Approved Drug Label (PDF)
4
Contraindications
(Additions and/or revisions are underlined)
- Pregnancy: Letrozole can cause fetal harm
- Known hypersensitivity to the active substance, or to any of the
excipients.
5
Warnings and Precautions
5.1 Bone Effects
(Additions and/or revisions are underlined)
…Results of a safety
study to evaluate safety in the adjuvant setting comparing the effect on
lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with
tamoxifen showed… Updated results from the BMD substudy (MA-17B)
in the extended adjuvant setting demonstrated that at 2 years patients
receiving letrozole had a median decrease from baseline of 3.8% in hip BMD
compared to a median decrease of 2.0% in the placebo group…
In the adjuvant
trial (BIG 1-98) the incidence of bone fractures at any time after
randomization was 14.7% for letrozole and 11.4% for tamoxifen at
a median follow-up of 96 months… In the extended adjuvant trial (MA-17), the incidence of bone
fractures at any time after randomization was 13.3% for letrozole and 7.8% for
placebo at a median follow-up of 62 months…
5.2 Cholesterol
(Additions and/or revisions are underlined)
…In the adjuvant
trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of
letrozole patients and 28.6% of tamoxifen patients… Also in the adjuvant setting, an increase
ofgreater than or equal to 1.5 x upper limit of normal (ULN) in total
cholesterol (generally nonfasting) was observed in patients on monotherapy who
had baseline total serum cholesterol within the normal range (i.e., less than
=1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840
(3.9%) patients on tamoxifen. Lipid lowering medications were required
for 29% of patients on letrozole and 20% on tamoxifen.
5.6 Embryo-Fetal Toxicity
(Newly added subsection)
Based on
post-marketing reports, findings from animal studies and the mechanism of
action, Femara can cause fetal harm and is contraindicated for use in pregnant
women. In post-marketing reports, use of letrozole during pregnancy resulted in
cases of spontaneous abortions and congenital birth defects. Letrozole caused
embryo-fetal toxicities in rats and rabbits at maternal exposures that were
below the maximum recommended human dose (MHRD) on a mg/m2 basis. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during therapy with Femara and for at
least 3 weeks after the last dose.
6
Adverse Reactions
(Additions and/or revisions are underlined)
The following
adverse reactions are discussed in greater detail in other sections of the
labeling.
- Bone effects
- Increases in cholesterol
- Fatigue and Dizziness
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
Adjuvant Treatment of
Early Breast Cancer
In study, BIG
1-98, the median treatment
duration of adjuvant treatment was 60 months and the median duration of
follow-up for safety was 96 months for patients receiving Femara and
tamoxifen.
Certain adverse
reactions were prospectively specified for analysis (see Table 1), based
on the known pharmacologic properties and side effect profiles of the two
drugs.
…Most adverse
reactions reported (approximately 75% of patients who reported AEs) were
Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version
2.0/Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4)
irrespective of relationship to study treatment in the adjuvant trial for the
monotherapy arms analysis (safety population).
Table 1:
Patients with Adverse Reactions (CTC Grades 1-4,) in the Adjuvant Study –
Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment
60 Months) (Table
has been revised; please refer to label)
At a median follow-up of 96 months, a higher incidence of events
was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding
fractures. A higher incidence was seen for tamoxifen compared to Femara
regarding thromboembolic events (4.6% vs 3.2%), and endometrial
hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).
Bone Study: Results of a safety trial in 263 postmenopausal women with
resected receptor positive early breast cancer in the adjuvant setting…
Lipid Study: In a safety trial in 263 postmenopausal women with resected
receptor positive early breast cancer at 24 months comparing the effects on
lipid profiles of adjuvant letrozole to tamoxifen…
In another postapproval
randomized, multicenter, open label, study of letrozole vs anastrozole in the
adjuvant treatment of postmenopausal women with hormone receptor and node
positive breast cancer (FACE, NCT00248170), the median duration of treatment
was 60 months for both treatment arms. Table 2 describes adverse reactions
(Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in
the adjuvant study (safety population).
