Simponi 50 mg solution for injection, pre filled syringe

New Patient Reminder Card 

Expression of the shelf-life has been amended from 24 months to 2 years. There is no actual change to the shelf-life. Some minor grammatical changes have been made throughout the SPC.

Update to section 4.6 of the SPC as a result of updated information on pregnancy. Editorial change to section 5.2. 

Section 5.1 is updated to add the results of the final report from the Go-Back Study (MK-8259-038).

SPC document format updated to html

Update to the ADR table of section 4.8 (SOC Neoplasms) of the SmPC with Kaposi’s Sarcoma

The following side effect has been added in the section 4.8, under skin and subcutaneous disorders:  ‘Worsening of symptoms of dermatomyositis’ (frequency not known).

Minor formatting updates

Change to section 4 - possible side effects (dermatomyositis)

Change to section 6 - date of revision

Reuploaded PIL due to technical error

Editorial and typo correction in Spanish language.

Editorial and typo correction in Finish language.

SPC change details: shelf life extension and introduction of room temperature storage option

Change to section 4.8 – addition of “Lichenoid reactions” to Rare side effects under “Skin and subcutaneous tissue disorders”

Broadening of the pJIA indication in the EU; added information on “Traceability” and “Excipients”; changed reference “Simponi” to “golimumab”; change to excipients naming convention; adverse drug reaction changed to adverse reaction

Change to section 4.2  & 4.4 – update the name of the Patient Reminder Card, previously called Patient Alert Card

update the information on maintenance regimen for patients with ulcerative colitis weighing <80 kg based on analyses of PK, efficacy and safety from the pivotal C0524T18 study
 

SPC change details:   Sections 4.8 and section 5.1 have been updated with the results from the extension study in UC and nr Axial SpA.  PLEASE NOTE: The SPC for 50mg pre-filled pen and for 50mg pre-filled syringe have been joined with this variation update. Therefore, the number of sections now reflect the information for both 50mg presentations(pen and syringe). However, there are no changes to the text itself in any of the sections which are joint (sections 1, 2, 3, 4.4, 6.4, 6.5, 6.6 and 8).

Sections that have changed:  Change to Section 4.4 - Special warnings and precautions for use, Change to Section 4.8 - Undesirable and Change to Section 10 - Date of revision of the text

SPC change details:   The SPC has been revised to:  a) Clarify that infections may present as disseminated rather than localized disease;  b)  Emphasize the risks of invasive fungal infections;  c) Clarify that leukemia has been observed in clinical trials in addition to the post-marketing setting;  d) Clarify that cases of congestive heart failure (CHF) with fatal outcomes have been observed.

Sections that have changed:     Change to Section 4.1 - Therapeutic indications, Change to Section 4.2 - Posology and method of administration, Change to Section 4.4 - Special warnings and precautions for use, Change to Section 4.8 - Undesirable effects, Change to Section 5.1 - Pharmacodynamic properties, Change to Section 5.2 - Pharmacokinetic properties, Change to Section 10 - Date of revision of the text

Sections that have changed:  change to Section 6.3 - Shelf life, Change to Section 10 - Date of revision of the text, Change to separate SPCs covering individual presentations

SPC change details:   Shelf-life changed from 1 year to 18 months and text revision date from January 2015 to May 2015

Sections 9 & 10 
 Reasons for submission: Approval of PSUV/058 IFU-Indicator

Approval of Type II variation to register bullous skin reactions as an uncommon adverse reaction 

The changes made to the SmPC are as follows:

Section 4.2 Posology and method of administration

‘for all of the above indications’ now precedes the 2 paragraphs on clinical response under RA, PsA and AS.

Section 4.8 Undesirable effects

‘within each frequency grouping, adverse reactions are presented in order of decreasing seriousness’ has been added before the table of ADRs.

 
Amendment of the AE reporting details to HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

Section 5.1 Pharmacodynamic properties

‘HAQ’ has been replaced with ‘HAQ DI’

Section 6.5 Nature and content of container

1.0ml has been deleted from the description of type I glass: (1.0ml Type I glass)

Other changes have been applied throughout:

·        ‘ml’ now reads ‘mL’

·        ‘medications’ have been replaced with ‘medicines’

·        ‘Older people’ has been replace with ‘Elderly’

Wording added in section 4.1 Therapeutic Indication:

Patients with bodyweight greater than 100 kg

In patients with RA, PsA or AS with a body weight of weighing more than 100 kg who do not achieve an adequate clinical response after 3 or 4 doses…………

Ulcerative colitis (UC)

Simponi is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6‑mercaptopurine (6‑MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Wording added in section 4.2 Posology and method of administration:

Ulcerative colitis

Patients with body weight less than 80 kg

Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 50 mg every 4 weeks, thereafter (see section 5.1).

