1. NAME OF THE MEDICINAL PRODUCT

Rituzena 100 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of rituximab.

Each mL of concentrate contains 10mg of 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

Concentrate for solution for infusion.

Clear, colourless liquid.

• 4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rituzena is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.

Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

Chronic lymphocytic leukaemia (CLL)

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

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

4.2 Posology and method of administration

Rituzena 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 Rituzena.

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocortico ould be considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy.

In patients withgranulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis,

methylprednisolone given intravenously for 1 to 3 days at a dose of 100 recommended prior to the first infusion of Rituzena (the last dose of given on the same day as the first infusion of Rituzena). This shoul 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly during and after Rituzena treatment.

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Rituz previously untreated or relapsed surface area per cycle, for up

Rituzena should be administe

administration of the glucocorticoid component of the chemotherapy if applicable.

Monotherapy

• Relapsed/refractory follicular lymphoma

The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with stage follicular lymphoma who are chemoresistant or are in their second or subsequent relapse therapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once for four weeks.

For retreatment with Rituzena monotherapy for patients who have responded to previous treatment with Rituzena monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

Rituzena should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of Rituzena have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Rituzena are recommended. When Rituzena is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Chronic lymphocytic leukaemia

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. F CLL patients whose lymphocyte counts are > 25 × 109/L it is recommended to administer prednisone/pred­nisolone 100 mg intravenous shortly before infusion with Rituzena to decrease t rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of Rituzena in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered o treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rituzena infusion.

Granulomatosis with polyangiitis and microscopic polyangiitis

Patients treated with Rituzena must be given the patient ale

The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (f

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena treatment, as appropriate.

Special populations

Elderly

No dose adjustment is

Paediatric population

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

Meth

epared Rituzena solution should be administered as an intravenous infusion through a ted line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

Subsequent doses of Rituzena can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.

4.3 Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lympho cvtic leukaemia

Hypersensitivity to the active substance or to murine proteins, 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.

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

Active, severe infections (see section 4.4).

Patients in a severely im

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease

ings 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.

• essive multifocal leukoencephalopathy (PML)

All patients treated with rituximab for rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including PML.

Very rare cases of fatal PML have been reported following the use of rituximab. 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 rituximab 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 detectio and suspension of rituximab therapy may lead to similar stabilisation or improved out

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion related reactions

Rituximab is associated with infusion-related reactions, which may b and/or other chemical mediators. Cytokine release syndrome may be from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine r anaphylactic and hypersensitivity reactions are described b

haracterised by severe dyspnoea, often accompanied by

n to fever, chills, rigors, urticaria, and angioedema. This e features of tumour lysis syndrome such as hyperuricaemia, perphosphataemia, acute renal failure, elevated lactate ay be associated with acute respiratory failure and death. The acute ccompanied by events such as pulmonary interstitial infiltration or

-ray. The syndrome frequently manifests itself within one or two hours

t infusion. Patients with a history of pulmonary insufficiency or those with nfiltration may be at greater risk of poor outcome and should be treated with

. Patients who develop severe cytokine release syndrome should have their infusion ediately (see section 4.2) and should receive aggressive symptomatic treatment.

l improvement of clinical symptoms may be followed by deterioration, these patients e closely monitored until tumour lysis syndrome and pulmonary infiltration have been ed or ruled out. Further treatment of patients after complete resolution of signs and symptoms s 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 only 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.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with rituximab (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 rituximab 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.

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 rituximab. 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. rv

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

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

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had

received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with rituximab may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received rituximab 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. 76% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

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

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 a suspected relationship to rituximab, treatment should be perman

Rheumatoid arthritis, granulomatosis with polyangiitis and microsc opi yangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthri The use of rituximab is not recommended in MTX-naïv relationship has not been established.

een reported in rheumatoid arthritis patients in the umatoid arthritis most infusion-related events reported in clinical trials erity. The most common symptoms were allergic reactions like headache, pruritus, throat i ushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion

of patients exp g any infusion reaction was higher following the first infusion than following the second infu f any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or inter , of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, y, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely or patients with pre-existing cardiac conditions and those who experienced prior pulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.

