FEMARA

Israel - English - Ministry of Health

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Active ingredient:
LETROZOLE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
L02BG04
Pharmaceutical form:
FILM COATED TABLETS
Composition:
LETROZOLE 2.5 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic group:
LETROZOLE
Therapeutic area:
LETROZOLE
Therapeutic indications:
Femara (letrozole tablets) is indicated for first-line treatment in postmenopausal women with hormone receptor positive or in whome hormone receptor status cannot be determined locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Extended adjuvant treatment of early breast cancer in post menopausal women who have received prior standard adjuvant tamoxifen therapy. Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Authorization number:
109 86 29281 00
Authorization date:
2013-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

23-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

09-11-2020

ﺔﻴﺻﻮﺗ ﺐﺴﺣ ﺝﻼﻌﻟﺍ ﻰﻠﻋ ﺔﺒﻇﺍﻮﻤﻟﺍ ﺐﺠﻳ .ﺐﻴﺒﻄﻟﺍ ﺍﺭﺎﻤﻴﻓ ﻝﻭﺎﻨﺗ ﻦﻋ ﺖﻔﻗﻮﺗ ﺍﺫﺇ ﻥﻭﺪﺑ ﺀﺍﻭﺪﻟﺎﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺯﻮﺠﻳ ﻻ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﺓﺮﺘﻓ" ﻩﻼــﻋﺃ ﺓﺮﻘﻔﻟﺍ ﻲﻓ

ﺎﻀﻳﺃ ﻱﺮﻈﻧﺃ "ﺝﻼﻌﻟﺍ ﺺﻴﺨﺸﺗ ﺐﺠﻳ !ﺔﻤﺘﻌﻟﺍ ﻲﻓ ﺔﻳﻭﺩﺃ ﻲﻟﻭﺎﻨﺘﺗ ﻻ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻦﻣ ﺪﻛﺄﺘﻟﺍﻭ ﺀﺍﻭﺪﻟﺍ ﻊﺑﺎﻃ ﻲﻌﺿ .ﺀﺍﻭﺩ ﺎﻬﻴﻓ ﻦﻴﻟﻭﺎﻨﺘﺗ ﺓﺮﻣ ﻞﻛ ﻲﻓ .ﻚﻟﺫ ﺮﻣﻷﺍ ﻡﺰﻟ ﺍﺫﺇ ﺔﻴﺒﻄﻟﺍ ﺕﺍﺭﺎﻈﻨﻟﺍ ﻝﻮﺣ ﺔﻴﻓﺎﺿﺇ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﻱﺮﻴﺸﺘﺳﺇ ،ﺀﺍﻭﺪــﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ .ﻲﻟﺪﻴﺼﻟﺍ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ (4 ﺐﺒﺴﻳ ﺪﻗ ﺍﺭﺎﻤﻴﻓ ﻝﺎﻤﻌﺘﺳﺇ ﻥﺇ ،ﺀﺍﻭﺩ ﻞﻜﺑ ﺎﻤﻛ .ﺕﻼﻤﻌﺘﺴﻤﻟﺍ ﺾﻌﺑ ﺪﻨﻋ ﺔﻴﺒﻧﺎﺟ

ﺎﺿﺍﺮﻋﺃ .ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻤﺋﺎﻗ ﻦﻣ ﻲﺸﻫﺪﻨﺗ ﻻ ﺽﺍﺮﻋﻷﺍ ﺐﻠﻏﺃ .ﺎﻬﻨﻣ

ﺎﻳﺃ ﻲﻧﺎﻌﺗ ﻻﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ،ﺔﻄﺳﻮﺘﻣ ﻰﺘﺣ ﺔﻔﻴﻔﺧ ﻥﻮﻜﺗ ﺔﻴﺒﻧﺎﺠﻟﺍ ﻊﻴﺑﺎﺳﺃ ﺓﺪﻋ ﻰﺘﺣ ﻡﺎﻳﺃ ﺓﺪﻋ ﺪﻌﺑ ﺓﺩﺎﻋ ﻲﻔﺘﺨﺗﻭ ﻞﺜﻣ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻦﻣ ﻢﺴﻗ .ﺝﻼﻌﻟﺍ ﻦﻣ ﻲﻠﺒﻬﻣ ﻑﺰﻧ ﻭﺃ ﺮﻌﺸﻟﺍ ﻂﻗﺎﺴﺗ ،ﺮﺤﻟﺍ ﻦﻣ ﺕﺎﺒﻫ ﺕﺎﻨﻴﺟﻭﺮﺘﺳﻹﺍ ﺺﻘﻧ ﺔﺠﻴﺘﻧ ﺙﺪﺤﺗ ﻥﺃ ﻦﻜﻤﻳ .ﻚﻤﺴﺟ ﻲﻓ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ ﻲﺘﻟﺍ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮــﻋﺃ :ﺓﺮﻴﻄﺧ ﻦﻴﻧﺎﻌﺗ ﺖﻨﻛ ﺍﺫﺇ

ﻻﺎﺣ ﺐﻴﺒﻄﻟﺍ ﺔﻌﺟﺍﺮﻣ ﺐﺠﻳ :ﺔﻴﻟﺎﺘﻟﺍ ﺕﻻﺎﺤﻟﺍ ﻯﺪﺣﺇ ﻦﻣ ﺽﺍﺮﻋﺃ) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮـــﻋﺃ ﻦﻴﺑ ﻦﻣ ﻦﻴﻠﻤﻌﺘﺴﻣ 1-10 ﻯﺪﻟ ﺮﻬﻈﺗ

:(1,000

ﻲﻓ ﺀﺰﺟ ﻱﺃ ﻲﻓ ﺭﺪﺧ ﻭﺃ ﻞﻠﺷ ،ﻡﺎﻋ ﻒﻌﺿ ∙ ،(ﻡﺪﻘﻟﺍ ﻲﻓ ﻭﺃ ﻉﺍﺭﺬﻟﺍ ﻲﻓ ﺔﺻﺎﺧ) ﻢﺴﺠﻟﺍ ﻖﻄﻨﻟﺍ ﻲﻓ ﺔﺑﻮﻌﺻ ﻭﺃ ،ﻥﺎﻴﺜﻏ ،ﻖﻴﺴﻨﺘﻟﺍ ﻥﺍﺪﻘﻓ ﺔﺘﻜﺳ ،ﻲﻏﺎﻣﺩ ﺏﺍﺮﻄﺿﻹ ﺔﻣﻼﻋ) ﺲﻔﻨﺘﻟﺍ ﻭﺃ

ﻼﺜﻣ ﻂﻏﺎﺿ ﻊﺑﺎﻃ ﻭﺫ ﺭﺪﺼﻟﺍ ﻲﻓ ﺊﺟﺎﻔﻣ ﻢﻟﺃ ∙ .(ﺐﻠﻘﻟﺍ ﻲﻓ ﺏﺍﺮﻄﺿﻹ ﺔﻣﻼﻋ) ﻱﺬﻟﺍ ﺪﻳﺭﻭ ﻝﻮﻃ ﻰﻠﻋ ﺪﺘﻤﻳ ﺭﺍﺮﻤﺣﺇﻭ ﺥﺎﻔﺘﻧﺇ

