Flixabi 100 mg powder for concentrate for solution for infusion

Section 4 Possible side effects

Uncommon:

Weight gain (for most patients, the weight gain was small).

Section 6 Contents of the pack and other information

What Flixabi contains

The other ingredients are sucrose, polysorbate 80 (E 433), monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate.

Section 4.8 Undesirable effects

Investigations:

Uncommon: Autoantibody positive, weight increased¹

¹At month 12 of the controlled period for adult clinical trials across all indications, the median weight increase was 3.50 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects. The median weight increase for inflammatory bowel disease indications was 4.14 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects, and the median weight increase for rheumatology indications was 3.40 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects.

Section 6.1 List of excipients

Polysorbate 80 (E 433)

Change to date of revision

Pregnancy, Breast-feeding and Vaccinations

·       In case you have received Flixabi while you were pregnant or if you are breast-feeding, it is important that you inform your baby’s doctor about it before your baby receives any vaccine. Your baby should not receive a ‘live vaccine’, such as BCG (used to prevent tuberculosis) within 12 months after birth or while you are breast-feeding, unless your baby’s doctor recommends otherwise.

 Keep this card with you for 4 months after your last dose of Flixabi, or in case of pregnancy for 12 months after the birth of your baby. Side effects may occur a long time after your last dose.

Section 2 has been updated as follows:

Warnings and precautions

…….

Vaccinations

·         Talk to your doctor if you recently have had or are due to have a vaccine.

·         You should receive recommended vaccinations before starting Flixabi treatment. You may receive some vaccines during treatment with Flixabi but you should not receive live vaccines (vaccines that contain a living but weakened infectious agent) while using Flixabi because they may cause infections.

·         If you received Flixabi while you were pregnant, your baby may also be at higher risk for getting an infection as a result of receiving a live vaccine during the first year of life. It is important that you tell your baby's doctors and other health care professionals about your Flixabi use so they can decide when your baby should receive any vaccine, including live vaccines such as the BCG vaccine (used to prevent tuberculosis).

·         If you are breast-feeding, it is important that you tell your baby’s doctors and other healthcare professionals about your Flixabi use before your baby is given any vaccine. For more information see section on Pregnancy and breast feeding.

Pregnancy, breast-feeding and fertility

…….

·        It is important that you tell your baby’s doctors and other healthcare professionals about your Flixabi use before your baby is given any vaccine. If you received Flixabi while pregnant, giving BCG vaccine (used to prevent tuberculosis) to your baby within 12 months after birth may result in infection with serious complications, including death. Live vaccines such as the BCG vaccine should not be given to your baby within 12 months after birth, unless your baby’s doctor recommends otherwise. For more information see section on vaccination.

·        If you are breast-feeding, it is important that you tell your baby’s doctors and other healthcare professionals about your Flixabi use before your baby is given any vaccine. Live vaccines should not be given to your baby while you are breast-feeding unless your baby’s doctor recommends otherwise.

·        Severely decreased numbers of white blood cells have been reported in infants born to women treated with Flixabi during pregnancy. If your baby has continual fevers or infections, contact your baby’s doctor immediately.

Section 4.4. has been updated as follows:

In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus Calmette-Guérin (BCG) infection has been reported following administration of BCG vaccine after birth. A twelve month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab. If infant infliximab serum levels are undetectable or infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clear clinical benefit for the individual infant (see section 4.6).

Section 4.5 has been updated as follows:

…….

It is recommended that live vaccines not be given concurrently with infliximab. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for 12 months following birth. If infant infliximab serum levels are undetectable or infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clear clinical benefit for the individual infant (see section 4.4).

Section 4.6 has been updated as follows:

Pregnancy

…..

Infliximab crosses the placenta and has been detected in the serum of infants up to 12 months following birth. After in utero exposure to infliximab, infants may be at increased risk of infection, including serious disseminated infection that can become fatal. Administration of live vaccines (e.g. BCG vaccine) to infants exposed to infliximab in utero is not recommended for 12 months after birth (see sections 4.4 and 4.5). If infant infliximab serum levels are undetectable or infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clear clinical benefit for the individual infant. Cases of agranulocytosis have also been reported (see section 4.8).

Additional information regarding live vaccines and breast-feeding added.

The following changes were made to the package leaflet:

6.            Contents of the pack and other information

Manufacturer

FUJIFILM Diosynth Biotechnologies Denmark ApS

Biotek Allé 1,

Hillerød, 3400,

Denmark

Biogen Netherlands B.V.

