MabThera 1400 mg Solution for Subcutaneous Injection

Republished to correct the Renewal date

EU SPC and PIL EMEA/H/C/00165/II/169.
Submission of the primary CSR for study WA29330 (Pemphix) in fulfilment of the first part of post approval commitment (PAES) listed in the Annex IID of MabThera Product Information In addition QRD template was adjusted to the latest version QRD 10.1 resulting in several editorial changes.
 

EU SPC and PIL EMEA/H/C/00165/II/169.
Submission of the primary CSR for study WA29330 (Pemphix) in fulfilment of the first part of post approval commitment (PAES) listed in the Annex IID of MabThera Product Information In addition QRD template was adjusted to the latest version QRD 10.1 resulting in several editorial changes.
 

EMEA/H/C/000165/II/0157 - HA Request. Final CSR for SABRINA (1400 mg SC). Section 5.1 of the SmPC updated at CHMP request

Existing text in SmPC updated with 9 year follow-up data (final CSR) at request from Rapporteur.

Underlined text has been added, text with strike-through deleted:

7.         MARKETING AUTHORISATION HOLDER

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

10.       DATE OF REVISION OF THE TEXT

16 March 2018

Underlined text has been added, text with strike-through deleted:

4.1       Therapeutic indications

MabThera 1400 mg solution for subcutaneous injection is indicated in adults for Non-‑Hodgkin’s lymphoma (NHL):

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4.2       Posology and method of administration

[…]

It is important to check the medicinal product labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed.

MabThera subcutaneous formulation is not intended for intravenous administration and should be given via subcutaneous injection only. The 1400 mg strength is intended for subcutaneous use in non Hodgkin lymphoma (NHL) only.

[…]

Method of administration

Subcutaneous injections:

MabThera 1400 mg subcutaneous formulation should be administered as subcutaneous injection only, over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

[…]

4.4       Special warnings and precautions for use

In order to improve traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non Hodgkin lymphoma (strength 1400 mg) and Treatment of Chronic Lymphocytic Leukaemia (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation.

[…]

Severe infusion-‑related reactions with fatal outcome have been reported during post-‑marketing use of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera intravenous IV infusion. They were characterized by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

[…]

Administration related reactions have been observed in up to 50% of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient nature (see section 4.8).

[…]

4.5       Interaction with other medicinal products and other forms of interaction

Currently, there are limited data on possible drug interactions with MabThera.

Co-‑administration with MabThera did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of MabThera.

Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera in rheumatoid arthritis patients.

[…]

4.8       Undesirable effects

[…]

In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

[…]

5.1       Pharmacodynamic properties

[…]

The objective of the first stage was to establish the rituximab subcutaneous dose that resulted in comparable MabThera subcutaneous formulation serum C_trough levels compared with MabThera intravenous formulation, when given as part of induction treatment every 3 weeks (see section 5.2). The results of this stage are given below, for stage 2, an additional 280 patients will be enrolled.

Stage 1 enrolled previously untreated patients (n=127) CD20-‑positive, Follicular Lymphoma (FL) Grade 1, 2 or 3a.

[…]

6.3       Shelf life

Unopened vial

30 months

After first opening

Once transferred from the vial into the syringe, the solution of MabThera subcutaneous formulation is physically and chemically stable for 48 hours at 2 °C -‑ 8 °C and subsequently for 8 hours at 30°C in diffuse daylight.

[…]

6.6       Special precautions for disposal and other handling

MabThera is provided in sterile, preservative-‑free, non-‑pyrogenic, single use vials. A peel-‑‑off sticker is included on the vials which specifies the strength, route of administration and indication. This sticker should be removed from the vial and stuck onto the syringe prior to  use. The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:

[…]

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2 June 2008

10.       DATE OF REVISION OF THE TEXT

26 May 2016

The following sections have been updated to correct typo-graphical errors / improved electronic presentation:

Section 2.0, 4.6, 4.9, 5.2, 5.3, 6.1, 6.5

Underlined Text = New Text

Strike Through Text = Deleted Text

4.4     Special warnings and precautions for use

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Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials; reported in up to 50% of patients at some time during treatment.  Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera subcutaneous administration. The majority of local cutaneous reactions seen following administration of MabThera subcutaneous formulation was mild or moderate and resolved without any specific treatment.

[ … ]

4.8     Undesirable effects

The information provided in this section pertains to the use of MabThera in oncology.