ﺎﻀﻳﺃ ﻥﻮﻜﻳ ﻥﺃ ﻦﻜﻤﻳﻭ

ﺍﺪﺟ

ﺎﺳﺎﺴﺣ ﻥﻮﻜﻳ .ﺲﻤﻠﻟﺍ ﺪﻨﻋ

ﺎﻤﻟﺆﻣ ﺕﺎﺣﺮﻘﺗ ﻭﺃ ﺓﺮﻳﺮﻌﺸﻗ ،

ﺍﺪﺟ ﺔﻴﻟﺎﻋ ﺔﻧﻮﺨﺳ

ﺎﻳﻼﺧ ﻲﻓ ﺺﻘﻧ) ﺕﺎﺛﻮﻠﺘﻟ ﺔﺠﻴﺘﻧ ﻢﻔﻟﺍ ﻲﻓ

ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ .ﺔﻳﺅﺮﻟﺍ ﻲﻓ ﻞﺻﺍﻮﺘﻣ ﺮﻴﻄﺧ ﺵﻮﺸﺗ ∙ ﺔﺠﺴﻧﺃ) ﺭﺎﺗﻭﻷﺍ ﻲﻓ ﻭﺃ ﺮﺗﻮﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﺇ ∙ .(ﻡﺎﻈﻌﻟﺎﺑ ﺕﻼﻀﻌﻟﺍ ﻂﺑﺮﺗ ﺔﻣﺎﺿ ﻯﺪﻟ ﺮﻬﻈﺗ ﺽﺍﺮﻋﺃ) ﺓﺭﺩﺎﻧ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ :(10,000 ﻦﻴﺑ ﻦﻣ ﻦﻴﻠﻤﻌﺘﺴﻣ 1-10 ،ﺭﺪﺼﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ∙ ،ﻕﺭﺯﻸﻟ ﻞﺋﺎﻣ ﺪﻠﺟ ،ﻊﻳﺮﺳ ﺐﻠﻗ ﻢﻈﻧ ،ﺀﺎﻤﻏﺇ ﻲﻓ ﻭﺃ ﻡﺪﻘﻟﺍ ﻲﻓ ،ﻉﺍﺭﺬﻟﺍ ﻲﻓ ﺊﺟﺎﻔﻣ ﻢﻟﺃ ﻭﺃ ﻞﻜﺸﺗ ﺔﻴﻟﺎﻤﺘﺣﻹ ﺕﺎﻣﻼﻋ) ﻡﺪﻘﻟﺍ ﺔﺣﺍﺭ .(ﺔﻳﻮﻣﺩ ﺓﺮﺜﺧ ﻂﺑﺮﺗ ﺔﻣﺎﺿ ﺔﺠﺴﻧﺃ) ﺮﺗﻮﻟﺍ ﻲﻓ ﻕﺰﻤﺗ ∙ .(ﻡﺎﻈﻌﻟﺎﺑ ﺕﻼﻀﻌﻟﺍ ﺖﻨﻛ ﻝﺎﺣ ﻲﻓ

ﻻﺎﺣ ﺐﻴﺒﻄﻟﺍ ﻍﻼﺑﺇ ﺐﺠﻳ ﻚﻟﺬﻛ ﺓﺮﺘﻓ ﻝﻼﺧ ﺔﻴﻟﺎﺘﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻦﻣ ﻦﻴﻧﺎﻌﺗ :ﺍﺭﺎﻤﻴﻓ ـﺑ ﺝﻼﻌﻟﺍ ﺓﺮﺠﻨﺤﻟﺍﻭ ﻪﺟﻮﻟﺍ ﻲﻓ ﺔﺻﺎﺧ ﺥﺎﻔﺘﻧﺇ ∙ .(ﻲﺴﺴﺤﺗ ﻞﻌﻓ ﺩﺮﻟ ﺕﺎﻣﻼﻋ) ﻥﺍﺪﻘﻓ ،ﻥﺎﻴﺜﻏ ،ﺪﻠﺠﻟﺍﻭ ﻦﻴﻨﻴﻌﻟﺍ ﺭﺍﺮﻔﺻﺇ ∙ ﺕﺎﻣﻼﻋ) ﻦﻛﺍﺩ ﻥﻮﻠﺑ ﻝﻮﺑ ،ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ .(hepatitis ـ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﻹ ﻰﻠﻋ ﺕﻼﺼﻳﻮﺣ ،ﺪﻠﺠﻟﺍ ﺭﺍﺮﻤﺣﺇ ،ﺢﻔﻃ ∙ ﺮﺸﻘﺗ ،ﻢﻔﻟﺍ ﻭﺃ ﻦﻴﻨﻴﻌﻟﺍ ،ﻦﻴﺘﻔﺸﻟﺍ ﻲﻓ ﺏﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ) ﺔﻧﻮﺨﺳ ،ﺪﻠﺠﻟﺍ .(ﺪﻠﺠﻟﺍ :ﺔﻴﻓﺎﺿﺇ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺽﺍﺮﻋﺃ)

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮــﻋﺃ ﻦﻣ ﺪﺣﺍﻭ ﻞﻤﻌﺘﺴﻣ ﻦﻣ ﺮﺜﻛﺃ ﻯﺪﻟ ﺮﻬﻈﺗ :(ﺓﺮﺸﻋ ﻝﻭﺮﺘﺴﻟﻮﻜﻟﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﺮﺤﻟﺍ ﻦﻣ ﺕﺎﺒﻫ ﻕﺎﻫﺭﺇ ؛(hypercholesterolaemia) ؛([ﺪﻴﺟ ﺮﻴﻏ ﻡﺎﻋ ﺭﻮﻌﺷ] ﻒﻌﺿ ﻞﻤﺸﻳ) ﻞﺻﺎﻔﻤﻟﺍﻭ ﻡﺎﻈﻌﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﺪــﺋﺍﺯ ﻕﺮﻌﺗ

.(arthralgia)

ﻩﺬﻫ ﻯﺪﺣﺇ ﺪﻳﺪﺷ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ .ﻚﺒﻴﺒﻃ ﻲﻌﺟﺍﺭ ،ﺮﺜﻛﺃ ﻭﺃ ﺽﺍﺮﻋﻷﺍ ﻯﺪﻟ ﺮﻬﻈﺗ ﺽﺍﺮﻋﺃ) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺢﻔﻃ :(100 ﻦﻴﺑ ﻦﻣ ﻦﻴﻠﻤﻌﺘﺴﻣ 1-10 ﺯﺎﻬﺠﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﺭﺍﻭﺩ ؛ﻉﺍﺪﺻ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ،ﻢﻀﻫ ﺮﺴﻋ ،ﺆﻴﻘﺗ ،ﻥﺎﻴﺜﻏ ﻞﺜﻣ ﻲﻤﻀﻬﻟﺍ ﻭﺃ ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﺓﺩﺎﻳﺯ ؛ﻝﺎﻬﺳﺇ ،ﻙﺎﺴﻣﺇ ؛ﺕﻼﻀﻌﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﻥﺍﺪﻘﻓ (osteoporosis) ﻡﺎﻈﻌﻟﺍ ﻞﺨﻠﺨﺗ ﻭﺃ ﻖﻗﺮﺗ ﻡﺎﻈﻌﻟﺍ ﻲﻓ ﺭﻮﺴﻛ ﻰﻟﺇ ﻱﺩﺆﻳ ﻱﺬﻟﺍ ﺮﻣﻷﺍ ﺓﺮﻘﻔﻟﺍ

ﺎﻀﻳﺃ ﻱﺮﻈﻧﺃ) ﺔﻨﻴﻌﻣ ﺕﻻﺎﺣ ﻲﻓ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ؛(«ﺔﻌﺑﺎﺘﻤﻟﺍﻭ ﺹﻮﺤﻔﻟﺍ» 2 ﻲﻓﻭ ﻦﻴﻣﺪﻘﻟﺍ ﻲﺘﺣﺍﺭ ﻲﻓ ،ﻦﻳﺪﻴﻟﺍ ،ﻦﻴﻋﺍﺭﺬﻟﺍ ؛ﻥﺯﻮﻟﺍ ﻲﻓ ﺓﺩﺎﻳﺯ ؛ﺏﺎﺌﺘﻛﺇ ؛(ﺔﻣﺫﻭ) ﻦﻴﻠﺣﺎﻜﻟﺍ ﻂﻐﺿ) ﻡﺪﻟﺍ ﻂﻐﺿ ﻉﺎﻔﺗﺭﺇ ؛ﺮﻌﺸﻟﺍ ﻂﻗﺎﺴﺗ ؛ﺪﻠﺠﻟﺍ ﻑﺎﻔﺟ ؛ﻦﻄﺒﻟﺍ ﻲﻓ ﻢﻟﺃ ؛(ﻊﻔﺗﺮﻣ ﻡﺩ ؛ﻊﻳﺮﺳ ﺐﻠﻗ ﻢﻈﻧ ،ﺐﻠﻗ ﺕﺎﺑﺮﺿ ؛ﻲﻠﺒﻬﻣ ﻑﺰﻧ ؛(ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﺇ) ﻞﺻﺎﻔﻤﻟﺍ ﺐﻠﺼﺗ .ﺭﺪﺼﻟﺍ ﻲﻓ ﻢﻟﺃ ﻩﺬﻫ ﻯﺪﺣﺇ ﺪﻳﺪﺷ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ .ﻚﺒﻴﺒﻃ ﻲﻌﺟﺍﺭ ،ﺮﺜﻛﺃ ﻭﺃ ﺽﺍﺮﻋﻷﺍ ﺽﺍﺮﻋﺃ) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮـــﻋﺃ ﻦﻴﺑ ﻦﻣ ﻦﻴﻠﻤﻌﺘﺴﻣ 1-10 ﻯﺪﻟ ﺮﻬﻈﺗ