Prins Mauritslaan 13,

1171 LP, Badhoevedorp

Netherlands

Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

The Netherlands

Section 2 has been updated with additional information on breast-feeding and section 4 has been updated with addition of dyslipidemia as undesirable effect with frequency “uncommon”.

Section 4.6 has been updated to add additional information on breastfeeding:

Limited data from published literature indicate infliximab has been detected at low levels in human milk at concentrations up to 5% of the maternal serum level. Infliximab has also been detected in infant serum after exposure to infliximab via breast milk. While systemic exposure in a breastfed infant is expected to be low because infliximab is largely degraded in the gastrointestinal tract, the administration of live vaccines to a breastfed infant when the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable. Infliximab could be considered for use during breast-feeding.

Section 4.8 has been updated with addition of dyslipidemia as undesirable effect with frequency “uncommon”

Minor editorial changes have been made to SPC.

Samsung Bioepis NL B.V. has been added as a manufacturer responsible for batch release site.

The following editorial  changes have been made to the Patient Reminder Card:

Flixabi 100 mg

Iinfliximab

Patient Reminder Card

......

Ask your doctor to record the type and date of last screening(s) for tuberculosis (TB) below:

Test:

Date:

Result:

.......

Before treatment with Flixabi

• Tell your doctor if you have an infection even if it is a very minor one.
• It is very important that you tell your doctor if you have ever had tuberculosis (TB), or if you have been in close contact with someone who has had TB. Your doctor will test you to see if you have TB. Ask your doctor to record the type and date of your last screening(s) for TB on the card.

Section 4.8: United Kingdom (Northern Ireland) details have been added to the reporting of suspected adverse reactions section in 4.8.

In section 6, local representative contact details for United Kingdom (Northern Ireland) have been added;  Biogen Netherlands BV has been added as a manufaturer, and name and address of Biogen Hillerod  has been changed to FUJIFILM .

‘Driving and using machines’ subsection of Section 2 has been updated from:

Flixabi is not likely to affect your ability to drive or use tools or machines. If you feel tired, dizzy, or unwell after having Flixabi, do not drive or use any tools or machines.

to:

Flixabi has minor influence on the ability to drive and use machines, e.g. dizziness, vertigo

Section 5, ‘How to store Flixabi’ section has been updated to include the following highlighted text:

……..

This medicine can also be stored in the original carton outside of refrigerated storage up to a maximum of 25 °C for a single period of up to six months, but not beyond the original expiry date. In this situation, do not return to refrigerated storage again. Write the new expiry date on the carton including day/month/year.

A number of editorial changes have been made throughout the SPC, including the following:

The highlighted text below has been added to 'Posology' sub section of section '4.2 Posology and method of administration':

'Rheumatoid arthritis

3 mg/kg given based on the body weight (bw) as an intravenous infusion followed by additional 3 mg/kg bw infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Flixabi must be given concomitantly with methotrexate.'

Section 4.4. ' Special warnings and precautions for use' has been updated to amend 'infusion reactions' to 'infused-related reactions'.

Also, 'Infections' subsection has been updated to include the following highlighted text:

'Patients must be monitored closely for infections including tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections before, during and after treatment with infliximab. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with infliximab must not be given if a patient develops a serious infection or sepsis.'
..............

Tuberculosis, mycobacterial infection, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients treated with infliximab.....'

Section 4 has been updated to include the following:

'Kaposi’s sarcoma, a rare cancer related to infection with human herpes virus 8. Kaposi’s sarcoma most commonly appears as purple lesions on the skin'

Section 4.8 has been updated to add Kaposi’s sarcoma as undesirable effect.

Section 5:

The following updates have been made:

It is recommended that when Flixabi is prepared for infusion, it is used as soon as possible (within 3 hours). However, if the solution is prepared in germ-free conditions, it can be stored in the refrigerator at 2°C to 8°C up to 34 days and for an additional 24 hours at 25°C after removal from refrigeration in a refrigerator at 2°C to 8°C for 24 hours.

Section 6 - ‘The following information is intended for healthcare professionals only:’

Section 3 – the following text has been added:

If stored refrigerated after reconstitution and dilution, the infusion solution must be allowed to equilibrate at room temperature to 25 °C for 3 hours prior to Step 4 (infusion). Storage beyond 24 hours at 2 °C to 8 °C applies to preparation of Flixabi in the infusion bag only.

Section 4- the following changes have been made:

Administer the infusion solution over a period of not less than the infusion time recommended. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less). Since no preservative is present, it is recommended that the administration of the solution for infusion is to be started as soon as possible and within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution/dilution has been taken place in controlled and validated aseptic conditions. When reconstitution and dilution are performed under aseptic conditions, Flixabi infusion solution can be used within 24 hours if stored at 2°C to 8°C. Do not store any unused portion of the infusion solution for reuse.