Patients with body weight greater than or equal to 80 kg

Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4 weeks, thereafter (see section 5.1).

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.

Available data suggest that clinical response is usually achieved within 12‑14 weeks of treatment (after 4 doses). Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Method of administration paragraph includes the sentence: If multiple injections are required, the injections should be administered at different sites on the body.

Wording added in section 4.4 Special warnings and precautions for use:

Lymphoma and leukaemia

………..

Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with other TNF-blocking agents (see section 4.8). This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. The majority of cases have occurred in adolescent and young adult males with nearly all on concomitant treatment with azathioprine (AZA) or 6‑mercaptopurine (6–MP) for inflammatory bowel disease. The potential risk with the combination of AZA or 6‑MP and Simponi should be carefully considered. A risk for the development for hepatosplenic T‑cell lymphoma in patients treated with TNF-blockers cannot be excluded.

Malignancies other than lymphoma

In the controlled portions of the Simponi Phase IIb and Phase III clinical trials in RA, PsA, AS, and UC,

Colon dysplasia/carcinoma

It is not known if golimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. In patients with newly diagnosed dysplasia treated with Simponi, the risks and benefits to the individual patient must be carefully reviewed and consideration should be given to whether therapy should be continued.

Potential for Medication errors

Simponi is registered in 50 mg and 100 mg strengths for subcutaneous administration. It is important that the right strength is used to administer the correct dose as indicated in the posology (see section 4.2). Care should be taken to provide the right strength to ensure that patients are not underdosed or overdosed.

Wording added in section 4.8 Undesirable effects:

There have been many changes in the frequencies of ADRs:

Added:

‘Not known’ frequency – hepatosplenic T-cell lymphoma

Within the description of adverse drug reactions the UC trial data has been added making extensive changes to the number of golimumab treated patients, the number of control patients, the incidence per 100 subject years. Additional information has been added to the following ADRs:

Infections

In the controlled period of UC trials of golimumab induction, serious infections were observed in 0.8% of golimumab-treated patients compared with 1.5% of control-treated patients.

Malignancies

Malignancies other than lymphoma

Through approximately 2 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general population.

Liver enzyme elevations

In the controlled period of the UC pivotal trials of golimumab induction , mild ALT elevations (> 1 and < 3 x ULN) occurred in similar proportions of golimumab-treated and control patients (8.0% to 6.9%, respectively). In controlled and uncontrolled periods of the UC pivotal trials with a mean follow-up of 1 year, the incidence of mild ALT elevations was 17.4% in patients receiving golimumab during the maintenance portion of the UC study.

……..

In the controlled periods of the pivotal UC trials, of golimumab induction, ALT elevations ≥ 5 x ULN occurred in similar proportions of golimumab-treated patients compared to placebo-treated patients (0.3% to 1.0%, respectively). In the controlled and uncontrolled periods of the pivotal UC trials with a mean follow-up of 1 year, the incidence of ALT elevations ≥ 5 x ULN was 0.7% in patients receiving golimumab during the maintenance portion of the UC study.

Wording added in section 5.1 Pharmacodynamic properties:

‘Immunosuppressants’ has been added to the Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNF‑α) inhibitors, ATC code: L04AB06

Ulcerative colitis

The efficacy of Simponi was evaluated in two randomized, double-blind, placebo-controlled clinical studies in adult patients.

The induction study (PURSUIT-Induction) evaluated patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) who had an inadequate response to or failed to tolerate conventional therapies, or were corticosteroid dependent. In the dose confirming portion of the study, 761 patients were randomized to receive either 400 mg Simponi SC at Week 0 and 200 mg at Week 2, 200 mg Simponi SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. The efficacy of Simponi through week 6 was assessed in this study.

The results of the maintenance study (PURSUIT-Maintenance) were based on evaluation of 456 patients who achieved clinical response from previous induction with Simponi. Patients were randomized to receive Simponi 50 mg, Simponi 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates, and/or immunomodulatory agents were permitted. Corticosteroids were to be tapered at the start of the maintenance study. The efficacy of Simponi through week 54 was assessed in this study.