:(1,000

،ﻖﻠﻗ ﻞﺜﻣ ﻲﺒﺼﻌﻟﺍ ﺯﺎﻬﺠﻟﺎﺑ ﻖﻠﻌﺘﺗ ﺕﺎﺑﺍﺮﻄﺿﺇ ،ﺓﺮﻛﺍﺬﻟﺍ ﻲﻓ ﻞﻛﺎﺸﻣ ،ﺱﺎﻌﻧ ،ﻂﺨﺳ ،ﺔﻴﺒﺼﻋ ﻲﻓ ﻕﺮﺤﺑ ﺭﻮﻌﺸﻟﺍ ﻭﺃ ﻢﻟﺃ ؛ﻕﺭﺃ ،ﻡﻮﻨﻟﺍ ﻰﻟﺇ ﻞﻴﻣ ﻖﻔﻨﻟﺍ ﺔﻣﺯﻼﺘﻣ) ﺪﻴﻟﺍ ﻞﺼﻔﻣ ﻲﻓ ﻭﺃ ﻦﻳﺪﻴﻟﺍ ؛ﺲﻤﻠﻟ ﺔﺻﺎﺧ ،ﺲﺤﻟﺍ ﻲﻓ ﻞﻠﺧ ؛(ﻲﻐﺳﺮﻟﺍ ﺞﻴﻬﺗ ،ﺔﻳﺅﺮﻟﺍ ﻲﻓ ﺵﻮﺸﺗ ﻞﺜﻣ ﻦﻴﻌﻟﺍ ﻲﻓ ﻞﻠﺧ ﺔﻜﺣ ﻞﺜﻣ ﺪﻠﺠﻟﺍ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ؛ﻦﻴﻌﻟﺍ ﻲﻓ ؛ﻞﺒﻬﻤﻟﺍ ﻑﺎﻔﺟ ﻭﺃ ﻞﺒﻬﻤﻟﺍ ﻦﻣ ﺕﺍﺯﺍﺮﻓﺇ ؛(ﻯﺮﺷ) ﻲﻓ ﺏﺍﺮﻄﺿﺇ ،ﺶﻄﻋ ؛ﺔﻧﻮﺨﺳ ؛ﻱﺪﺜﻟﺍ ﻲﻓ ﻢﻟﺃ ﺔﻴﺸﻏﻷﺍ ﻑﺎﻔﺟ ؛ﻢﻔﻟﺍ ﻑﺎﻔﺟ ،ﻕﺍﺬﻤﻟﺍ ﺔﺳﺎﺣ ﻚﻟﺎﺴﻤﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﺇ ؛ﻥﺯﻮﻟﺍ ﺺﻗﺎﻨﺗ ؛ﺔﻴﻃﺎﺨﻤﻟﺍ ﻉﺎﻔﺗﺭﺇ ؛ﻝﺎﻌﺳ ؛ﻝﻮﺒﺘﻟﺍ ﺓﺮﻴﺗﻭ ﺓﺩﺎﻳﺯ ،ﺔﻴﻟﻮﺒﻟﺍ ؛ﻦﻴﻨﻴﻌﻟﺍﻭ ﺪﻠﺠﻟﺍ ﺭﺍﺮﻔﺻﺇ ؛ﺕﺎﻤﻳﺰﻧﻹﺍ ﻯﻮﺘﺴﻣ ﺝﺎﺘﻧ) ﻡﺪﻟﺍ ﻲﻓ ﻦﻴﺑﻭﺮﻴﻠﻴﺒﻟﺍ ﻦﻣ ﺔﻴﻟﺎﻋ ﺕﺎﻳﻮﺘﺴﻣ .(ﺀﺍﺮﻤﺤﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﻚﻴﻜﻔﺗ ﻑﻭﺮﻌﻣ ﺮﻴﻏ ﺎﻬﻋﻮﻴﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮــﻋﺃ ﺕﺎﻴﻄﻌﻤﻟﺍ ﻦﻣ ﻉﻮﻴﺸﻟﺍ ﺮﻳﺪﻘﺗ ﻦﻜﻤﻳ ﻻ) :(ﺓﺮﻓﻮﺘﻤﻟﺍ ﻡﺎﻬﺑﻹﺍ ﻭﺃ ﻊﺒﺻﻷﺍ ﺎﻬﻴﻓ ﻰﻘﺒﻳ ﺔﻟﺎﺣ ،ﺩﺎﻧﺰﻟﺍ ﻊﺒﺻﺃ .ﺔﻴﻨﺜﻣ ﺔﻟﺎﺤﺑ ﻩﺬﻫ ﻯﺪﺣﺇ ﺪﻳﺪﺷ ﻞﻜﺸﺑ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ .ﻚﺒﻴﺒﻃ ﻲﻌﺟﺍﺭ ،ﺮﺜﻛﺃ ﻭﺃ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ ،ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﺮﻬﻇ ﺍﺫﺇ ﻦﻣ ﻦﻴﻧﺎﻌﺗ ﺎﻣﺪﻨﻋ ﻭﺃ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮــﻋﻷﺍ ،ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﻲﻓ ﺮﻛﺬﻳ ﻢﻟ ﻲﺒﻧﺎﺟ ﺽﺮﻋ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻚﻴﻠﻋ ﺓﺭﺍﺯﻮﻟ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻟﺍ ﻥﺎﻜﻣﻹﺎﺑ ﻎﻴﻠﺒﺗò ﻂﺑﺍﺮﻟﺍ ﻰﻠﻋ ﻂﻐﻀﻟﺍ ﺔﻄﺳﺍﻮﺑ ﺔﺤﺼﻟﺍ ﺩﻮﺟﻮﻤﻟﺍ åﻲﺋﺍﻭﺩ ﺝﻼﻋ ﺐﻘﻋ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻊﻗﻮﻤﻟ ﺔﻴﺴﻴﺋﺮﻟﺍ ﺔﺤﻔﺼﻟﺍ ﻰﻠﻋ ﻰﻟﺇ ﻚﻬﺟﻮﻳ ﻱﺬﻟﺍ (

www.health.gov.il

،ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻠﻟ ﺮﺷﺎﺒﻤﻟﺍ ﺝﺫﻮﻤﻨﻟﺍ :ﻂﺑﺍﺮﻟﺍ ﺢﻔﺼﺗ ﻖﻳﺮﻃ ﻦﻋ ﻭﺃ

https://sideeffects.health.gov.il

؟ﺀﺍﻭﺪﻟﺍ ﻦﻳﺰﺨﺗ ﺔﻴﻔﻴﻛ (5 ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻆﻔﺣ ﺐﺠﻳ !ﻢﻤﺴﺘﻟﺍ ﻲﺒﻨﺠﺗ ∙ ﻦﻋ

ﺍﺪﻴﻌﺑ ﻖﻠﻐﻣ ﻥﺎﻜﻣ ﻲﻓ ﺮﺧﺁ ﺀﺍﻭﺩ ﻞﻛﻭ ﻭﺃ/ﻭ ﻝﺎﻔﻃﻷﺍ ﺔﻳﺅﺭ ﻝﺎﺠﻣﻭ ﻱﺪﻳﺃ ﻝﻭﺎﻨﺘﻣ

.ﻢﻤﺴﺘﻟﺎﺑ ﻢﻬﺘﺑﺎﺻﺇ ﻱﺩﺎﻔﺘﻟ ﻚﻟﺫﻭ ،ﻊﺿﺮﻟﺍ ﻦﻣ ﺔﺤﻳﺮﺻ ﺕﺎﻤﻴﻠﻌﺗ ﻥﻭﺪﺑ ﺆﻴﻘﺘﻟﺍ ﻲﺒﺒﺴﺗ ﻻ

ﺐﻴﺒﻄﻟﺍ ﺀﺎﻀﻘﻧﺇ ﺪﻌﺑ ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﺯﻮﺠﻳ ﻻ ∙ ﻱﺬﻟﺍ (