For information related to the autoimmune indications, please refer to the SmPC of MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local injection sitecutaneous reactions. Local cutaneous reactions, including injection site reactions, were very common in patients receiving MabThera subcutaneous formulation in trials SparkThera (BP22333) and SABRINA (BO22334),.  In the phase 3 SABRINA trial (BO22334), local cutaneous reactions were reported in up to 250% of patients at some time during treatmentreceiving subcutaneous MabThera.  The most common local cutaneous reactions in the MabThera subcutaneous arm were injection site erythema (13%), injection site pain (7%), and injection site oedema (4%). Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritis and rash. All reactionsEvents seen following subcutaneous administration were mild or moderate, apart from one patient who experienced one episode of grade 3 injection site rash and one patient reported a grade 3 dry mouth.reported a local cutaneous reaction of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2).  Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections.

Adverse reactions reported in MabThera subcutaneous formulation usage

The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in two open-label trials involving patients with follicular lymphoma during induction and maintenance (SABRINA BO22334) and during maintenance only (SparkThera BP22333). In trial BO22334SABRINA, severe administration-related reactions (grade≥3) were reported in two patients  (2%) following administration of MabThera subcutaneous formulation (one patient reporting grade 3 injection site rash, and one patient reporting grade 3 dry mouth), both occurring after induction cycle 2 i.e. the first MabThera subcutaneous formulation dose given to each patient.  These events were Grade 3 injection site rash and dry mouth.

In trial BP22333SparkThera, no severe administration-related reactions were reported.

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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. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

IMB HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.iewww.hpra.ie

e-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mthttp://www.medicinesauthority.gov.mt/adrportal

e-mail: postlicensing.medicinesauthority@gov.mt

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9       Overdose

Limited experience with doses higher than the approved dose of intravenous MabThera formulation is available from clinical trials in humans. The highest intravenous dose of MabThera tested in humans to date is 5000 mg (2250 mg/m²), tested in a dose escalation study in patients with chronic lymphocytic leukaemia. No additional safety signals were identified.

Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.

One Three patients in the MabThera subcutaneous formulation trial SABRINA (BO22334) were, inadvertently received 2280 mgadministered subcutaneous formulation via through the intravenous route up to a maximum rituximab dose of 2780mg with no untoward effect.

Patients who experience overdose or medication error should be closely monitored.

In the post-marketing setting five cases of MabThera overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5.1     Pharmacodynamic properties

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Trial BO22334 (SABRINA)

A two-stage phase III, international, multi-centre, randomised, controlled, open-label trial was conducted in patients with previously untreated follicular lymphoma, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation in combination with CHOP or CVP versus MabThera intravenous formulation in combination with CHOP or CVP.

The objective of the first stage was to establish the rituximab subcutaneous dose that resulted in comparable MabThera subcutaneous formulation serum C_trough levels compared with MabThera intravenous formulation, when given as part of induction treatment every 3 weeks (see section 5.2). The results of this stage are given below, for stage 2, an additional 280 patients will be enrolled.

Stage 1 enrolled previously untreated patients (n=127) CD20-positive, Follicular Lymphoma (FL) Grade 1, 2 or 3a.

The objective of stage 2 was to provide additional efficacy and safety data for subcutaneous rituximab compared with rituximab IV using the 1400 mg subcutaneous dose established in stage 1.  Previously untreated patients with CD20-positive, Follicular Lymphoma Grade 1, 2 or 3a (n=283) were enrolled in the stage 2.

The overall trial design was identical among both stages and patients were randomized into the following two treatment groups:

In stage 1, previously untreated patients (n=127) suffering from CD20 positive, follicular lymphoma (FL) grade 1, 2 or 3a were randomized into the following two treatment groups:

·        MabThera subcutaneous formulation (n= 63205): first cycle MabThera intravenous formulation plus 7 cycles of MabThera subcutaneous formulation in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.

MabThera intravenous formulation was used at the standard dose of 375 mg/m² body surface area.

MabThera subcutaneous formulation was given at a fixed dose of 1400 mg.

Patients achieving at least partial response (PR) were entered on the MabThera subcutaneous formulation maintenance therapy once every 8 weeks for 24 months.

·          MabThera intravenous formulation (n= 20564): 8 cycles of MabThera intravenous formulation in

combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.

MabThera intravenous formulation was used at the standard dose of 375 mg/m².

Patients achieving at least PR were entered on MabThera intravenous formulation maintenance           therapy once every 8 weeks for 24 months.