Table 6

Key efficacy outcomes from PURSUIT - Induction and PURSUIT - Maintenance

More Simponi-treated patients demonstrated sustained mucosal healing (patients with mucosal healing at both Week 30 and Week 54) in the 50 mg group (42%, nominal p < 0.05) and 100 mg group (42%, p < 0.005) compared with patients in the placebo group (27%).

Among the 54% of patients (247/456) who were receiving concomitant corticosteroids at the start of PURSUIT-Maintenance, the proportion of patients who maintained clinical response through Week 54 and were not receiving concomitant corticosteroids at Week 54 was greater in the 50 mg group (38%, 30/78) and 100 mg group (30%, 25/82) compared with the placebo group (21%, 18/87). The proportion of patients who eliminated corticosteroids by Week 54 was greater in the 50 mg group (41%, 32/78) and 100 mg group (33%, 27/82) compared with the placebo group (22%, 19/87).

At Week 6, Simponi significantly improved quality of life as measured by change from baseline in a disease specific measure, IBDQ (inflammatory bowel disease questionnaire). Among patients who received Simponi maintenance treatment, the improvement in quality of life as measured by IBDQ was maintained through week 54.

Wording added in section 5.2 Pharmacokinetic properties:

Elimination

………..

Following induction doses of 200 mg and 100 mg golimumab at week 0 and 2, respectively, and maintenance doses of 50 mg or 100 mg golimumab subcutaneously every 4 weeks thereafter to patients with UC, serum golimumab concentrations reached steady state approximately 14 weeks after the start of therapy. Treatment with 50 mg or 100 mg golimumab subcutaneous every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 0.9 ± 0.5 mg/ml and 1.8 ± 1.1 mg/ml, respectively.

In UC patients treated with 50 mg or 100 mg golimumab subcutaneously every 4 weeks, concomitant use of immunomodulators did not have a substantial effect on steady-state trough levels of golimumab.

Linearity

………. Following a single SC dose in healthy subjects, approximately dose-proportional pharmacokinetics were also observed over a dose range of 50 mg to 400 mg.

Wording added in section 6.6 Special precautions for disposal and other handling:

Simponi should not be used if the solution is discoloured, cloudy or containing visible foreign particles. (this sentence has been deleted from section 6.5 and added to section 6.6)

Section 4.2 and 4.4

‘Elderly patients’ has been replaced with ‘older people’.

Section 4.8:

‘Interstitial lung disease’ has been moved from Rare in the tabulated list of ADRs to Uncommon within SOC, thoracic and mediastinal disorders.

In line with the updated QRD template and Appendix V the following text will be added for reporting of suspected adverse reactions:

Wording added in section 4.4:

Vaccinations/therapeutic infectious agents

Patients treated with Simponi may receive concurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6). In patients receiving anti-TNF therapy, No limited data are available on the response to vaccination with live vaccines, risk of infection or on the secondary transmission of infection by with the administration of live vaccines to patients receiving Simponi. Use of live vaccines could result in clinical infections, including disseminated infections.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Simponi.

Wording added in section 4.5:

Live vaccines/therapeutic infectious agents

Live vaccines should not be given concurrently with Simponi (see sections 4.4 and 4.6).

Addition of text on TB risks/prophylaxis in section 4.4 :

“Cases of active tuberculosis have occurred in patients treated with Simponi during and after treatment for latent tuberculosis. Patients receiving Simponi should be monitored closely for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection.”

The changes made to the SmPC are as follows:

·       Warnings on concomitant use with other biologicals
Data based on a summary of published information from studies where anti-TNF treatment has been combined with another biological DMARD has resulted in updates to sections 4.4 and 4.5 of the SmPC in order to add a warning and updated information regarding concomitant use of golimumab/infliximab with other biological therapeutics.

·        MCC and melanoma safety warning
Following assessment melanoma is considered a drug class effect based on postmarketing data and the reporting rate associated with these data across TNF inhibitors, including infliximab and golimumab. The frequency category  is “rare” for of melanoma and "not known" for Merkel cell carcinoma, this has resulted in updates to sections 4.4 and 4.8 of the SmPC to add a warning and safety information regarding cases of melanoma and MCC. In addition, Section 4.4, subsection Malignancies, of the SmPC has been updated to advise that periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

The following changes to the SmPC were adopted:

•  Addition of Rare side effect 'skin exfoliation' to section 4.8 Undesirable effects, under Skin and subcutaneous tissue disorders.