exp.date

) ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺦﻳﺭﺎﺗ ﺮﻴﺸﻳ .ﺔﺒﻠﻌﻟﺍ ﺮﻬﻇ ﻰﻠﻋ ﺮﻬﻈﻳ ﻦﻣ ﺮﻴﺧﻷﺍ ﻡﻮﻴﻟﺍ ﻰﻟﺇ ﺔﻴﺣﻼﺼﻟﺍ ﺀﺎﻀﻘﻧﺇ .ﺮﻬﺸﻟﺍ ﺲﻔﻧ ﻦﻋ ﺪﻳﺰﺗ ﺓﺭﺍﺮﺣ ﺔﺟﺭﺪﺑ ﻦﻳﺰﺨﺘﻟﺍ ﺯﻮﺠﻳ ﻻ ∙ .ﺔﻳﻮﺌﻣ ﺔﺟﺭﺩ 30 ﺔﻴﻐﺑ ﺔﻴﻠﺻﻷﺍ ﺔﺒﻠﻌﻟﺍ ﻲﻓ ﻦﻳﺰﺨﺘﻟﺍ ﺐﺠﻳ ∙ .ﺔﺑﻮﻃﺮﻟﺍ ﻦﻣ ﺹﺍﺮﻗﻷﺍ ﺔﻳﺎﻤﺣ ﺔﺒﻠﻌﻟﺍ ﺖﻧﺎﻛ ﺍﺫﺇ ﻝﺎﻤﻌﺘﺳﻹﺍ ﺯﻮﺠﻳ ﻻ ∙ .ﺐﻄﻋ ﺕﺎﻣﻼﻋ ﺎﻬﻴﻠﻋ ﻭﺪﺒﺗ ﻭﺃ ،ﺔﺑﻮﻄﻌﻣ ﺔﻴﻓﺎﺿﺇ ﺕﺎﻣﻮﻠﻌﻣ (6 ﺔﻟﺎﻌﻔﻟﺍ ﺓﺩﺎﻤﻠﻟ ﺔﻓﺎﺿﻹﺎﺑ ﺀﺍﻭﺪﻟﺍ ﻱﻮﺘﺤﻳ

:

ﺎﻀﻳﺃ :ﺹﺮﻘﻟﺍ ﺐﻴﻛﺮﺗ

l a c t o s e

m o n o h y d r a t e ,

microcrystalline cellulose, maize

starch, sodium starch glycolate,

magnesium stearate and silica

colloidal anhydrous.

:ﺀﻼﻄﻟﺍ ﺐﻴﻛﺮﺗ

hypromellose, talc, macrogol

8000, iron oxide yellow (E172),

titanium dioxide (E171).

ﻦﻋ ﺔﻤﻬﻣ ﺕﺎﻣﻮﻠﻌﻣ” 2 ﺓﺮﻘﻔﻟﺍ

ﺎﻀﻳﺃ ﻱﺮﻈﻧﺃ .“ﺀﺍﻭﺪﻟﺍ ﺕﺎﺒﻛﺮﻣ ﺾﻌﺑ ﺔﺒﻠﻌﻟﺍ ﻯﻮﺘﺤﻣ ﻮﻫ ﺎﻣﻭ ﺀﺍﻭﺪﻟﺍ ﻭﺪﺒﻳ ﻒﻴﻛ ∙ ﺹﺍﺮﻗﻷﺍ .ﺔﻴﻠﻄﻣ ﺹﺍﺮﻗﺄﻛ ﻕ

ﻮﺴﻣ ﺍﺭﺎﻤﻴﻓ

.ﻦﻛﺍﺩ ﺮﻔﺻﺃ ﻥﻮﻠﺑ ﺓﺮﻳﺪﺘﺴﻣ ﻲﻫ ﺔﻴﻠﻄﻤﻟﺍ ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻲﻓ «

» ﺔﺑﺎﺘﻜﻟﺎﺑ ﺔﻤﻠﻌﻣ ﻲﻫﻭ .ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻲﻓ «

30 ﺕﺍﺫ ﺔﺒﻠﻋ ﻲﻓ ﻕ

ﻮﺴﻣ ﺍﺭﺎﻤﻴﻓ

ﺎﺻﺮﻗ :ﻪﻧﺍﻮﻨﻋﻭ ﺩﺭﻮﺘﺴﻤﻟﺍﻭ ﺯﺎﻴﺘﻣﻹﺍ ﺐﺣﺎﺻ ∙ ،7126 ﺏ.ﺹ ،.ﺽ.ﻡ ﻞﻴﺋﺍﺮﺳﺇ ﺲﻴﺗﺭﺎﭬﻮﻧ .ﺐﻴﺑﺃ ﻞﺗ ﺔﻳﻭﺩﻷﺍ ﻞﺠﺳ ﻲﻓ ﺀﺍﻭﺪــﻟﺍ ﻞﺠﺳ ﻢﻗﺭ ∙ :ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻲﻓ ﻲﻣﻮﻜﺤﻟﺍ

109 86 29281

.2020 ﻝﻭﻷﺍ ﻦﻳﺮﺸﺗ ﻲﻓ ﺎﻫﺩﺍﺪﻋﺇ ﻢﺗ

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS

(PREPARATIONS)

-

1986

The medicine is dispensed with a

doctor’s prescription only

FEMARA

®

Film-coated tablets

Composition:

Active ingredient:

Each film-coated tablet contains:

Letrozole 2.5 mg

Inactive

ingredients

and

allergens:

See section 6 “Further Information”.

See also in section 2 “Important

information regarding some of the

ingredients of the medicine”.

Read this package insert

carefully in its entirety before

using this medicine. This leaflet

contains concise information about

the medicine. If you have further

questions, refer to the doctor or

pharmacist.

This medicine has been prescribed

for the treatment of your ailment.

Do not pass it on to others. It may

harm them even if it seems to you

that their ailment is similar.

1. WHAT IS THE MEDICINE

INTENDED FOR?

∙ Adjuvant treatment of early-stage

breast cancer in postmenopausal

women.

∙ Extended adjuvant treatment

of early-stage breast cancer

in postmenopausal women

following standard adjuvant

tamoxifen therapy.

∙ Treatment

advanced

metastatic breast cancer in

postmenopausal women.

∙ Treatment of advanced breast

cancer

postmenopausal

women with disease progression

following

treatment

with

antioestrogens.

Therapeutic group: Aromatase

inhibitors (antioestrogens).

This medicine is a hormonal (also

called “endocrine”) breast cancer

treatment. Growth of breast

cancer is frequently stimulated by

oestrogens, which are female sex

hormones. Femara reduces the

amount of oestrogen by blocking

an enzyme (“aromatase”) involved

in the production of oestrogens and

may therefore block the growth of

breast cancers that need oestrogen

to grow. As a consequence, tumour

cells slow down or stop growing

and/or spreading to other parts of

the body.

If you have any questions about

how Femara works or why it has

been prescribed for you, ask your

doctor.

2. BEFORE

USING

THE

MEDICINE

Follow all the doctor’s instructions

carefully. They may differ from

the general information in this

leaflet.

X

Do not use the medicine

if:

∙ you are allergic (hypersensitive)

to letrozole or to any of the

other ingredients contained in

the medicine (listed in section

6 “Further Information” in this

leaflet).

∙ you

still

have

menstrual

periods, i.e., if you have not yet

gone through menopause.

∙ you are pregnant.

∙ you are breast-feeding.

If any of these conditions apply

to you, do not take this

medicine and talk to your

doctor.

Special warnings regarding use

of the medicine:

!

Talk

to

your

doctor

or

pharmacist before taking

Femara if:

∙ you

have

severe

kidney

disease.

∙ you have severe liver disease.

∙ you have a history of osteoporosis

or bone fractures (see also “Tests

and follow-up” in section 2).

If any of these conditions apply

to you, tell your doctor. Your

doctor will take this information

into account during your treatment

with Femara.

Letrozole may cause inflammation

in tendons or tendon injury (see

section 4). At any sign of tendon

pain or swelling - rest the painful

area and contact your doctor.

!

Children and adolescents

(below 18 years)

This medicine is not intended for

children and adolescents under 18

years of age.

!

Elderly people (65 years of

age and above)

Patients 65 years of age and

over can use Femara at the same

dosage as other adults.

!

Tests and follow-up

You should only take Femara under

strict medical supervision.

Your doctor will regularly monitor

your condition to check whether

the treatment is having the right

effect.

Femara may cause thinning

wasting

your

bones

(osteoporosis) due to the reduction

of oestrogens in your body. Your

doctor may decide to measure your

bone density (a way of monitoring

for osteoporosis) before, during

and after treatment.

!

Drug interactions:

If you are taking, or have

recently

taken,

other

medicines, including non-

prescription medicines and

food supplements, inform the

doctor or pharmacist. Especially

if you are taking:

∙ tamoxifen

treatments that contain other

antioestrogens or oestrogens

∙ phenytoin

∙ clopidogrel

!

Use of the medicine and

food

The tablet can be taken with or

without food.

!