Table 2:
Adverse Reactions (CTC Grades 1-4), Occurring in at least 5% of Patients in
Either Treatment Arm, by Preferred Term (Safety set) (Table has been added; please refer to
label)
The following
adverse reactions were also identified in less than 5% of the 2049 patients
treated with letrozole and not included in the table: fall, vertigo,
hyperbilirubinemia, jaundice, and chest pain.
Extended Adjuvant
Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
In study MA-17,
the median duration of
extended adjuvant treatment was 24 months and the median duration of follow- up
for safety was 28 months for patients receiving Femara and placebo.
Table 3
describes the adverse reactions occurring at a frequency of at least 5% in any
treatment group during treatment…
Table 3:
Adverse Reactions Occurring in at least 5% of Patients in either Treatment
Arm
Updated Analysis,
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration
of 60 Months
The extended
adjuvant treatment trial (MA-17) was unblinded early…
Lipid substudy: In the extended adjuvant setting (MA-17),
based on a median duration of follow-up of 62 months, there was no significant
difference between Femara and placebo in total cholesterol or in any lipid
fraction over 5 years.
First-Line Treatment
of Advanced Breast Cancer
In study P025 a total of 455 patients were treated for a
median time of exposure of 11 months in the Femara arm (median 6 months in
the tamoxifen arm)…
Adverse reactions
that were reported in at least 5% of the patients treated with Femara 2.5 mg or
tamoxifen 20 mg in the first-line treatment study are shown in Table 4.
Table 4:
Adverse Reactions Occurring in at least 5% of Patients in either Treatment
Arm
Second-Line Treatment
of Advanced Breast Cancer
Study
discontinuations in the megestrol acetate comparison study (AR/BC2) for
adverse reactions other than progression of tumor were 5/188 (2.7%) on Femara
0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol
acetate… In the
aminoglutethimide comparison study (AR/BC3), discontinuations for
reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg Femara, 7/185
(3.8%) on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide.
Adverse reactions
that were reported in at least 5% of the patients treated with Femara 0.5 mg,
Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled
trials AR/BC2 and AR/BC3 are shown in Table 5.
Table 5:
Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in
Either Treatment Arm
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
The following
adverse reactions have been identified during postapproval use of Femara.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Eye Disorders: blurred vision
Hepatobiliary
Disorders: increased
hepatic enzymes, hepatitis
Immune System
Disorders: anaphylactic
reactions, hypersensitivity reactions
Nervous System
Disorders: carpal tunnel
syndrome, trigger finger
Pregnancy: spontaneous abortions, congenital birth
defects
Skin and
subcutaneous disorders:
angioedema, toxic epidermal necrolysis, erythema multiforme
7
Drug Interactions
(Additions and/or revisions are underlined)
Tamoxifen
Coadministration of
Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma
levels of 38% on average (study P015). Clinical experience in the
second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the
therapeutic effect of Femara therapy is not impaired if Femara is administered
immediately after tamoxifen.
Cimetidine
A pharmacokinetic
interaction study with cimetidine (study P004) showed no clinically
significant effect on letrozole pharmacokinetics.
Warfarin
An interaction
study (P017) with warfarin showed no clinically significant effect of
letrozole on warfarin pharmacokinetics.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
Based on
post-marketing reports, findings from animal studies and the mechanism of
action, Femara can cause fetal harm and is contraindicated for use in pregnant
women. In post-marketing reports, use of letrozole during pregnancy resulted in
cases of spontaneous abortions and congenital birth defects; however, the data
are insufficient to inform a drug-associated risk.
In animal
reproduction studies, administration of letrozole to pregnant animals during
organogenesis resulted in increased
post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal
malformation affecting the renal and skeletal systems in rats and rabbits at
doses approximately 0.1 times the daily maximum recommended human dose (MRHD)
on a mg/m2 basis.
