Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The frequencies of adverse reactions for Femara are mainly based on data collected from clinical trials.
Up to approximately one third of the patients treated with Femara 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, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.

Important additional adverse reactions that may occur with Femara are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events).
The frequency category for these adverse reactions is described in Table 1.

Tabulated list of adverse reactions
The frequencies of adverse reactions for Femara 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 Femara:

Table 1
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Infections and infestations
Uncommon:          Urinary tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon:          Tumour pain1
Blood and lymphatic system disorders
Uncommon:          Leukopenia
Immune system disorders
Not known:         Anaphylactic reaction
Metabolism and nutrition disorders
Very common:       Hypercholesterolaemia
Common:            Decreased appetite, increased appetite
Psychiatric disorders

FEM API OCT20 V1                                                           REF UK SMPC APR 2020 Common:            Depression
Uncommon:          Anxiety (including nervousness), irritability
Nervous system disorders
Common:            Headache, dizziness
Uncommon:          Somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia, hypoaesthesia), dysgeusia, cerebrovascular accident, carpal tunnel syndrome
Eye disorders
Uncommon           Cataract, eye irritation, blurred vision
Cardiac disorders
Common:            Palpitations1
Uncommon:          Tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia)
Vascular disorders
Very common:       Hot flushes
Common:            Hypertension
Uncommon:          Thrombophlebitis (including superficial and deep vein thrombophlebitis)
Rare:              Pulmonary embolism, arterial thrombosis, cerebral infarction Respiratory, thoracic and mediastinal disorders
Uncommon:          Dyspnoea, cough
Gastrointestinal disorders
Common:            Nausea, dyspepsia1, constipation, abdominal pain, diarrhoea, vomiting
Uncommon:          Dry mouth, stomatitis1
Hepatobiliary disorders
Uncommon:          Increased hepatic enzymes, hyperbilirubinemia, jaundice Not known:         Hepatitis
Skin and subcutaneous tissue disorders
Very common:       Hyperhidrosis
Common:            Alopecia, rash (including erythematous, maculopapular, psoriaform, and vesicular rash), dry skin
Uncommon:          Pruritus, urticaria
Not known:         Angioedema, toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders
Very common:       Arthralgia
Common:            Myalgia, bone pain1, osteoporosis, bone fractures, arthritis Uncommon:          Tendonitis
Rare:              Tendon rupture
Not known:         Trigger finger
Renal and urinary disorders
Uncommon:          Pollakiuria
Reproductive system and breast disorders
Common:            Vaginal haemorrhage
Uncommon:          Vaginal discharge, vulvovaginal dryness, breast pain General disorders and administration site conditions
Very common:       Fatigue (including asthenia, malaise)
Common:            Peripheral oedema, chest pain
Uncommon:          General oedema, mucosal dryness, thirst, pyrexia
Investigations
Common:            Weight increased
Uncommon:          Weight decreased

FEM API OCT20 V1                                                       REF UK SMPC APR 2020 1
Adverse drug reactions reported only in the metastatic setting
Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following tables provide information on significant differences in Femara versus tamoxifen monotherapy and in the Femara-tamoxifen sequential treatment therapy: 
Table 2        Adjuvant Femara monotherapy versus tamoxifen monotherapy – adverse events with significant differences

Femara, incidence rate              Tamoxifen, incidence rate
N=2448                                N=2447
During      Any time after           During      Any time after treatment     randomization          treatment     randomization
(Median 5y)     (Median 8y)          (Median 5y)     (Median 8y)
Bone fracture                              10.2%          14.7%                 7.2%           11.4% Osteoporosis                                5.1%           5.1%                 2.7%            2.7% Thromboembolic events                       2.1%           3.2%                 3.6%            4.6% Myocardial infarction                       1.0%           1.7%                 0.5%            1.1% Endometrial hyperplasia /                   0.2%           0.4%                 2.3%            2.9% endometrial cancer
Note: “During treatment” includes 30 days after last dose. “Any time” includes follow-up period after completion or discontinuation of study treatment.
Differences were based on risk ratios and 95% confidence intervals.

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

Femara monotherapy          Femara->tamoxifen         Tamoxifen->Femara N=1535                      N=1527                    N=1541
5 years                  2 yrs-> 3 yrs             2 yrs-> 3 yrs
Bone fractures                  10.0%                       7.7%*                     9.7% Endometrial                      0.7%                      3.4%**                    1.7%** proliferative disorders
Hypercholesterolaemia               52.5%                    44.2%*                   40.8%* Hot flushes                         37.6%                   41.7%**                   43.9%** Vaginal bleeding                     6.3%                    9.6%**                   12.7%** * Significantly less than with Femara monotherapy
** Significantly more than with Femara monotherapy
Note : Reporting period is during treatment or within 30 days of stopping treatment 
Description of selected adverse reactions
Cardiac adverse reactions
In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were reported for Femara 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 Femara (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.

FEM API OCT20 V1                                                             REF UK SMPC APR 2020 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 Femara 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 Femara, compared with 3 years for placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/