Pregnancy, breast-feeding

and fertility

∙ You should only take Femara if you

have gone through menopause.

However, your doctor should

discuss with you the use of

effective contraception, as you

may still have the potential

to become pregnant during

treatment

with

Fe m a r a .

∙ You must not take Femara if you

are pregnant or breast-feeding,

as it may harm your baby.

!

Driving

and

use

of

machines

If you feel dizzy, tired, drowsy or

generally unwell, do not drive or

operate any tools/machines until

you feel that these effects have

passed.

!

Important

information

regarding

some

of

the

ingredients of the medicine

Femara contains lactose (milk

sugar). If you have been told by

your doctor that you have an

intolerance to certain sugars,

contact your doctor before taking

this medicine.

Femara contains sodium.

The amount of sodium is less than

23 mg per tablet, i.e., essentially

“sodium-free”.

3. HOW SHOULD YOU USE THE

MEDICINE?

Always

preparation

according

doctor’s

instructions.

Check

with

your

doctor

pharmacist

sure

regarding

dosage

and treatment regimen of the

preparation.

The dosage and treatment regimen

will be determined by the doctor

only. The usual dosage is generally

one tablet of Femara once a day.

D o

n o t

e x c e e d

t h e

recommended dose.

Mode of administration

Swallow the tablet whole with

a glass of water or other liquid.

There is no information regarding

crushing/splitting/chewing.

Taking Femara at the same time

each day will help you remember

when to take the tablet.

Duration of treatment

Continue taking Femara every day

for as long as your doctor tells you.

You may need to take the medicine

for months or even years. If you

have any questions about how

long to keep taking Femara, talk

to your doctor.

If you accidentally take a

higher dosage

If you took an overdose, or if

a child, or anyone else, has

accidentally

swallowed

medicine, immediately refer

to the doctor or proceed to a

hospital emergency room and

bring the medicine package with

you. Medical treatment may be

necessary.

FEM APL OCT20 V1

If you forget to take the

medicine

∙ If it is almost time for your next

dose (i.e., within 2 or 3 hours),

skip the dose you missed and

take your next dose at the

regular time.

∙ Otherwise, take the dose as soon

as you remember, and then take

the next tablet as you would

normally.

∙ Do not take a double dose to

make up for the one that you

missed.

Adhere to the treatment as

recommended by the doctor.

If you stop taking Femara

Do not stop treatment with the

medicine without consulting the

doctor.

See also the section above

“Duration of treatment”.

Do not take medicines in the

dark! Check the label and

the dose each time you take

medicine. Wear glasses if you

need them.

If you have further questions

regarding

use

of

this

medicine, consult the doctor

or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of

Femara may cause side effects

in some users. Do not be alarmed

when reading the list of side

effects. You may not suffer from

any of them.

Most of the side effects are mild

to moderate and will generally

disappear after a few days to a few

weeks of treatment. Some of the

side effects, such as hot flushes,

hair loss or vaginal bleeding may

be due to the lack of oestrogens

in your body.

Side effects that may be

severe:

Refer to a doctor immediately

if you suffer from any of the

following conditions:

Uncommon side effects (effects

that occur in 1-10 in 1,000

users):

∙ Weakness, paralysis or loss of

feeling in any part of the body

(particularly arm or leg), loss

of coordination, nausea, or

difficulty speaking or breathing

(sign of a brain disorder, e.g.,

stroke).

∙ Sudden oppressive chest pain

(sign of a heart disorder).

∙ Swelling and redness along a

vein which is extremely tender

and possibly painful when

touched.

∙ Severe fever, chills or mouth

ulcers due to infections (lack of

white blood cells).

∙ Severe

persistent

blurred

vision.

∙ Inflammation of a tendon or

tendonitis (connective tissues

that

connect

muscles

bones).

Rare side effects (effects that

occur in 1-10 in 10,000 users):

∙ Difficulty breathing, chest pain,

fainting, rapid heart rate, bluish

skin discoloration, or sudden

arm, leg or foot pain (signs that

a blood clot may have formed).

∙ Rupture of a tendon (connective

tissues that connect muscles to

bones).

You should also inform the doctor

immediately if you suffer from any

of the following symptoms during

treatment with Femara:

∙ Swelling mainly of the face

and throat (signs of allergic

reaction).

∙ Yellow skin and eyes, nausea,

loss of appetite, dark-coloured

urine (signs of hepatitis).

∙ Rash, red skin, blistering of the

lips, eyes or mouth, skin peeling,

fever (signs of skin disorder).

Additional side effects:

Very common side effects

(effects that occur in more than

1 user in 10):

H o t

f l u s h e s ;

i n c re a s e d

l e v e l

c h o l e s t e r o l

(hypercholesterolaemia); fatigue

(including weakness [generally

feeling

unwell]);

increased

sweating; pain in bones and joints

(arthralgia).

If one or more of these effects

affect you severely, refer to your

doctor.

Common side effects (effects that

occur in 1-10 in 100 users):

Skin rash; headache; dizziness;

gastrointestinal disorders such

as nausea, vomiting, indigestion,

constipation, diarrhoea; increase in

or loss of appetite; pain in muscles;

thinning or wasting of your bones

(osteoporosis), leading to bone

fractures in some cases (see also

“Tests and follow-up” in section

2); swelling of arms, hands, feet

and ankles (oedema); depression;

weight increase; hair loss; raised

blood pressure (hypertension);

abdominal pain; dry skin; vaginal

bleeding; palpitations, rapid heart

rate; joint stiffness (arthritis); chest

pain.

If one or more of these effects

affect you severely, refer to your

doctor.

Uncommon side effects (effects

that occur in 1-10 in 1,000

users):

Nervous system disorders such as

anxiety, nervousness, irritability,

drowsiness, memory problems,

somnolence, insomnia; pain or

burning sensation in the hands or

wrist (carpal tunnel syndrome);

impairment of sensation, especially

that of touch; eye disorders such

as blurred vision, eye irritation;

skin disorder such as itching

(urticaria); vaginal discharge or

dryness; breast pain; fever; thirst,

taste disorder, dry mouth; dryness

of mucous membranes; weight

decrease; urinary tract infection,

increased frequency of urination;

cough; increased level of enzymes;

yellowing of the skin and eyes; high

blood bilirubin levels (a breakdown

product of red blood cells).

Side

effects

of

unknown

frequency (the frequency can not

be estimated from the available

data):

Trigger finger, a condition in which

your finger or thumb catches in a

bent position.

If one or more of these effects

affect you severely, refer to your

doctor.

If a side effect occurs, if any

of the side effects worsen, or

if you suffer from a side effect

not mentioned in the leaflet you

should consult your doctor.

Side effects can be reported to

the Ministry of Health by clicking

on the link “Report Side Effects

of Drug Treatment” found on the

Ministry of Health homepage

(www.health.gov.il) that directs

you to the online form for reporting

side effects, or by entering the

link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE

BE STORED?

∙ Avoid poisoning! This medicine

and any other medicine must be

kept in a closed place out of the

reach and sight of children and/

or infants to avoid poisoning.

Do not induce vomiting unless

clearly indicated by the doctor.

∙ Do not use the medicine after

the expiry date (exp. date)

appearing on the package. The

expiry date refers to the last day

of that month.

∙ Do not store at a temperature

exceeding 30°C.

∙ Store in the original package

to protect the tablets from

moisture.

∙ Do not use if the package

is damaged or has signs of

tampering.

6. FURTHER INFORMATION

In addition to the active

ingredient, the medicine also

contains:

Tablet composition:

l a c t o s e

m o n o h y d r a t e ,

microcrystalline cellulose, maize

starch, sodium starch glycolate,

magnesium stearate and silica

colloidal anhydrous.

Coating composition:

hypromellose, talc, macrogol

8000, iron oxide yellow (E172),

titanium dioxide (E171).

See also in section 2 “Important

information regarding some

ingredients

medicine”.

What does the medicine

look like and what are the

contents of the package

Femara is marketed as film-

coated tablets. The film-coated

tablets are round and dark yellow

in colour. They are marked with

“FV” on one side and “CG” on

the other side.

Femara is marketed in packages

of 30 tablets.

Registration holder and

importer and its address:

Novartis Israel Ltd., P.O.B 7126,

Tel Aviv.

∙ Registration number of the

medicine in the National Drug

Registry of the Ministry of Health:

109 86 29281

Revised in October 2020.

FEM APL OCT20 V1

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Femara

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance: letrozole.

Each film

-

coated tablet contains 2.5 mg letrozole.

Each tablet contains 61.5 mg of lactose monohydrate.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablets.