At the end of the induction phase, 90.5% of patients in the MabThera subcutaneous arm achieved an overall response compared with 84.4%, of patients in the MabThera intravenous arm. The proportion of patients with a complete response (complete response and unconfirmed complete response) was 46.0% in the MabThera subcutaneous arm and 29.7% in the MabThera intravenous arm. In the pooled analysis of 410 patients the overall response rate point estimates were 84.4% (95% CI: 78.7; 89.1) and 83.4% (95% CI: 77.6; 88.2) in the MabThera IV and subcutaneous arms, respectively.  Complete response rate point estimates were 31.7% (95% CI: 25.4; 38.6) and 32.7% (95% CI: 26.3; 39.6) in the MabThera IV and subcutaneous arms, respectively.  Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were not notably different from the ITT population.

The overall response rate point estimates for the pooled analysis of 410 patients in SABRINA stages 1 and 2 are shown in table 2.

Table 1       SABRINA (BO22334) Response Rate Point Estimates (Intent to Treat Population)

ORR – Overall Response Rate

CRR – Complete Response Rate

Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were not notably different from the ITT population.

Immunogenicity

Data from the development programme of MabThera subcutaneous formulation indicate that the formation of anti-rituximab antibodies (HACAs) after subcutaneous administration is comparable with that observed after intravenous administration. Throughout Stage 1 of trial BO22334, anti-rituximab antibodies were observed in 1/57 (2%) and 1/57 (2%) of patients in the intravenous and subcutaneous cohorts, respectively, among patients who were antibody-negative at baseline. Anti-rHuPH20 (Recombinant human hyaluronidase) antibodies were observed in 2/57 (4%) and 2/53 (4%) of patients in the intravenous and subcutaneous cohorts, respectively, among patients who were antibody-negative at baseline. In the SABRINA trial (BO22334) the incidence of treatment-induced/enhanced anti-rituximab antibodies in the subcutaneous group was low and similar to that observed in the IV group (2% vs. 1%, respectively).  The incidence of treatment-induced/enhanced anti-rHuPH20 antibodies was 6% in the IV group compared with 9% in the subcutaneous group, and none of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.  There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy.

The overall proportion of patients found to have anti-rHuPH20 antibodies remained generally constant over the follow-up period in both cohorts. There was no apparent relationship between HACAs or anti-rHuPH20 antibodies and adverse events. The clinical relevance of the development of HACAs or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not known.

There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy [SABRINA].

Clinical experience of MabThera concentrate for solution for infusion in Non-Hodgkin’s lymphoma

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Results from three other randomized trials using MabThera in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key results from all four trials are summarized in table 23.

Table 23     Summary of key results from four phase III randomized trials evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma

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After a median observation time of 25 months from randomization, maintenance therapy with MabThera resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to oberservation in patients with previously untreated follicular lymphoma (Table 43).

Significant benefit from maintenance treatment with MabThera was also seen for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy (TNCT) and overall response rate (ORR) (Table 43). The results of the primary analysis were confirmed with longer follow-up (median observation time: 48 months) and have been added to Table 3 4 to show the comparison between the 25 and 48 month follow-up periods.

Table 34     Maintenance phase: overview of efficacy results MabThera vs. observation after 48 months median observation time (compared with results of primary analysis based on 25 months median observation time)

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The final efficacy analysis included all patients randomized to both parts of the trial. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 45).

Table 45     Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)

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Table 56     Maintenance phase: overview of efficacy results MabThera vs. observation (28 months median observation time)

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The benefit of MabThera maintenance treatment was confirmed in all subgroups analysed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (table 56). MabThera maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Although subgroups were small, MabThera maintenance treatment provided a significant benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

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5.2     Pharmacokinetic properties

Absorption

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Trial BP22333 (SparkThera)

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The comparison of predicted median C_max data for MabThera subcutaneous formulation and intravenous formulation are summarized in Table 67. 

Table 67:  Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of MabThera SC compared to MabThera IV

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Distribution/Elimination

Geometric mean C_trough and geometric mean AUCτ from the BPP22333 and BO22334 trials are summarized in Table 78.

Table 78: Distribution/Elimination - Pharmacokinetic parameters of MabThera subcutaneous compared to MabThera intravenous

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9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2 June 2008

10.     DATE OF REVISION OF THE TEXT

22 January 2015

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 June 1998

Date of latest renewal: 2008

10.     DATE OF REVISION OF THE TEXT

21 March 201423 May 2014