MABTHERA 1600 MG SOLUTION FOR SUBCUTANEOUS INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

MabThera 1600 mg solution for subcutaneous injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL contains 120 mg of rituximab.

Each vial contains 1600 mg/ 13.4 mL rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear to opalescent, colourless to yellowish liquid with pH of 5.2 – 5.8 and osmolality of 300 – 400 mOsmol/kg.

4.1

Therapeutic indications

MabThera is indicated in adults in combination with chemotherapy for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL). Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy.

See section 5.1 for further information.

4.2 Posology and method of administration

MabThera should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available (see section 4.4).

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of MabThera.

Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy-.

Posology

The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1600 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered.

Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

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 1600 mg strength is intended for subcutaneous use in CLL only.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 × 109/L it is recommended to administer prednisone/pred­nisolone 100 mg intravenous shortly before administration with MabThera to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of MabThera in combination with chemotherapy for previously untreated and relapsed/refractory patients is: MabThera intravenous formulation 375 mg/m2 body surface area administered on day 0 of the first cycle of treatment followed by MabThera subcutaneous formulation injected at a fixed dose of 1600 mg per cycle, on day 1 of each subsequent cycle (in total: 6 cycles).

The chemotherapy should be given after MabThera administration.

Dose adjustments during treatment

No dose reductions of MabThera are recommended. When MabThera is given in combination with

chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be

applied (see section 4.8).

Special populations

Paediatric population

The safety and efficacy of MabThera in children below 18 years has not been established. No data are available.

Elderly

No dose adjustment is required in elderly patients (aged >65 years).

Method of administration

Subcutaneous injections

MabThera 1600 mg subcutaneous formulation should be administered as subcutaneous injection only, over approximately 7 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars.

No data are available on performing the injection in other sites of the body, therefore injections should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous administration should preferably be given at different sites.

If an injection is interrupted it can be resumed at the same site or another location may be used, if appropriate.

Intravenous infusion administration

The Summary of Product Characteristics (SmPC) of MabThera 100 mg and 500 mg concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

4.3 Contraindications

Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

4.4 Special warnings and precautions for use

Treacibility

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

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of nonHodgkin’s lym­phoma (strength 1400 mg) and Treatment of CLL (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation.

Progressive multifocal leukoencephalopathy

Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of MabThera must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of MabThera therapy may lead to similar stabilisation or improved outcome.

Infusion/Admi­nistration-related reactions

MabThera is associated with infusion/admi­nistration-related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the route of administration of MabThera and can be observed with both formulations.

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 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).

Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (>25 × 109/L) of circulating malignant cells, such as patients with CLL who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 × 109/L.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of MabThera. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.

Since hypotension may occur during MabThera administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to giving MabThera.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with MabThera intravenous formulation (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

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).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials. 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.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk of experiencing an administration related reaction is generally observed at cycle one. Beginning the therapy with MabThera intravenous infusion would allow a better handling of the administration reactions by slowing or stopping the intravenous infusion.

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced healthcare professional. Premedication consisting of an analgesic/anti­pyretic and an antihistamine should always be administered before each dose of MabThera subcutaneous formulation. Premedication with glucocorticoids should also be considered.

Patients should be observed for at least 15 minutes following MabThera subcutaneous administration. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions.

Patients should be instructed to contact their treating physician immediately if symptoms that are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 × 109/L and/or platelet counts < 75 × 109/L as clinical experience in this population is limited. The MabThera intravenous formulation has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during MabThera therapy.

Infections

Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in patients receiving the MabThera intravenous formulation including fulminant hepatitis with fatal outcome. The majority of these patients were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with MabThera. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Very rare cases of PML have been reported during post-marketing use of the MabThera intravenous formulation in CLL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

Immunisation

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-live vaccinations; however, with non-live vaccines response rates may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received the MabThera intravenous formulation as monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 69% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases, but this has not been investigated in clinical trials.

Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella and varicella) were maintained for at least 6 months after treatment with MabThera.

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens – Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event, with suspected relationship to MabThera, treatment should be permanently discontinued.

4.5 Interaction with other medicinal products and other forms of interaction

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

In CLL patients, 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.

Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential must employ effective contraceptive methods during and for 12 months after treatment with MabThera.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. There are no adequate and well controlled data from studies in pregnant women, however transient B cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3).For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast feeding

Limited data on rituximab excretion into breast milk suggest very low milk levels (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 1.5 years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breastfeeding is not recommended while being treated with rituximab and optimally for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab or recombinant human hyaluronidase (rHuPH20) on reproductive organs.

4.7 Effects on ability to drive and use machines

No studies on the effects of MabThera on the ability to drive and use machines have been performed, although the pharmacological activity and adverse reactions reported to date suggest that MabThera would have no or negligible influence on the ability to drive and use machines.

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 cutaneous reactions.

Local cutaneous reactions including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the NHL phase 3 trial SABRINA (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving 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%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who 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. Similar events were observed in the CLL SAWYER trial (BO25341) and were reported in up to 42% of patients in the MabThera subcutaneous arm. Most common local cutaneous reactions were injection site erythema (26%), injection site pain (16%), and injection site swelling (5%). Two patients in SAWYER trial who experienced Grade 3 local cutaneous reactions (injection site erythema, injection site pain and injection site swelling).

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 -three clinical trials: SparkThera and SABRINA (the two trials in NHL) and SAWYER the CLL trial.

In trial SABRINA, severe administration-related reactions (grade>3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth.

In trial SparkThera, no severe administration-related reactions were reported. In SAWYER (BO25341), severe administration-related reactions (Grade >3) were reported in four patients (5%) following MabThera subcutaneous administration. These events were Grade 4 thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria.

Adverse reactions reported in MabThera intravenous formulation usage

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse reactions (ADRs) in patients receiving MabThera were infusion-related reactions which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1 % after eight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 30–55 % of patients during clinical trials in patients with NHL and in 30–50 % of patients during clinical trial in patients with CLL.

The most frequent reported or observed serious adverse reactions were:

Infusion-related reactions (including cytokine-release

syndrome, tumour-lysis             s­yndrome), see section 4.4.

Infections, see section 4.4.

Cardiovascular disorders, see section 4.4.

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.

Tabulated list of adverse reactions

Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/ma­intenance or in combination with chemotherapy _____________­____________________

The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the MabThera-arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12 % of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

Infections

MabThera induces B-cell depletion in about 70–80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localized candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% in FC.

Progression of Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions

In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1 %, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), grade 3/4 neutropenia (R-CVP 24% vs. CVP 14%;

R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), grade 3/4 pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies with MabThera intravenous formulation in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1×109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1×109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with MabThera plus FC.There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.

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.

Cardiovascular adverse reactions

Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibri­llation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

Cases of interstitial lung disease, some with fatal outcome have been reported.

Neurologic disorders

During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of Non-Hodgkin’s lymphoma (NHL). In the majority of these cases, MabThera was administered with chemotherapy.

IgG levels

In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the MabThera groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the MabThera group. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Patient subpopulations – MabThera monotherapy

Elderly (> 65 years):

The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to younger patients (<65 years).

Bulky disease:

There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these two groups.

Re-treatment:

The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).

Patient subpopulations – MabThera combination therapy

Elderly (> 65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refrac­tory CLL.

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).

Yellow Card Scheme

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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 CLL. No additional safety signals were identified.

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

Three patients in the MabThera subcutaneous NHL formulation trial SABRINA (BO22334) were inadvertently adminstered subcutaneous formulation through the intravenous route up to a maximum rituximab dose of 2780 mg with no untoward effect.

Patients who experience overdose or medication error with MabThera 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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously.

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of all B cell non-Hodgkin’s lym­phomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalise upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcy receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD 20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B cell counts declined below normal following completion of the first dose of MabThera. In patients treated for hematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg MabThera separated by a 14 day interval.

Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether MabThera was administered as monotherapy or in combination with methotrexate.

Clinical experience of MabThera subcutaneous formulation in chronic lymphocytic leukaemia

A two-part phase Ib, multicenter, randomized, open-label, parallel-group trial (SAWYER BO25341) was conducted in patients with previously untreated CLL, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation in combination with chemotherapy.

The objective of the Part 1 was to select a MabThera subcutaneous formulation dose that resulted in comparable MabThera serum Ctrough levels compared with MabThera intravenous formulation. A total of 64 patients with CLL were enrolled at any point prior to cycle 5 during their treatment with MabThera intravenous formulation in combination with chemotherapy. The dose of 1600 mg of MabThera subcutaneous formulation was selected for the Part 2 of the study.