Film-coated tablet, dark yellow, round, slightly biconvex with bevelled edges. One side bears the

imprint “FV”, the other “CG”.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

Extended adjuvant treatment of early breast cancer in postmenopausal women who have received

prior standard adjuvant tamoxifen therapy.

First-line treatment in postmenopausal women with hormone receptor positive, or in whom the

hormone receptor status cannot be determined, locally advanced or metastatic breast cancer.

Treatment

advanced

breast

cancer

postmenopausal

women

with

disease

progression

following anti-oestrogen therapy.

4.2

Posology and method of administration

Posology

Adult and elderly patients

The recommended dose of Femara is 2.5 mg once daily. No dose adjustment is required for elderly

patients.

In patients with advanced or metastatic breast cancer, treatment with Femara should continue until

tumour progression is evident.

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In the adjuvant and extended adjuvant setting, treatment with Femara should continue for 5 years or

until tumour relapse occurs, whichever is first.

Paediatric population

Femara is not recommended for use in children and adolescents. The safety and efficacy of Femara 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.

Renal impairment

No dosage adjustment of Femara is required for patients with renal insufficiency with creatinine

clearance ≥10 ml/min. Insufficient data are available in cases of renal insufficiency with creatinine

clearance lower than 10 ml/min (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment of Femara 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

Femara should be taken orally and can be taken with or without food.

A 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).

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

Menopausal status

In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulating hormone

(FSH) and/or oestradiol levels should be measured before initiating treatment with Femara. Only women

of postmenopausal endocrine status should receive Femara.

Renal impairment

Femara has not been investigated in a sufficient number of patients with a creatinine clearance lower than

10 ml/min. The potential risk/benefit to such patients should be carefully considered before administration

of Femara.

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

Femara 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

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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.

Tendonitis and tendon rupture

Tendonitis and tendon ruptures (rare) may occur. Close monitoring of the patients and appropriate

measures (e.g. immobilisation) must be initiated for the affected tendon (see section 4.8).

Other warnings

Co-administration of Femara 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).

As the tablets contain lactose, Femara is not recommended for patients with rare hereditary problems of

galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.

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 Femara in combination with oestrogens or other

anticancer

agents,

other

than

tamoxifen.

Tamoxifen,

other

anti-oestrogens

oestrogen-containing

therapies

diminish

pharmacological

action

letrozole.

addition,

co-administration

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 unknown. 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, clopidrogel).

4.6

Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential

Femara 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 Femara 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), Femara may cause congenital malformations when administered during pregnancy.

Studies in animals have shown reproductive toxicity (see section 5.3).

Femara is contraindicated during pregnancy (see sections 4.3 and 5.3).

Breast-feeding

unknown

whether

letrozole

metabolites

excreted

human

milk.

risk

newborns/infants cannot be excluded.

Femara is contraindicated during breast-feeding (see section 4.3).

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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

Femara has minor influence on the ability to drive and use machines. Since fatigue and dizziness have

been observed with the use of Femara and somnolence has been reported uncommonly, caution is advised

when driving or using machines.

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.

most

frequently

reported

adverse

reactions

clinical

studies

were

flushes,

hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.

Important

additional

adverse

reactions

that

occur

with

Femara

are:

skeletal

events

such

osteoporosis

and/or

bone

fractures

cardiovascular

events

(including

cerebrovascular

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 pain

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

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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:

Uncommon:

Palpitations

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, stomatitis

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 pain

, 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

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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

treatment

(Median 5y)

Any time after

randomization

(Median 8y)

During

treatment

(Median 5y)

Any time after

randomization

(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 /

endometrial cancer

0.2%

0.4%

2.3%

2.9%

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

proliferative disorders

0.7%

3.4%**

1.7%**

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.

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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/

4.9

Overdose

Isolated cases of overdose with Femara have been reported.

No specific treatment for overdose is known; treatment should be symptomatic and supportive.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase

inhibitor, ATC code: L02BG04.

Pharmacodynamic effects

The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases

where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used.

In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme,

which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone and

oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can

therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively

binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis

in all tissues where present.

In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg, and 2.5 mg letrozole suppress serum

oestrone and oestradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is

achieved in 48-78 hours.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed plasma

concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients

treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the

limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses.

Oestrogen suppression was maintained throughout treatment in all these patients.

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Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not

been observed. No clinically relevant changes were found in the plasma concentrations of cortisol,

aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among

postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test

performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg,

and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and

mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among

healthy postmenopausal women after 0.1 mg, 0.5 mg, and 2.5 mg single doses of letrozole or in plasma

concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to

5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic

precursors. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function

as evaluated by TSH, T4, and T3 uptake test.

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. Femara for 5 years; C. tamoxifen for 2 years followed by Femara for 3 years;

D. Femara 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 Femara 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

Femara

N=4003

Tamoxifen

N=4007

HR

1

(95% CI)

P

Femara

N=4003

Tamoxifen

N=4007

HR

1

(95% CI)

P

Disease-free survival (primary)

- events (protocol definition

0.81

(0.70, 0.93)

0.003

0.86

(0.77, 0.96)

0.008

Overall survival (secondary)

Number of deaths

0.86

(0.70, 1.06)

0.87

(0.75, 1.01)

HR = Hazard ratio; CI = Confidence interval

Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

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.

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Results at a median follow-up of 96 months (monotherapy arms only)

The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of Femara 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 96 months (ITT population)

Femara

N=2463

Tamoxifen

N=2459

Hazard Ratio

1

(95% CI)

P Value

Disease-free survival events (primary)

0.87 (0.78, 0.97)

0.01

Time to distant metastasis (secondary)

0.86 (0.74, 1.01)

0.06

Overall survival (secondary) - deaths

0.89 (0.77, 1.02)

0.08

Censored analysis of DFS

0.83 (0.74, 0.92)

Censored analysis of OS

0.81 (0.70, 0.93)

Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

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.

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)

N

Number of

events

1

Hazard

ratio

2

(97.5% confidence

interval)

Cox model

P-value

[Letrozole→]Tamoxifen

1460

254

1.03

(0.84, 1.26)

0.72

Letrozole

1464

249

1 Protocol definition, including second non-breast primary malignancies, after switch / beyond two years

2 Adjusted by chemotherapy use

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)

Hazard ratio

(99% CI)

1.04 (0.85, 1.27)

Letrozole→Tamoxifen

Tamoxifen

2

Number of patients

1540

1548

Number of patients with DFS events (protocol

Page 10 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

definition)

Hazard ratio

(99% CI)

0.92 (0.75, 1.12)

Adjusted by chemotherapy use (yes/no)

626 (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 favour of

tamoxifen at each time point.

Extended adjuvant treatment (MA-17)

multicentre,

double-blind,

randomised,

placebo-controlled

study

(MA-17),

over

5,100 postmenopausal

women

with

receptor-positive

unknown

primary

breast

cancer

completed adjuvant treatment with tamoxifen (4.5 to 6 years) were randomised to either Femara 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 Femara 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: (Femara 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

Consequently, after 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 Femara for up to 5 years. Over 60% of

eligible patients (disease-free at unblinding) opted to switch to Femara. The final analysis included

1,551 women who switched from placebo to Femara at a median of 31 months (range 12 to 106 months)

after completion of tamoxifen adjuvant therapy. Median duration for Femara 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 Femara.

Page 11 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

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

Median follow-up 28 months

Median follow-up 62 months

Letrozole

N=2582

Placebo

N=2586

HR (95% CI)

P

value

Letrozole

N=2582

Placebo

N=2586

HR (95%

P

value

Disease-free survival

3

Events

92 (3.6%)

155 (6.0%)

0.58

(0.45, 0.76)

0.00003

(8.1%)

(11.1%)

0.75

(0.63, 0.89)

4-year DFS rate

94.4%

89.8%

94.4%

91.4%

Disease-free survival

3

, including deaths from any cause

Events

122 (4.7%)

193 (7.5%)

0.62

(0.49, 0.78)

(13.3%)

(15.5%)

0.89

(0.77, 1.03)

5 year DFS rate

90.5%

80.8%

88.8%

86.7%

Distant metastases

Events

57 (2.2%)

93 (3.6%)

0.61

(0.44, 0.84)

(5.5%)

(6.5%)

0.88

(0.70, 1.10)

Overall survival

Deaths

51 (2.0%)

62 (2.4%)

0.82

(0.56, 1.19)

236 (9.1%)

232 (9.0%)

1.13

(0.95, 1.36)

Deaths

(9.1%)

(6.6%)

0.78

(0.64, 0.96)

HR = Hazard ratio; CI = Confidence Interval

When the study was unblinded in 2003, 1551 patients in the randomised placebo arm (60%

of those eligible to switch – i.e. who were disease-free) switched to letrozole at a median

31 months after randomisation. The analyses presented here ignore the selective crossover.