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 rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment, patients should be re-evaluated for any po risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab.

V) screening should be performed in all patients before initiation of treatment

with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be comp ted with other appropriate markers as per local guidelines. Patients with active hepatitis B uld not be treated with rituximab. Patients with positive hepatitis B serology (either or HBcAb) should consult liver disease experts before start of treatment and should be ored and managed following local medical standards to prevent hepatitis B reactivation.

ate neutropenia

Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).

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 a suspected relationship to rituximab, treatment should be permanently discontinued.

Immunisation

Physicians should review the patient’s vac­cination status and follow current immunisation guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted.

Patients treated with rituximab may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treate with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% v

42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given rituximab as compared to patients only receiving methotrexate. Should non-live vacci required whilst receiving rituximab therapy, these should be completed at least 4 wee commencing the next course of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/se­quential use of other DMARDs in rheumatoid a The concomitant use of rituximab and anti-rheumatic therapies rheumatoid arthritis indication and posology is not recommende

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologi nts and/or DMARDs are used following rituximab therapy.

ts may increase the risk of malignancy. On the basis of in rheumatoid arthritis patients (see section 4.8) the present data increased risk of malignancy. However, the possible risk for the rs cannot be excluded at this time.

h other medicinal products and other forms of interaction

re limited data on possible medicinal product interactions with rituximab.

ients, co-administration with rituximab did not appear to have an effect on the okinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of abine and cyclophosphamide on the pharmacokinetics of rituximab.

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

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

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

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 should use effective contraceptive methods during and for 12 months following treatment with rituximab.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to rituximab 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 rituximab during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with rituximab and for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the Safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia)

The overall safety profile of rituximab 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 rituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were IRRs 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 rituximab.

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 trials in patients with CLL

The most frequent reported or observed serious adverse drug reactions were:

• IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with „+“ where the frequency count was based only on severe (> grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported

1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below

3 see also section haematologic adverse reactions below

4 see also section infusion-related reactions below. Rarely fatal cases reported

5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituxima therapy

6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions

7 includes fatal cases

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

Description of selected adverse reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, 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 infusions and is <1% of patients by the eighth cycle of rituximab-containing treatment.

Infections

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab 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 rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoetic 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 (progressive multifocal leukoencephalopathy (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 rituximab in combination with

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 v disturbance, headache, seizures and altered mental status, with or without associated h diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases 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 ob d in patients receiving

rituximab for treatment of non-Hodgkin’s lymphoma. In the majority o e cases, rituximab was

administered with chemotherapy.

Skin and subcutaneous tissue disorders

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

pulations – rituximab monotherapy

s (> 65 years):

ce of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared er 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 rituximab was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).

Patient subpopulations – rituximab combination therapy

Elderly patients (^ 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.

Summary of the safety profile (rheumatoid arthritis)

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is summarised in the sections below. In clinical trials more than 3,100 patients received at least o treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2,400 patients received two or more courses of treatment with over 1,000 havin received 5 or more courses. The safety information collected during post-marketing experience reflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 × 1,000 mg of rituximab separated by an interval of two we

methotrexate (10–25 mg/week). Rituximab infusions were administered a of 100 mg methylprednisolone; patients also received treatment with oral

Tabulated list of adverse reactions

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with 733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the postmarketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a se IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of rituximab. Patients with a history of a serious infusion reactio therapy for RA were excluded from entry. The incidence, types and severity of IRRs with that observed historically. No serious IRRs were observed.

Infections

The overall rate of infection was approximately 94 per 100 patient years i patients. The infections were predominately mild to moderate and cons respiratory tract infections and urinary tract infections. The incidence

or required IV antibiotics, was approximately 4 per 100 patient did not show any significant increase following multiple co tract infections (including pneumonia) have been report in the rituximab-arms compared to control arms.