The objective of the Part 2 was to establish the non-inferiority in observed Ctrough levels between the selected MabThera subcutaneous dose and the reference MabThera intravenous dose.

A total of 176 patients with CLL were randomized into the following two treatment groups:

MabThera subcutaneous (n= 88); 1st cycle of MabThera intravenous 375 mg/m2 in combination with chemotherapy plus subsequent cycles (2–6) of MabThera subcutaneous 1600mg in combination with chemotherapy.

MabThera intravenous (n= 88); 1st cycle of MabThera intravenous 375 mg/m2 in combination with chemotherapy followed by up to 5 cycles of MabThera intravenous 500 mg/m2 in combination with chemotherapy.

The response rates for the analysis of 176 patients in SAWYER Part 2 are shown in Table 2.

Table 2 Efficacy results for SAWYER (BO25341) (Intent to Treat Population)

ORR – Overall Response Rate

CRR – Complete Response Rate

PFS – Progression-Free Survival (proportion with event, disease progression/relapse or death from any cause)

a – at 3 month follow-up visit (Part 2)

b – at time of final analysis (median follow-up 53 months)

Overall the results confirm that MabThera subcutaneous formulation 1600 mg has a comparable benefit/risk profile to that of MabThera intravenous formulation 500 mg/m2.

Immunogenicity

Data from the development programme of MabThera subcutaneous formulation indicate that the formation of anti-rituximab antibodies after subcutaneous administration is comparable with that observed after intravenous administration. In SAWYER trial (BO25341) the incidence of treatment-induced/enhanced anti-rituximab antibodies was similar in the two treatment arms; 15% intravenous vs. 12% subcutaneous. The incidence of treatment-induced/enhanced anti-rHuPH20 antibodies, only measured in patients in the subcutaneous arm was 12%. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.

The clinical relevance of the development of anti-rituximab or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not known. There was no impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety, efficacy or PK of MabThera.

Clinical experience of MabThera concentrate for solution for infusion in CLL

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1–3) every 4 weeks for 6 cycles or MabThera in combination with FC (R-FC). MabThera was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 2a and Table 2b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 3) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p = 0.0319, log-rank test) (Table 2a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 2b).

Table 2a First–line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for MabThera plus FC vs. FC alone – 48.1 months median observation time

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable

: only applicable to patients achieving a CR, nPR, PR

: only applicable to patients achieving a CR

Table 2b First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage (ITT) – 48.1 months median observation time

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 months in the R-FC group and 20.6 months in the FC group (p=0.0002, log–rank test). The benefit in terms of PFS was observed in almost all patient subgroups analysed according to disease risk at baseline. A slight but not significant improvement in overall survival was reported in the R-FC compared to the FC arm.

No PK/clinical data are available in patients with a refractory or relapsing disease.

Table 3 Treatment of relapsed/refractory chronic lymphocytic leukaemia -overview of efficacy results for MabThera plus FC vs. FC alone (25.3 months median observation time)

Response rate and CR rates analysed using Chi–squared Test.

: only applicable to patients achieving a CR, nPR, PR; NR: not reached          n.a. not

applicable

: only applicable to patients achieving a CR;

Results from other supportive studies using MabThera in combination with other chemotherapy regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of previously untreated and/or relapsed/refractory CLL patients have also demonstrated high overall response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especially myelotoxicity). These studies support the use of MabThera with any chemotherapy.

Data in approximately 180 patients pre–treated with MabThera have demonstrated clinical benefit (including CR) and are supportive for MabThera re–treatment.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with CLL. See Section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption

MabThera at a fixed dose of 1600 mg was administered for 5 cycles subcutaneously at 4-weekly intervals, following the first cycle of MabThera intravenous formulation, in previously untreated CLL patients in combination with chemotherapy (fludarabine and cyclophosphamide (FC). The serum