Stratified by receptor status, nodal status and prior adjuvant chemotherapy.

Protocol definition of disease-free survival events: loco-regional recurrence, distant metastasis or

contralateral breast cancer.

Exploratory analysis, censoring follow-up times at the date of switch (if it occurred) in the placebo

arm.

Median follow-up 62 months.

Median follow-up until switch (if it occurred) 37 months.

In the MA-17 bone substudy in which concomitant calcium and vitamin D were given, greater decreases

in BMD compared to baseline occurred with Femara 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 Femara 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.

Page 12 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

First-line treatment

One controlled double-blind trial was conducted comparing Femara (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

Femara

N=453

Tamoxifen

N=454

Time to progression

Median

9.4 months

6.0 months

(95% CI for median)

(8.9, 11.6 months)

(5.4, 6.3 months)

Hazard ratio (HR)

0.72

(95% CI for HR)

(0.62, 0.83)

P

<0.0001

Objective response

rate (ORR)

CR+PR

145 (32%)

95 (21%)

(95% CI for rate)

(28, 36%)

(17, 25%)

Odds ratio

1.78

(95% CI for odds ratio)

(1.32, 2.40)

P

=0.0002

Time

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 Femara and 6.4 months for tamoxifen in patients with soft tissue disease only and median

8.3 months for Femara and 4.6 months for tamoxifen in patients with visceral metastases.

Study design allowed patients to cross over upon progression to the other therapy or discontinue from the

study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was

virtually completed by 36 months. The median time to crossover was 17 months (Femara to tamoxifen)

and 13 months (tamoxifen to Femara).

Femara treatment in the first-line therapy of advanced breast cancer resulted in a median overall survival

of 34 months compared with 30 months for tamoxifen (logrank test P=0.53, not significant). The absence

of an advantage for Femara on overall survival could be explained by the crossover design of the study.

Second-line treatment

Two well-controlled clinical trials were conducted comparing two letrozole doses (0.5 mg and 2.5 mg) to

megestrol acetate and to aminoglutethimide, respectively, in postmenopausal women with advanced

breast cancer previously treated with anti-oestrogens.

Time to progression was not significantly different between letrozole 2.5 mg and megestrol acetate

P

=0.07). Statistically significant differences were observed in favour of letrozole 2.5 mg compared to

megestrol acetate in overall objective tumour response rate (24% vs 16%,

P

=0.04), and in time to

treatment failure (

P

=0.04). Overall survival was not significantly different between the 2 arms (

P

=0.2).

Page 13 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

In the second study, the response rate was not significantly different between letrozole 2.5 mg and

aminoglutethimide (

P

=0.06). Letrozole 2.5 mg was statistically superior to aminoglutethimide for time to

progression (

P

=0.008), time to treatment failure (

P

=0.003) and overall survival (

P

=0.002).

Male breast cancer

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

5.2

Pharmacokinetic properties

Absorption

Letrozole

rapidly

completely

absorbed

from

gastrointestinal

tract

(mean

absolute

bioavailability: 99.9%). Food slightly decreases the rate of absorption (median t

1 hour fasted versus

2 hours fed; and mean C

129 ± 20.3 nmol/litre fasted versus 98.7 ± 18.6 nmol/litre fed) but the extent

of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of

clinical relevance, and therefore letrozole may be taken without regard to mealtimes.

Distribution

Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of

letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg

C-labelled

letrozole,

approximately

radioactivity

plasma

unchanged compound. Systemic

exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its

apparent volume of distribution at steady state is about 1.87

0.47 l/kg.

Biotransformation

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway

of letrozole (CL

= 2.1 l/h) but is relatively slow when compared to hepatic blood flow (about 90 l/h).

The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this

metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a

minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg

labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in

urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours

(84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two

unidentified metabolites, and 6% to unchanged letrozole.

Elimination

The apparent terminal elimination half-life in plasma is about 2 to 4 days. After daily administration of

2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are

approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are

1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a

single

dose,

indicating

slight

non-linearity

pharmacokinetics

letrozole

upon

daily

administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no

continuous accumulation of letrozole occurs.

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 5mg). 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).

Special populations

Elderly

Age had no effect on the pharmacokinetics of letrozole.

Page 14 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

Renal impairment

In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance 9-

116 ml/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. 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).

Hepatic impairment

In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of

the volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects,

still

within

range

seen

subjects

without

impaired

function.

study

comparing

pharmacokinetics of letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe

hepatic impairment (Child-Pugh C) to those in healthy volunteers (N=8), AUC and t

increased by 95 and

187%, respectively. Thus, Femara should be administered with caution to patients with severe hepatic

impairment and after consideration of the risk/benefit in the individual patient.

5.3

Preclinical safety data

In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of

systemic or target organ toxicity.

Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs letrozole

caused signs of moderate toxicity at 100 mg/kg.

In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can be

attributed to the pharmacological action of the compound. The no-adverse-effect level was 0.3 mg/kg in

both species.

Oral administration of letrozole to female rats resulted in decreases in mating and pregnancy ratios and

increases in pre-implantation loss.

Both

in vitro

in vivo

investigations of letrozole's mutagenic potential revealed no indications of any

genotoxicity.

In a 104-week rat carcinogenicity study, no treatment-related tumours were noted in male rats. In female

rats, a reduced incidence of benign and malignant mammary tumours at all the doses of letrozole was

found.

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

tumors was observed at all doses of letrozole tested. These tumors were considered to be related to the

pharmacological inhibition of estrogen synthesis and may be due to increased LH resulting from the

decrease in circulating estrogen.

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

Page 15 of 15

FEM API OCT20 V1

REF UK SMPC APR 2020

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).

Preclinical observations were confined to those associated with the recognised pharmacological action,

which is the only safety concern for human use derived from animal studies.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablets content: lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch

glycolate, magnesium stearate and silica colloidal anhydrous.

Coating: hypromellose, talc, macrogol 8000, iron oxide yellow (E 172), titanium dioxide (E 171).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Do not store above 30°C. Protect from moisture.

6.5

Nature and contents of container

PVC/PE/PVDC/aluminium blisters.

Pack of 30 tablets.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

REGISTRATION HOLDER AND ITS ADDRESS

Novartis Israel Ltd. P.O.B 7126, Tel-Aviv.

8.

REGISTRATION NUMBER

109 86 29281

Revised in October 2020.

ךיראת

:

,רבוטקואב

5102

םש

רישכת

תילגנאב

רפסמו

םושירה

:

Femara [29281]

:םושירה לעב םש

סיטרבונ מ"עב לארשי

!דבלב תורמחהה טוריפל דעוימ הז ספוט

רוחש טסקט

רשואמ טסקט

יתחת וק םע טסקט

רשואמה ןולעל טסקט תפסוה

הצוח וק םע טסקט

רשואמה ןולעהמ טסקט תקיחמ

בוהצב ןמוסמה טסקט

הרמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

4. CLINICAL

PARTICULARS

Text from approved PI dated March

2012.

Text from approved PI dated March

2012.

Text from approved PI dated March

2012.

4.2

Posology and method of administration

.....

Paediatric population

Femara is not recommended for use in

children and adolescents. The safety and

efficacy of Femara 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.

…..

Method of administration

Femara should be taken orally and can be

taken with or without food.

A 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).

4.4

Special warnings and precautions for use

Menopausal status

In patients whose menopausal status is unclear,

luteinising

hormone

(LH),

follicle-stimulating

hormone (FSH) and/or oestradiol levels should be

measured before initiating treatment with Femara.

Only women of postmenopausal endocrine status

should receive Femara.

…..

Other warnings

Co-administration

Femara

with

tamoxifen,

other

anti-oestrogens

oestrogen-containing

therapies should be avoided as these substances

diminish

pharmacological

action

letrozole (see section 4.5).

tablets

contain

lactose,

Femara

recommended for

patients

with

rare hereditary

problems

galactose

intolerance,

severe

lactase

deficiency

glucose-galactose

malabsorption.

4.5

Interaction

with

other

medicinal

products and other forms of interaction

…..

There is no clinical experience to date on the use

Femara

combination

with

oestrogens

other

anticancer

agents,

other

than

tamoxifen.

