ≥10 ml/min.

Hepatic impairment
No dose adjustment of Letrozole Mylan is required for patients with mild to moderate hepatic insufficiency (Child-Pugh A or B). Insufficient data are available for patients with severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision (see sections 4.4 and 5.2).

Method of administration
Letrozole should be taken orally and can be taken with or without food.

4.3 Contraindications

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
 Premenopausal endocrine status;
 Pregnancy (see section 4.6);
 Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Meopausal status
In patients whose postmenopausal status is unclear, luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with letrozole.

Only women of postmenopausal endocrine status should receive 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 (see section 5.2).

Bone Effects
Letrozole is a potent oestrogen-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 (see sections 4.2, 4.8 and 5.1).

Other warnings
Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

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 oestrogens or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-oestrogens or oestrogen-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-oestrogens or oestrogens should be avoided.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unkown. 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).

4.6 Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential
Letrozole should only be used in women with a clearly established postmenopausal status (see section 4.4). 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. Studies in animals have shown reproductive toxicity (see section 5.3).

Letrozole is contraindicated during pregnancy (see section 4.3 and 5.3).

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 (see section 4.3).

Fertility
The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.

4.7 Effects on ability to drive and use machines

Letrozole has minor influence on the ability to drive and use machines

4.8 Undesirable effects

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 setting 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 listing 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:

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥10%, common ≥1% to <10%, uncommon ≥0.1% to <1%, rare ≥0.01% to <0.1%, very rare <0.01%, not known (cannot be estimated from the available data).

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:

Table 2     Adjuvant Letrozole  monotherapy versus tamoxifen monotherapy – adverse events with significant differences

Table 3     Sequential treatment versus Letrozole monotherapy – adverse events with significant differences 

 

Description of selected adverse reactions

Cardiac adverse reactions
In the adjuvant setting, in addition to the date presented in Table 2, the following adverse events were reported for letrozole and tamoxifen, respectively (at median treatment duration of 60 months plus 30 days): angina requiring surgery (1.0% vs. 1.0%); cardiac failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident/transient ischaemic attack (2.1% vs. 1.9%).

In the extended adjuvant setting for letrozole (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), respectively: angina requiring surgery (0.8% vs. 0.6%); new or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient ischaemic attack* (1.5% vs. 0.8%) were reported.

Events marked * were statistically significantly different in the two treatment arms.

Skeletal adverse reactions
For skeletal safety data from the adjuvant setting, please refer to Table 2.

In the extended adjuvant setting, significantly more patients treated with letrozole experienced bone fractures or osteoporosis (bone fractures, 10.4% and osteoporosis, 12.2%) than patients in the placebo arm (5.8% and 6.4%, respectively). Median duration of treatment was 5 years for letrozole, compared with 3 years for placebo.

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor. ATC code: L02B G04

Adjuvant treatment

Study BIG 1-98
BIG 1-98 was a multicentre, double-blind study in which over 8,000 postmenopausal women with hormone receptor-positive early breast cancer were randomised to one of the following treatments:
A. tamoxifen for 5 years; B. letrozole for 5 years; C. tamoxifen for 2 years followed by letrozole for 3 years; D. letrozole for 2 years followed by tamoxifen for 3 years.

The primary endpoint was disease-free survival (DFS); secondary efficacy endpoints were time to distant metastasis (TDM), distant disease-free survival (DDFS), overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer and time to breast cancer recurrence.

Efficacy results at a median follow-up of 26 and 60 months
Data in Table 4 reflect the results of the Primary Core Analysis (PCA) based on data from the monotherapy arms (A and B) and from the two switching arms (C and D) at a median treatment duration of 24 months and a median follow-up of 26 months and at a median treatment duration of 32 months and a median follow-up of 60 months.

The 5-year DFS rates were 84% for letrozole and 81.4% for tamoxifen.