The background
risk of major birth defects and miscarriage for the indicated population is
unknown. However, the background risk in the U.S. general population of major
birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized
pregnancies.
Data
Animal Data
In a fertility
and early embryonic development toxicity study in female rats, oral administration of letrozole
starting 2 weeks before mating until pregnancy day 6 resulted in an increase in
pre-implantation loss at doses greater than or equal to 0.003 mg/kg/day
(approximately 0.01 times the maximum recommended human dose on a mg/m2 basis).
In an
embryo-fetal developmental toxicity study in rats, daily administration of oral
letrozole during the period of organogenesis at doses greater than or equal to
0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m2 basis) resulted in
embryo-fetal toxicity including intrauterine mortality, increased
resorptions and postimplantation loss, decreased numbers of live fetuses and
fetal anomalies including absence and shortening of renal papilla, dilation of
ureter, edema and incomplete ossification of frontal skull and metatarsals.
Letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately
0.01 times the maximum recommended human dose on a mg/m2 basis) and
caused fetal domed head and cervical/centrum vertebral fusion.
In the
embryo-fetal development toxicity study in rabbits, daily administration
of oral letrozole during the period of organogenesis at doses greater than or
equal to 0.002 mg/kg (approximately 0.01 times the maximum recommended human
dose on a mg/m2 basis) resulted in embryo-fetal toxicity including
intrauterine mortality, increased resorption, increased postimplantation loss
and decreased numbers of live fetuses. Fetal anomalies included incomplete
ossification of the skull, sternebrae, and fore- and hind legs.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
It is not known if
letrozole is present in human milk. There are no data on the effects
of letrozole on the breastfed infant or milk production. Exposure of lactating
rats to letrozole was associated with impaired reproductive performance of the
male offspring. Because of the potential for serious adverse reactions in breastfed
infants from Femara, advise lactating women not to breastfeed while taking Femara
and for at least 3 weeks after the last dose.
Data
Animal Data
In a postnatal
developmental toxicity study in lactating rats, letrozole was administered
orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day 0 through day 20 of
lactation. The reproductive performance of the male offspring was impaired at
letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum
recommended human dose on a mg/m2 basis), as reflected by decreased mating and
pregnancy ratios. There were no effects on the reproductive performance of female
offspring.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Pregnancy
Testing
Based on animal
studies, Femara can cause fetal harm when administered to a pregnant woman.
Females of reproductive potential should have a pregnancy test prior to
starting treatment with Femara.
Contraception
Females
Based on animal
studies, Femara can cause fetal harm when administered to a pregnant woman.
Advise females of reproductive potential to use effective contraception during
treatment with Femara and for at least 3 weeks after the last dose.
Infertility
Females
Based on studies
in female animals, Femara may impair fertility in females of reproductive
potential.
Males
Based on studies in
male animals, Femara may impair fertility in males of reproductive potential.
8.4 Pediatric Use
(Additions and/or revisions are underlined)
The safety and
effectiveness in pediatric patients have not been established.
Letrozole administration
to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3
mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone
maturation, bone mineral density) and neuroendocrine and reproductive
developmental perturbations of the hypothalamic-pituitary axis. Administration
of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult
patients receiving the recommended dose of 2.5 mg/day…
8.5 Geriatric Use
(Additions and/or revisions are underlined)
For the extended
adjuvant setting (MA-17), more than 5,100 postmenopausal women were
enrolled in the clinical study…
In the adjuvant
setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled
in the clinical study…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or
revisions are underlined)
Embryo-Fetal Toxicity
Advise females
of reproductive potential of the potential risk to a fetus and to use effective
contraception during Femara therapy and for at least 3 weeks after the last
dose. Advise females to contact their healthcare provider if they become
pregnant, or if pregnancy is suspected, during treatment with Femara.
Lactation
Advise women not to breastfeed during
Femara treatment and for at least 3 weeks
after the last dose.
Infertility
Advise females and males of reproductive potential of the potential
for reduced fertility from FEMARA.
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