Section 6.3 has been updated as follows:

After reconstitution, and dilution:

Chemical and physical in use stability of the reconstituted diluted solution has been demonstrated for for  up to 34 days at 2°C to 8°C and for an additional  24 hours at 25°C after removal from refrigeration. From a microbiological point of view, the product  infusion solution should be administered immediately used as soon as possible but within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally should not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has been taken place in controlled and validated aseptic conditions.

Section 6.6 has been updated as follows:

The following text has been added to section 3:

If stored refrigerated after reconstitution and dilution, the infusion solution must be allowed to equilibrate at room temperature to 25 °C for 3 hours prior to Step 4 (infusion). Storage beyond 24 hours at 2 °C to 8 °C applies to preparation of Flixabi in the infusion bag only.

The following text has been amended in section 4:

Administer the infusion solution over a period of not less than the infusion time recommended (see section 4.2). Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less). Since no preservative is present, it is recommended that the administration of the solution for infusion is to be started as soon as possible and within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution/dilution has been taken place in controlled and validated When reconstitution and dilution are performed under aseptic conditions (see section 6.3 above). Flixabi infusion solution can be used within 24 hours if stored at 2 °C to 8 °C. Do not store any unused portion of the infusion solution for reuse.

Changes made are as follows:

- The Patient Alert Card has been renamed to Patient Reminder Card

- The following information on heart failure has been removed from the Flixabi Patient Reminder Card, in order to be aligned with the reference product:

Before treatment with Flixabi

• • Tell your doctor if you have any heart problems such as mild heart failure.

During treatment with Flixabi

• • Tell your doctor straight away if you notice signs of a heart problem. Signs include shortness of breath, swelling of the feet or changes in your heartbeat.

Possible side effects section has been updated as follows:

• Signs of a nervous system problem (including eye problems) such as signs of a stroke (sudden numbness or weakness of your face, arm or leg, especially on one side of your body; sudden confusion, trouble speaking or understanding; trouble seeing in one or both eyes, trouble walking, dizziness, loss of balance or coordination or a severe headache), fits, tingling/or numbness in any part of your body, or weakness in arms or legs, changes in eyesight such as double vision or other eye problems

Section 4.8 has been updated to add the following to the tabulated list of adverse reactions, with a frequency of unknown:

'Cerebrovascular accidents in close temporal association with infusion.'

Also, the following paragraph has been expanded as shown below:

'Events (some fatal) of myocardial ischaemia/infarction and arrhythmia have been reported, some in close temporal association with infusion of infliximab; cerebrovascular accidents have also been reported in close temporal association with infusion of infliximab.'

Section 4.4 ' Special warnings and precautions for use' has been updated as follows:

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.

Section 4.8

Acute generalised exanthematous pustulosis (AGEP) added as a rare skin and subcutaneous reaction.

Section 4.8:

Lichenoid reactions has been added to rare undesirable effects section.

Section 6.5 has been updated from:

...

Flixabi is available in packs containing 1 vial and multipacks containing 2, 3, 4, and 5 (2, 3, 4, and 5 packs of 1) vials. Not all pack sizes may be marketed.

to:

...

Flixabi is available in packs containing 1, 2, 3, 4, and 5 vial(s). Not all pack sizes may be marketed.

Section 4.2 has been updated to 'special alert card' to 'patient alert card'.

Section 4.4, sub section on Tuberculosis and Malignancies and lymphoproliferative disorders: wording on warning re colon cancer nd dysplasia has been updated. Also, the warning on screening test for tuberculosis was updated.

Section 4.8 has been updated as follows:

In section 7, the MA holder has been changed from:

​​

Samsung Bioepis UK Limited

5th floor

Profile West

950 Great West Road

Brentford

Middlesex TW8 9ES

United Kingdom

​​

to

​​

Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

The Netherlands

The sections of the SPC outlined above have been updated in line with the reference product PI update.

Section 6.3 has been updated as follows:

Before reconstitution:

36 months at 2°C – 8°C.

Flixabi may be stored at temperatures up to a maximum of 25°C for a single period of up to 6 months, but not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal from refrigerated storage, Flixabi must not be returned to refrigerated storage.

After reconstitution:

Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used as soon as possible but within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C.

Section 6.4 has been updated as follows:

Store in a refrigerator (2°C - 8°C).

For storage conditions up to 25°C before reconstitution of the medicinal product, see section 6.3.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

• Black inverted triangle is now in larger size font.
• In section 6.3, the shelf life has been changed from 24 to 30 months.