Table 4     Primary Core Analysis: Disease-free and overall survival,at a median follow-up of 26 months and at median follow-up of 60 months (ITT population)  

	Primary Core Analysis
	Median follow-up 26 months			Median follow-up 60 months
	Letrozole N=4003	Tamoxifen N=4007	HR1 (95% CI) P	Letrozole N=4003	Tamoxifen N=4007	HR1 (95% CI) P
Disease- free survival (primary) – events (protocol definition2)	351	428	81 (0.70, 0.93) 0.003	585	664	0.86 (0.77, 0.96) 0.008
Overall survival (secondary) Number of deaths	166	192	0.86 (0.70, 1.06)	330	374	0.87 (0.75, 1.01)
HR = Hazard ratio; CI = Confidence interval 1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no) 2 DFS events: loco- regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event

 

Results at a median follow-up of 73 months (monotherapy arms only)

The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of letrozole  monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 5.

Table 5     Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up of 73 months (ITT population)

 

	Letrozole	Tamoxifen N=2459	Hazard Ratio1 (95% CI)	P Value
Disease- free survival (primary)2	509	565	0.88 (0.78, 0.99)	0.03
Time to distant metastasis (secondary)	257	298	0.85 90.72, 1.00)	0.045
Overall survival (secondary)- deaths	303	343	0.87 (0.75, 1.02)	0.08
Censored analysis of DFS3	509	543	0.85 (0.75, 0.96)
Censored analysis of OS3	303	338	0.82 (0.70, 0.96)
1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no) 2 DFS events: loco- regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event 3  Observations in the tamoxifen arm censored at the date of selectively switching to letrozole

 

Sequential Treatments Analysis (STA)

The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 1-98, namely whether sequencing of tamoxifen and letrozole would be superior to monotherapy. There were no significant differences in DFS, OS, SDFS, or DDFS from switch with respect to monotherapy (Table 6).

Table 6     Sequential treatments analysis of disease-free survival with letrozole as initial endocrine agent (STA switch population)

 

 

There were no significant differences in DFS, OS, SDFS or DDFS in any of the STA from randomisation pairwise comparisons (Table 7).

Table 7     Sequential Treatments Analyses from randomisation (STA-R) of disease-free survival (ITT STA-R population) 

	Letrozole → Tamoxifen	Letrozole
Number of patients	1540	1546
Number of patients with DFS events (protocol definition)	236	248
Hazard ratio1 (99% CI)	0.96 (0.76, 1.21)
	Letrozole → Tamoxifen	Tamoxifen2
Number of patients	1540	1548
Number of patients with DFS events (protocol definition)	236	269
Hazard ratio1 (99% CI)	0.87 (0.69, 1.09)
1              Adjusted by chemotherapy use (yes/no) 2              624 (40%) patients selectively crossed to letrozole after tamoxifen arm unblinded in 2005

Study D2407
Study D2407 is an open-label, randomised, multicentre post approval safety study designed to compare the effects of adjuvant treatment with letrozole and tamoxifen on bone mineral density (BMD) and serum lipid profiles. A total of 262 patients were assigned either letrozole for 5 years or tamoxifen for 2 years followed by letrozole for 3 years.

At 24 months there was a statistically significant difference in the primary end-point; the lumbar spine BMD (L2-L4) showed a median decrease of 4.1% for letrozole compared to a median increase of 0.3% for tamoxifen.

No patient with a normal BMD at baseline became osteoporotic during 2 years of treatment and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).

The results for total hip BMD were similar to those for lumbar spine but less pronounced.
There was no significant difference between treatments in the rate of fractures – 15% in the letrozole arm, 17% in the tamoxifen arm.

Median total cholesterol levels in the tamoxifen arm were decreased by 16% after 6 months compared to baseline and this decrease was maintained at subsequent visits up to 24 months. In the letrozole arm, total cholesterol levels were relatively stable over time, giving a statistically significant difference in favor of tamoxifen at each time point.

Extended adjuvant treatment (MA-17)
In a multicentre, double-blind, randomised, placebo-controlled study (MA-17), over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who had completed adjuvant treatment with tamoxifen (4.5 to 6 years) were randomised to either letrozole or placebo for 5 years.

The primary endpoint was disease-free survival, defined as the interval between randomisation and the earliest occurrence of loco-regional recurrence, distant metastasis, or contralateral breast cancer.