Tamoxifen,

other

anti-oestrogens

oestrogen-

containing

therapies

diminish

pharmacological action of letrozole. In addition,

co-administration of tamoxifen with letrozole has

been

shown

substantially

decrease

plasma

concentrations of letrozole. Co-administration of

Text from approved PI dated March

2012.

4.8 Undesirable effects

Skin and subcutaneous tissue disorders

Very rare: Anaphylactic reaction

Metabolism and nutrition disorders

Common: Hypercholesterolemia

Vascular disorders

Uncommon:

…..

Ischemic

cardiac

events…

new or worsening angina…..; angina

requiring surgery…..; myocardial infarction …..;

thromboembolic event…..; stroke/TIA…..

Vascular disorders

Uncommon: ….. Hypertension…..

Gastrointestinal disorders

Uncommon: Abdominal pain…..

Hepatobiliary disorders

Very rare: Hepatitis

Skin and subcutaneous tissue disorders

Common: ….. Increased sweating…..

Uncommon: ….. dry skin…..

Very rare: Angioedema….. toxic

epidermal necrolysis, erythema

multiforme

Reproductive

system

and

breast

disorders

Uncommon: Vaginal bleeding…..

letrozole with tamoxifen, other anti-oestrogens or

oestrogens should be avoided.

…..

4.6

Fertility, pregnancy and lactation

…..

Fertility

pharmacological

action

letrozole

reduce

oestrogen

production

aromatase

inhibition.

premenopausal

women,

inhibition of oestrogen synthesis leads to feedback

increases

gonadotropin

(LH,

FSH)

levels.

Increased FSH levels in turn stimulate follicular

growth, and can induce ovulation.

4.8 Undesirable effects

Immune system disorders

Unknown: Anaphylactic reaction

Metabolism and nutrition disorders

Very common: Hypercholesterolemia

Cardiac disorders

Uncommon: ischaemic cardiac events (including

worsening

angina,

angina

requiring

surgery,

angina

pectoris,

myocardial

infarction

and myocardial ischaemia)

Vascular disorders

Common: Hypertension

Gastrointestinal disorders

Common: ….. abdominal pain…..

Hepatobiliary disorders

Not known: Hepatitis

Skin and subcutaneous tissue disorders

Very common: Increased sweating

Common: ….. dry skin

known:

Angioedema,

toxic

epidermal

necrolysis, erythema multiforme

Reproductive system and breast disorders

Common: Vaginal bleeding

:ךיראת

,רבוטקואב

5102

םש

רישכת

תילגנאב

רפסמו

םושירה

:

Femara [29281]

:םושירה לעב םש

סיטרבונ לארשי מ"עב

!דבלב תורמחהה טוריפל דעוימ הז ספוט

רוחש טסקט

רשואמ טסקט

יתחת וק םע טסקט

רשואמה ןולעל טסקט תפסוה

הצוח וק םע טסקט

רשואמה ןולעהמ טסקט תקיחמ

בוהצב ןמוסמה טסקט

הרמחה

תושקובמה תורמחהה

ןולעב קרפ

טסקט

יחכונ

שדח טסקט

2

שומיש ינפל . הפורתב

תועגונה תודחוימ תורהזא

ל

שומיש :הפורתב

.הרומח הילכ תלחממ תלבוס ךניה םא

.הרומח דבכ תלחממ תלבוס ךניה םא

.....

!

תורחא תופורת תליטנ

תורחא תופורת תחקול תא םא

םא וא ללוכ ,תרחא הפורתב לופיט התע הז תרמג לע ירפס ,ןוזמ יפסותו םשרמ אלל תופורת חקורל וא אפורל ךכ

.....

!

הקנהו ןוירה

ץעוויהל שי הקינמ וא ןוירהב ךניהו הדימב הפורת תליטנ ינפל חקורב וא אפורב .יהשלכ

תאו הדימב הרמפב שמתשהל ןיא .ךלש רבועב עוגפל יושע רבדה ןכש ןוירהב

,תסו אלל םישנל קר תדעוימ הרמפו רחאמ אל ןוירה יבגל תולבגמהש יאדוול בורק ולוחי ילע

ה םא ,םלוא

וא הנורחאל הקספ ךלש תסו תועגונה תודחוימ תורהזא שומישב שומישל :הפורתב

ירפס ,הרמפב לופיטה ינפל

ל

וא אפור

ל

חקור

םא

:

םא ךל שי מ תלבוס ךניה הילכ תלחמ .הרומח

םא ךל שי מ תלבוס ךניה דבכ תלחמ .הרומח

םא טסוא לש הירוטסיה ךל שי

סיזורופו

וא

תומצעב םירבש

תוקידב" םג יאר( ףיעס תחת "בקעמו

.....

תורחא תופורת תליטנ

תחקול תא םא

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ןהשלכ

-

יפסותו םשרמ אלל תופורת ללוכ ןוזמ הנוזת .חקורל וא אפורל ךכ לע ירפס ,

דחוימב

אפורה תא עדייל שי

חקורה וא

תא םא

חקול

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םיליכמה םילופיט

יטנא

וא םירחא םינגורטסא םינגורטסא

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הקנה

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:

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םא שי הקינמ וא ןוירהב ךניה ינפל חקורב וא אפורב ץעוויהל

תליטנ יהשלכ הפורת

תופורתב שומישה

ןוירה

הרמפ לוטיל שי קר םא תא תרבע תולבה ליג ךלש אפורה םלוא . ךתיא חחושל ךירצ

תודוא םיליעי העינמ יעצמאב שומישה

הו רבעמה ליגל הבורק ךניה םא

ךלש תסו לע ,הרידס אל

יבגל אפורב ץעוויהל ךי תא ןכש ,העינמ יעצמאב שומישב ךרוצה .ןוירהל סנכיהל היושע

שי .הרמפב ךלש לופיטה ךלהמב קינהל ןיא .הקינמ ךניהו הדימב ךלש אפורה תא עדייל

תלעב ןיידע ךניהו ןכתיי ןכש ב תורהל תלוכי

לופיטה ךלהמ .הרמפב

ןוירהב תאו הדימב הרמפב שמתשהל ןיא ב עוגפל יושע רבדה ןכש ךלש רבוע

תדעוימ הרמפו רחאמ תצלמומ םישנל קר אלל וה תקספה רחאל יאדוול בורק ,תסו .ךילע ולוחי אל ןוירה יבגל תולבגמהש

םא ,םלוא וא הנורחאל תולבה ליגל תסנכנ וא הנורחאל הקספ ךלש תסוה ליגב תאש תולבה תסוהו רבעמה ליגל הבורק ךניה םא אפורב ץעוויהל ךילע ,הרידס אל ךלש ךלש ןכש ,העינמ יעצמאב שומישב ךרוצה יבגל ש ןכתיי תא תלוכי תלעב שע סנכיהל היו ןוירהל תורהל

הקנה

ל ןיא שי .הרמפב ךלש לופיטה ךלהמב קינה .הקינמ ךניהו הדימב ךלש אפורה תא עדייל

ןוירהב ךניה םא הרמפ לוטיל ןיא הקינמ וא

ןכש

רבדה

קיזהל לולע קוניתל

ךלש

.....

3

ישמתשת דציכ . ?הפורתב

בקעמו תוקידב

יאופר החגשה תחת הרמפ לוטיל שי

.דבלב תינדפק

רחא יתרגיש ןפואב בוקעי ךלש אפורה תא שי לופיטל םא קודבל תנמ לע ךבצמ טקפאה

העפשהה יוצרה

ל םורגל הלולע הרמפ

וא תוקקדיה ( ךייתומצע לש לודלד סיזורופואטסוא

)

.ךפוגב ןגורטסאב הדירי בקע

אפורה יושע ךלש םג טילחהל

ל

דודמ תא תואירב

תופיפצ ךלש םצעה

)

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פל

נ

י

,

וא ךלהמב .לופיטה רחאל

הלולע וז הפורתו תויה וא תוקקדיה םורגל לש לודלד ( ךייתומצע סיזורופואטסוא

.)

4

יאוול תועפות .

.....

םא אפורל דימ תונפל שי

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ךרואל תוימומדאו תוחיפנ ךל שי שיגר וניהש דירו

באוכ ףא ןכתיו ה לש תקלדל םינמיס( עגמל

דירו םד שירק תורצוויהב הרושקה

[thrombophlebitis

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דואמ תוחיכש יאוול תועפות תולולע( מ רתוי לע עיפשהל

לכמ

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ףיעסב יאר(

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