MabThera Cmax at Cycle 6 was lower in the subcutaneous arm than the intravenous, with geometric mean (CV%) values of 202 (36.1) pg/mL and 280 (24.6) Lig/ml. with the resulting geometric mean ratio (Cmax, Sc/Cmax, IV) of 0.719 (90% CI: 0.653, 0.792). The geometric mean tmax in the MabThera subcutaneous group was approximately 3 days as compared to the tmax occuring at or close to the end of the infusion for the MabThera intravenous group. The geometric mean Ctrough (Cv%) values at Cycle 5 (pre-dose Cycle 6) were higher among the MabThera subcutaneous group than the MabThera intravenous group; 97.5 Ug/mL (42.6) versus 61.5 blg/mL (63.9) respectively with a resulting adjusted geometric mean ratio [90% CI] of 1.53 [1.27–1.85]. Similarly, the geometric mean AUC (Cv%) values at Cycle 6 were higher among the subcutaneous group than the intravenous group; 4088 |ig^day/mL (34.2) versus 3630 |ig^day/mL (32.8) respectively) with a resulting adjusted geometric mean ratio [90% CI] of 1.10 [0.98–1.24].

Based on popPK analysis of study BO25341 (SAWYER) an absolute bioavailability of 68.4% was estimated.

Distribution/E­limination

The estimated half-life of Mabthera subcutaneous formulation of 1600 mg is 30 days, the estimated clearance is 0.22 L/day and the volume of distribution of the central compartment is 4.65 L.

Special populations

As typical for monoclonal antibodies, rituximab PK parameters depended on body size measures. All clearance and volume parameters increased with BSA. In addition, central volume was slightly (9%) lower in females compared to males. Absorption parameters of subcutaneous formulation, decreased with increasing BMI. Conditional simulations that summarized the impact of all body size dependencies on rituximab exposure demonstrated that, while fixed subcutaneous dosing leads to larger differences in exposure (Ctrough and AUCT) between subjects with low and high body sizes compared to body-weight-adjusted intravenous dosing, it allows to maintain Ctrough and AUCt values for all body-size groups at the levels not lower than levels attained by intravenous dosing, thus achieving at least the same target saturation as for intravenousdosing. For subjects weighing > 90 kg, Ctrough values were the same for the intravenous and subcutaneous regimens. For subjects weighing 60–90 kg and < 60 kg, average Ctrough values following intravenous dosing were approximately 16% and 34% lower compared to the subcutaneous regimen, respectively. Similarly, for subjects in the high BSA tritile, Ctrough values were the same for the intravenous and subcutaneous regimens. For subjects in the middle and low BSA tritiles, average Ctrough values following intravenous dosing were approximately 12% and 26% lower compared to the subcutaneous regimen.

In addition to dependence on body size, time-dependent clearance was higher in subjects with higher baseline tumour size, which is consistent with target-mediated elimination. Higher time-dependenet clearance in subjects with higher disease burden would lead to lower initial exposure and longer time needed to achieve the same exposure as in subjects with lower burden of the disease.

5.3 Preclinical safety data

Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 100 mg/kg (treatment on gestation days 20–50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted post natally and was accompanied by a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 6 months of birth and did not compromise the reaction to immunization.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule. No long-term animal studies have been performed to establish the carcinogenic potential of rituximab.

Specific studies to determine the effects of rituximab or rHuPH20 on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed. Additionally, no effects on semen quality were shown for rHuPH20.

In embryofetal developmental studies in mice, rHuPH20 caused reduced fetal weight and loss of implantations at systemic exposures sufficiently in excess of human therapeutic exposure.

There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure to rHuPH20.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Recombinant human hyaluronidase (rHuPH20) L-histidine

L-histidine hydrochloride monohydrate

a,a-trehalose dihydrate

L-methionine

Polysorbate 80 (E433)

Water for injections

6.2 Incompati­bilities

No incompatibilities between MabThera subcutaneous formulation and polypropylene or polycarbonate syringe material or stainless steel transfer and injection needles and polyethylene Luer cone stoppers have been observed.

6.3 Shelf life

Unopened vial

3 years

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.

From a microbiological point of view, the product should be used immediately. If not used immediately, preparation should take place in controlled and validated aseptic conditions. In use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from light.

For storage conditions after first opening see section 6.3.

6.5 Nature and contents of container

Colourless type I glass vial with butyl rubber stopper with aluminium over seal and a blue plastic flip-off disk, containing 1600 mg/13.4 mL of rituximab.

Each carton contains one vial.

6.6 Special precautions for disposal

MabThera is provided in sterile, preservative-free, non-pyrogenic, single use vials. Use sterile needle and syringe to prepare MabThera. 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:

Needles and syringes should never be reused

Place all used needles and syringes into a sharps container (puncture-proof disposable container).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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