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Safety in lactation: Drugs for chronic bowel disorders

21 September 2020Additional information relating to breastfeeding To be used in conjunction with individual drug entries for specific information and guidance. Aminosalicylates for chronic bowel disorders Mesalazine…

In use product safety assessment report for infliximab biosimilars

24 August 2020The availability of seven infliximab preparations (the intravenous originator, four intravenous biosimilars and two subcutaneous products) in the UK market creates a potential for confusion…

Safety in Lactation: Systemic preparations for eczema and psoriasis

7 January 2019Drugs used orally or parenterally for severe eczema and psoriasis have a varied pharmacology, mainly either modifying the immune response to the disease or modifying…
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Refrigerated Storage

RemicadeMerck Sharp & Dohme Limited

Merck Sharp & Dohme Limited
Remicade
Powder for concentrate for solution for infusion, 100mg

Remicade 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, Remicade must not be returned to refrigerated storage.

See above
No
15 May 2020
London MI Service

RemsimaNapp Pharmaceuticals

Napp Pharmaceuticals
Remsima
100 mg powder for concentrate for solution for infusion

In the event of an inadvertent temperature excursion the following data may be used:
The vials may also be stored at ambient 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, Remsima must not be returned to refrigerated storage.

In-house stability data from the manufacturers have shown that the unopened vials may be kept up to 40°C ± 2°C for 3 months. Remsima must not be returned to refrigerated storage.

In-house stability data from the manufacturers have shown that the unopened vials may be kept up to -25°C ± 5°C for 30 days.

Following exposure to cycling stability condition of -20°C ±5°C to 40°C±2°C for a total period of 12 days in-house stability from the manufacturer have shown that unopened vials can be kept up to 36 months. In this case, the product can be returned to the fridge.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

Yes- Reduce to 6 months from the date of exposure to temperatures of up to 25°C. Reduce to 3 months from the date of exposure if stored above 25°C. Reduce to 30 days from the date of exposure if stored below 2°C.
Yes - See the information above.
15 May 2020
London MI Service

InflectraPfizer

Pfizer
Inflectra
100 mg powder for concentrate for solution for infusion

In the event of an inadvertent temperature excursion the following data may be used:
Inflectra 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, Inflectra must not be returned to refrigerated storage.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

Reduce to 6 months from the day of exposure.
No

Please contact Pfizer for products exposed to conditions other than described above. Refer to the current BNF for company contact details.

7 July 2020
London MI Service

FlixabiBiogen Biosimilars

Biogen Biosimilars
Flixabi
100 mg powder for concentrate for solution for infusion

In the event of an inadvertent temperature excursion the following data may be used:
Flixabi is stable for a single period of 6 months when exposed to temperatures of up to 25°C. Flixabi must not be returned to refrigerated storage and the new expiry date must be written on the carton.
Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

Contact Biogen directly for any additional information in all cases where a deviation from the recommended storage conditions has occurred. Refer to the current BNF for company contact details.

6 Months
No
19 March 2021
London MI service

Lactation Safety Information

For rheumatoid arthritis

For rheumatoid arthritis
See summary
Moderate amount of published evidence of safety indicates negligible amounts in breast milk which are likely to be degraded in the infant’s GI tract
Very long half-life increases risk of accumulation in breastfed infants
Although large protein molecules may appear in colostrum, risk to preterm infants and neonates is considered to be small and unproven
15 September 2019

For psoriasis

For psoriasis
Topical psoriasis preparation / corticosteroid if appropriate
Moderate amount of published evidence of safety indicates negligible amounts in breast milk which are likely to be degraded in the infant’s GI tract
Very long half-life increases risk of accumulation in breastfed infants
Although large protein molecules may appear in colostrum, risk to preterm infants and neonates is considered to be small and unproven
16 September 2019

For inflammatory bowel disease

For inflammatory bowel disease
See summary
Moderate amount of published evidence of safety indicates negligible amounts in breast milk which are likely to be degraded in the infant’s GI tract
Very long half-life increases risk of accumulation in breastfed infants
Although large protein molecules may appear in colostrum, risk to preterm infants and neonates is considered to be small and unproven
15 September 2019

New Medicines

RemsimaRheumatoid arthritis (RA), inflammatory bowel disease and more - subcutaneous formulation

Information

Remsima
Biosimilar - new route of administration, strength and pharmaceutical form
Celltrion
Celltrion