Cardiovascular adverse reactions

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treated patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

of posterior reversible encephalopathy syndrome (PRES) reversible posterior

ncephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

ance, headache, seizures and altered mental status, with or without associated hypertension. A agnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Neutropenia

Events of neutropenia were observed with rituximab treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and

Rituximab (n=99)

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149–470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3–15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. 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 recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy. V’

Hepatitis B reactivation

A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the postmarketing setting.

Hypogammaglobu­linaemia

Hypogammaglobu­linaemia (IgA, IgG or IgM below the lower limit o granulomatosis with polyangiitis and microscopic polyangiitis patient months, in the active-controlled, randomised, double-blind, multicent

rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 2 cyclophosphamide group. There was no increased rate in patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the rituximab group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in rituximab-treated patients. The effect of multiple rituximab courses on the development of neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been studied in clinical trials.

Skin and subcutaneous tissue disorders

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

Reportingof 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 via the national reporting system listed in Appendix V.

4.9 Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab 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

5.1 Pharmacodynamic properties

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia itial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of rituximab as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95% 41% – 56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to rituximab. A statistically significant correlation was noted between response rates and bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.

Initial treatment, weekly for 8 doses

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single lesion > 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. The ORR was 36 % (CI95% 21% – 51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were re-treated with 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of the patients had received two courses of rituximab before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI95 % 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1 –5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow up of patients was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1 % for patients in the CVP group.

Results from three other randomised trials using rituximab in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-a) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key

ronic lymphocytic leukaemia

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.

Table 6 Treatment of relapsed/refractory chronic lymphocytic leukaemia – overview

of efficacy results for rituximab plus FC vs. FC alone (25.3 months medi 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;

Results from other supportive studies using rituximab 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 rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical benefit (including CR) and are supportive for rituximab 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 follicular lymphoma and chronic lymphocytic leukaemia. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis

(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day) for 3–6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s gra­nulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR) at 6 months (Table 7).

Efficacy was observed both for patients with newly diagnosed disease and for patien disease (Table 8).

Table 7

Rituximab (n

Complete remis;

months by disease status

Table 8

imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared with four in the cyclophosphami­de group.

Retreatment with rituximab

Based upon investigator judgment, 15 patients received a second course of rituximab therapy for treatment of relapse of disease activity which occurred between 6 and 18 months after the first course of rituximab. The limited data from the present trial preclude any conclusions regarding the efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses (i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent relapse. The efficacy and safety of rituximab in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 mo None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance o HACA formation in rituximab-treated patients is unclear. rv

5.2 Pharmacokinetic properties

Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab doses ranged from 100 to 500 mg/m2), the typical populati timates of nonspecific

clearance (CL1), specific clearance (CL2) likely contributed by B tumour burden, and

central compartment volume of distribution (V1) were 0.14 L/day, 0. /day, and 2.7 L, respectively. The estimated median terminal elimination half-l f rituximab was 22 days (range,

6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability in CL2 of rituximab i ata from 161 patients given 375

ly doses. Patients with higher CD19-positive cell owever, a large component of inter-individual for CD19-positive cell counts and tumour lesion size. HOP therapy. This variability in V1 (27.1% and 19.0%) m2) and concurrent CHOP therapy, respectively, were rmance status had no effect on the pharmacokinetics of ose adjustment of rituximab with any of the tested covariates l reduction in its pharmacokinetic variability.

intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4 L naive to rituximab, yielded a mean Cmax following the fourth

ge, 77.5 to 996.6 ^g/mL). Rituximab was detectable in the serum of completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusi i, s panning from a mean of 243 ^g/mL (range, 16 – 582 ^g/mL) after the first infusion to 550 ige, 171 – 1177 ^g/mL) after the eighth infUsion.

pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in ombination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 ^g/mL (range, 97 – 764 ^g/mL) after the fifth 500 mg/ m2 infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51