The first planned interim analysis at a median follow-up of around 28 months (25% of patients being followed up for at least 38 months), showed that letrozole significantly reduced the risk of breast cancer recurrence by 42% compared with placebo (HR 0.58; 95% CI 0.45, 0.76; P=0.00003). The benefit in favour of letrozole was observed regardless of nodal status. There was no significant difference in overall survival: (letrozole 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

Consequently, after the the first interim analysis the study was unblinded and continued in an open-label fashion and patients in the placebo arm were allowed to switch to letrozole for up to 5 years. Over 60% of eligible patients (disease-free at unblinding) opted to switch to letrozole. The final analysis included 1,551 women who switched from placebo to letrozole at a median of 31 months (range 12 to 106 months) after completion of tamoxifen adjuvant therapy. Median duration for letrozole after switch was 40 months.

The final analysis conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with letrozole.

Table 8     Disease-free and overall survival (Modified ITT population)

 

 

In the MA-17 bone substudy in which concomitant calcium and vitamin D were given, greater decreases in BMD compared to baseline occurred with letrozole compared with placebo. The only statistically significant difference occurred at 2 years and was in total hip BMD (letrozole median decrease of 3.8% vs placebo median decrease of 2.0%).

In the MA-17 lipid substudy there were no significant differences between letrozole and placebo in total cholesterol or in any lipid fraction.

In the updated quality of life substudy there were no significant differences between treatments in physical component summary score or mental component summary score, or in any domain score in the SF-36 scale. In the MENQOL scale, significantly more women in the letrozole arm than in the placebo arm were most bothered (generally in the first year of treatment) by those symptoms deriving from oestrogen deprivation – hot flushes and vaginal dryness. The symptom that bothered most patients in both treatment arms was aching muscles, with a statistically significant difference in favour of placebo.

Neoadjuvant treatment
A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 2.5 mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2-T4c, N0-2, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. Based on clinical assessment there were 55% objective responses in the letrozole arm versus 36% for the tamoxifen arm (P<0.001). This finding was consistently confirmed by ultrasound (letrozole 35% vs tamoxifen 25%, P=0.04) and mammography (letrozole 34% vs tamoxifen 16%, P<0.001). In total 45% of patients in the letrozole group versus 35% of patients in the tamoxifen group (P=0.02) underwent breast-conserving therapy). During the 4-month pre-operative treatment period, 12% of patients treated with letrozole and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

First-line treatment
One controlled double-blind trial was conducted comparing letrozole 2.5 mg to tamoxifen 20 mg as first-line therapy in postmenopausal women with advanced breast cancer. In 907 women, letrozole was superior to tamoxifen in time to progression (primary endpoint) and in overall objective response, time to treatment failure and clinical benefit.

The results are summarised in Table 9:

Table 9     Results at a median follow-up of 32 months

variable	Statistic	Letrozole N=453	Tamoxifen N=454
Time to progression	Median (95% CI for median) Hazard ratio (HR) (95% CI for HR) P	9.4 months (8.9, 11.6 months)	6.0 months (5.4, 6.3 months) 0.72 (0.62, 0.83) < 0.0001
Objective response rate (ORR)	CR + PR   (95% CI for rate) Odds ratio (95% CI for odds ratio) P	145 (32%)   (28,36%)	95 (21%)   (17,25%) 1.78 (1.32, 2.40) 0.0002

Time to progression was significantly longer, and response rate significantly higher for letrozole irrespective of whether adjuvant anti-oestrogen therapy had been given or not. Time to progression was significantly longer for letrozole irrespective of dominant site of disease. Median time to progression was 12.1 months for letrozole and 6.4 months for tamoxifen in patients with soft tissue disease only and median 8.3 months for letrozole and 4.6 months for tamoxifen in patients with visceral metastases.

Male breast cancer
Use of letrozole in men with breast cancer has not been studied.

Special populations

Eldery
Age had no effect on the pharmacokinetics of letrozole.

5.3 Preclinical safety data

Letrozole was embryotoxic and foetotoxic in pregnant rats and rabbits following oral administration at clinically relevant doses. In rats that had live foetuses, there was an increase in the incidence of foetal malformations including domed head and cervical/centrum vertebral fusion. An increased incidence of foetal malformations was not seen in the rabbit. It is not known whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct drug effect (see sections 4.3 and 4.6).

(REF: IT/H/0177/IB/008- Art.30)

Shelf Life increased to 3 years

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