Development and Regulatory status

Launched
Launched
Phase III Clinical Trials
March 2020
Apr 21Celltrion Healthcare announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended Remsima SC for direct use of subcutaneous therapy without IV loading in patients with rheumatoid arthritis (RA). As a result of the CHMP opinion, if agreed by European Commission (EC), Remsima SC 120 mg can be used without IV infusion both for new and existing RA patients [16].
Jun 20Additional indications for the subcutaneous formulation recommended for EU approval by CHMP - these have been extended to include all those of the IV formulation to include treatment of adult patients with Crohn´ s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis [15].
Mar 20Celltrion announces launch of subcutaneous Remsima, indicated for treatment of patients with RA [13].
Mar 20Price for 2 x 120mg prefilled syringes or pens = £755.32 [14].
Nov 19Approved in EU for RA [12].
Oct 19Celltrion filed data to the EMA to support subcutaneous administration of Remsima in all current licensed indications for Remsima. The CHMP asked for more data on use in patients with IBD and this has delayed their recommendation on use in IBD. A decision is expected by end of July 2020 [10].
Sep 19CHMP recommends approval of a new route of administration, strength and pharmaceutical form: Remsima 120 mg solution for injection for subcutaneous use in prefilled pens or syringes. This pharmaceutical form will be available in addition to the existing one: 100 mg, powder for concentrate for solution for infusion. Remsima for subcutaneous use is authorised only in the rheumatoid arthritis indication. The indication will be use in combination with methotrexate, for reduction of signs and symptoms as well as the improvement in physical function in adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate, and in adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs [9].
Dec 18Preregistration for Rheumatoid arthritis in European Union (SC) [6].
Sep 18Celltrion plans to submit its application for Remsima SC to the EMA in the second half of 2018 [1].

Category

TNF inhibitor
Around 1.5 men and 3.6 women per 10,000 people develop RA each year [2].
Rheumatoid arthritis (RA), inflammatory bowel disease and more - subcutaneous formulation
Subcutaneous injection

Trial or other data

Oct 19Data presented by Celltrion at the UEG Week in Barcelona from a multicentre, open-label, randomised Phase 1, pivotal study showed that the SC formulation of CT-P13 (biosimilar infliximab) was non-inferior to IV formulation of CT-P13 in terms of pharmacokinetics in inflammatory bowel disease patients at week 22 CT-P13 SC also showed comparable efficacy and safety to CT-P13 IV for patients with Crohn’s disease (CD) and ulcerative colitis (UC) up to week 30. In the study, 136 patients were enrolled and 131 were randomised (66 to CT-P13 SC and 65 to CT-P13 IV). After loading doses of IV 5mg/kg at weeks 0 and 2, patients were randomised at week 6 to receive either CT-P13 SC 120mg (<80kg) or 240mg (≥80kg) every 2 weeks in the CT-P13 SC arm, or CT-P13 IV 5mg/kg every 8 weeks in the CT-P13 IV arm. The Phase 1 pivotal study demonstrated that CT-P13 SC showed non-inferiority in PK to CT-P13 IV as determined by the trough concentration, pre-dose level (Ctrough) at week 22. In terms of efficacy, both clinical response and remission in patients were induced and maintained, and the overall efficacy results of CT-P13 SC were comparable. The combined clinical remission rates for CD and UC patients at week 30 were comparable between CT-P13 IV and CT-P13 SC (66.7%, 44 out of 66 patients in CT-P13 SC arm and 54.7%, 35 out of 64 patients in CT-P13 IV, p=0.1620). The safety profile of CT-P13 SC was comparable to CT-P13 IV. In addition, fewer patients were found to have positive anti-drug-antibodies with CT-P13 SC compared to CT-P13 IV [11].
Aug 19A study investigating pharmacokinetics, efficacy and safety of CT-P13 SC in patients with rheumatoid arthritis (RA) over a one-year treatment period was presented at EULAR June 2019. This enrolled 50 patients, of whom 48 were randomly assigned at Week 6 into 4 cohorts (1:1:1:1 ratio). The mean Ctrough (pre-dose serum concentration of CT-P13 before next dose injection) of SC cohorts throughout the study visits were higher than those of the intravenous (IV) cohort after randomization at Week 6. Ctrough levels increased with SC dose and were sufficiently higher than the target therapeutic concentration (1 μg/mL) throughout the study period. Overall, the efficacy results of CT-P13 SC up to Week 54 were comparable to those of CT-P13 IV. Disease improvement by Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP) and American College of Rheumatology 20% response criteria (ACR20) were comparable across all four cohorts. Safety profiles at Week 6 in SC cohorts were generally comparable to those of IV cohort and appeared similar to those previously reported for IV infliximab. All injection site reactions were grade 1 or 2. No malignancy or death was reported.[7] This appears to be EUDRA-CT no 2016-002125-11 [8].
Jun 19In PIII trial comparing IV and SC infliximab (n= 348), data at 54 weeks showed that the subcutaneous (SC) formulation of CT-P13 bi-weekly was comparable in terms of the efficacy and safety when investigated against eight-weekly IV form of CT-P13 in rheumatoid arthritis (RA) [5].
Apr 19Results of PIII RCT (NCT02096861; n=308) are published; the study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn´s disease (proportion of patients with decrease of ≥70 points in Crohn´s Disease Activity Index from baseline to week 6 in CT-P13 group=69.4% vs 74.3% infliximab; difference −4.9%) [4].
Oct 18PIII efficacy trial found subcutaneous administration of infliximab biosimilar (CT‑P13) was comparable in terms of efficacy and safety with IV administration of CT‑P13 (Remsima/Inflectra) up to Week 30 in patients with active Crohn’s disease (CD) [3].
Aug 18PIII trials completed [1].

Evidence based evaluations