• L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.

  re ng first /mL for 2

  /mL for the2 x minal elimination for the 2 × 1000

  
  

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 5 and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacoki dose proportional over the limited dose range studied. Mean Cmax for serum rituxim

infusion ranged from 157 to 171 ^g/mL for 2 × 500 mg dose and ranged from 298 × 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 500 mg dose and ranged from 355 to 404 ^g/mL for the 2 × 1000 mg dose. Me; n , half-life ranged from 15 to 16 days for the 2 × 500 mg dose group and 17 to 21 da mg dose group. Mean Cmax was 16 to 19% higher following secon infusion for both doses.

The pharmacokinetics of rituximab were assessed following tw of 500 mg and 1000 mg

upon re-treatment in the second course. Mean Cmax for serum ab following first infusion was 170 to 175 ^g/mL for 2 × 500 mg dose and 317 to 370 ^g/r. L r 2 × 1000 mg dose. Cmax following second infusion, was 207 ^g/mL for the 2 × 500 mg dose and ranged from 377 to 386 ^g/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the 2 × 1000 mg dose.

PK parameters for rituximab were comparable over the two treatment courses.

nti-TNF inadequate responder population, following the ks apart), were similar with a mean maximum serum

rminal half-life of 19.2 days.

Granulomatosis with polyangiif

Based on the populatio acokinetic analysis of data in 97 patients with granulomatosis with polyangiitis and micr opic polyangiitis who received 375 mg/m2 rituximab once weekly for four doses, the estimated terminal elimination half-life was 23 days (range, 9 to 49 days).

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these patients appear similar to what has been observed in rheumatoid arthritis patients.

mab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in nomolgus 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 immunisation.

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 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.

• 6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Tri-sodium citrate dihydrate

Polysorbate 80

Water for injections

• 6.2 Incompati­bilities

  e bags or infusion sets

  
  

No incompatibilities between rituximab and polyvinyl chloride or po have been observed.

6.3 Shelf life

Unopened vial

3 years

Diluted product

The prepared infusion solution of rituximab is at 2 °C – 8 °C and subsequently 12 hours at ro

6.6 Special precautions for disposal and other handling

1. NAME OF THE MEDICINAL PRODUCT

Rituzena 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 mg of rituximab.

Each mL of concentrate contains 10mg of 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

Concentrate for solution for infusion.

Clear, colourless liquid.

• 4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rituzena is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.

Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

Chronic lymphocytic leukaemia (CLL)

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

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

4.2 Posology and method of administration

Rituzena 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 Rituzena.

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocortico ould be considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy.

In patients withgranulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis,

methylprednisolone given intravenously for 1 to 3 days at a dose of 100 recommended prior to the first infusion of Rituzena (the last dose of given on the same day as the first infusion of Rituzena). This shoul 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly during and after Rituzena treatment.

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Rituz previously untreated or relapsed surface area per cycle, for up

Rituzena should be administe

administration of the glucocorticoid component of the chemotherapy if applicable.

Monotherapy

• Relapsed/refractory follicular lymphoma

The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with stage follicular lymphoma who are chemoresistant or are in their second or subsequent relapse therapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once for four weeks.

For retreatment with Rituzena monotherapy for patients who have responded to previous treatment with Rituzena monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

Rituzena should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of Rituzena have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Rituzena are recommended. When Rituzena is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Chronic lymphocytic leukaemia

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. F CLL patients whose lymphocyte counts are > 25 × 109/L it is recommended to administer prednisone/pred­nisolone 100 mg intravenous shortly before infusion with Rituzena to decrease t rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of Rituzena in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered o treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rituzena infusion.

Granulomatosis with polyangiitis and microscopic polyangiitis

Patients treated with Rituzena must be given the patient ale

The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (f

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena treatment, as appropriate.

Special populations

Elderly

No dose adjustment is

Paediatric population

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

Meth

epared Rituzena solution should be administered as an intravenous infusion through a ted line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

Subsequent doses of Rituzena can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.