The changes to the product information (PI) include:

• Inclusion of Nausea to section 4.8 of the SmPC and section 4 of the PIL.
• Updates to the SmPC and PIL in line with QRD 8.0 for all other affected sections – PI Standard layout and terminology.

Scope
Section 4.8 of the SmPC is updated to include new clinical trial safety information for infections, malignancies, neurological events and liver enzyme elevations.

Indication extension: PsA structural damage
Scope: Extension of the indication to include psoriatic arthritis (PsA) structural damage. Section 4.1 has been updated to add the reduction in the rate of progression of peripheral joint damage in (PsA). Section 5.1 is updated regarding maintenance of the effects in signs and symptoms and physical function in PsA patients.
Background: wording has been added to the PsA indication to reflect data on structural joint damage measured by X-ray. Changes to section 5.1 are based on newly submitted X-ray data from the long-term extension of study C0524T08. This study was the basis for the initial approval of PsA.

Leukemia and sarcoidosis
Scope: Update of section 4.8 of the SmPC regarding the frequency of leukaemia and inclusion of sarcoidosis, the latter in response to a CHMP request.
Background: The changes are in line with earlier recommendations from CHMP for sarcoidosis; however the frequency category is rare instead of unknown as one case has been reported from a clinical study. Since a case of T-cell type acute leukemia has been reported from a clinical study, the SmPC has been updated to change the frequency of leukemia from “not known” to “rare”, and remove the asterisk noting that leukemia has not been observed in clinical studies with golimumab.

Safety update related to neurological event
Scope: A paragraph has been added to section 4.8, stating that a greater incidence of demyelination (Neurological events) was observed in the golimumab 100 mg group compared with the golimumab 50 mg group. A cross-reference to section 4.8 has been added in the Neurological events paragraph in section 4.4.
Background: This change was proposed further to an additional review of demyelination events conducted to evaluate the occurrence of demyelinating disorders in the 100 mg group relative to 50 mg group.

The Simponi SmPC has been updated to add information relating to transplacental transfer of golimumab to section 4.6. 

Section 4.6: Pregnancy now reads:

There are no adequate data on the use of golimumab in pregnant women. Due to its inhibition of TNF, golimumab administered during pregnancy could affect normal immune responses in the newborn. Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The use of golimumab in pregnant women is not recommended; golimumab should be given to a pregnant woman only if clearly needed.

Golimumab crosses the placenta. Following treatment with a TNF-blocking monoclonal antibody during pregnancy, the antibody has been detected for up to 6 months in the serum of the infant born by the treated woman. Consequently, these infants may be at increased risk of infection. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother’s last golimumab injection during pregnancy (see sections 4.4 and 4.5).

Section 4.4 and 4.6 of the SmPC have minor edits as a result of this change.

Section 4.8 of the SmPC has been updated to include vasculitis (systemic) as a rare side effect to Immune system disorders and vasculitis (cutaneous) as an uncommon side effect to Skin and subcutaneous tissue disorders.

These adverse drug reactions (ADR) were added to the SmPC following a request from the US Food and Drug Administration (FDA) to all manufacturers of TNFα blockers that vasculitis may be a potential safety issue associated with this class of drugs. The Marketing Authorisation Holder (MAH) reviewed the data on vasculitis to determine whether it should be added as an ADR for golimumab in the core reference labeling.

Also included in this revision is the change in the name of the MAH from Centocor B.V. to Janssen Biologics B.V.

Text has been added on the maintenance of treatment effect in patients with rheumatoid arthritis (RA), the revisions are based on data from the on going study in patients with inadequate response to DMARDS, data was provided up to week 104. For the 50 mg + MTX group it was determined that 54% (48/89) of subjects remained on the approved dose throughout the 2 years period. The ACR20/50/70 responses for these patients at week 104 have been added to section 5.1 of the SmPC, as well as information on maintenance of improvement in HAQ and SF-36 physical compontent.

The update of the information on immunogenicity data in section 5.1 was also supported appropriately by summarised data from all Phase 3 studies with golimumab in rheumatologic indications.