4.3 Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lympho cvtic leukaemia

Hypersensitivity to the active substance or to murine proteins, 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.

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

Active, severe infections (see section 4.4).

Patients in a severely im

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease

ings 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.

• essive multifocal leukoencephalopathy (PML)

All patients treated with rituximab for rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including PML.

Very rare cases of fatal PML have been reported following the use of rituximab. 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 rituximab 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 detectio and suspension of rituximab therapy may lead to similar stabilisation or improved out

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion related reactions

Rituximab is associated with infusion-related reactions, which may b and/or other chemical mediators. Cytokine release syndrome may be from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine r anaphylactic and hypersensitivity reactions are described b

haracterised by severe dyspnoea, often accompanied by

n to fever, chills, rigors, urticaria, and angioedema. This e features of tumour lysis syndrome such as hyperuricaemia, perphosphataemia, acute renal failure, elevated lactate ay be associated with acute respiratory failure and death. The acute ccompanied by events such as pulmonary interstitial infiltration or

-ray. The syndrome frequently manifests itself within one or two hours

t infusion. Patients with a history of pulmonary insufficiency or those with nfiltration may be at greater risk of poor outcome and should be treated with

. Patients who develop severe cytokine release syndrome should have their infusion ediately (see section 4.2) and should receive aggressive symptomatic treatment.

l improvement of clinical symptoms may be followed by deterioration, these patients e closely monitored until tumour lysis syndrome and pulmonary infiltration have been ed or ruled out. Further treatment of patients after complete resolution of signs and symptoms s 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 only 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.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with rituximab (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 rituximab 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.

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 rituximab. 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. rv

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

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

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had

received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with rituximab may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received rituximab 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. 76% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

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

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 a suspected relationship to rituximab, treatment should be perman

Rheumatoid arthritis, granulomatosis with polyangiitis and microsc opi yangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthri The use of rituximab is not recommended in MTX-naïv relationship has not been established.

een reported in rheumatoid arthritis patients in the umatoid arthritis most infusion-related events reported in clinical trials erity. The most common symptoms were allergic reactions like headache, pruritus, throat i ushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion

of patients exp g any infusion reaction was higher following the first infusion than following the second infu f any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or inter , of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, y, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely or patients with pre-existing cardiac conditions and those who experienced prior pulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.

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 rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment, patients should be re-evaluated for any po risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab.

V) screening should be performed in all patients before initiation of treatment

with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be comp ted with other appropriate markers as per local guidelines. Patients with active hepatitis B uld not be treated with rituximab. Patients with positive hepatitis B serology (either or HBcAb) should consult liver disease experts before start of treatment and should be ored and managed following local medical standards to prevent hepatitis B reactivation.

ate neutropenia

Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).

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 a suspected relationship to rituximab, treatment should be permanently discontinued.

Immunisation

Physicians should review the patient’s vac­cination status and follow current immunisation guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted.

Patients treated with rituximab may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treate with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% v

42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given rituximab as compared to patients only receiving methotrexate. Should non-live vacci required whilst receiving rituximab therapy, these should be completed at least 4 wee commencing the next course of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/se­quential use of other DMARDs in rheumatoid a The concomitant use of rituximab and anti-rheumatic therapies rheumatoid arthritis indication and posology is not recommende

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologi nts and/or DMARDs are used following rituximab therapy.

ts may increase the risk of malignancy. On the basis of in rheumatoid arthritis patients (see section 4.8) the present data increased risk of malignancy. However, the possible risk for the rs cannot be excluded at this time.

h other medicinal products and other forms of interaction

re limited data on possible medicinal product interactions with rituximab.

ients, co-administration with rituximab did not appear to have an effect on the okinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of abine and cyclophosphamide on the pharmacokinetics of rituximab.

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

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

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

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 should use effective contraceptive methods during and for 12 months following treatment with rituximab.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to rituximab 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 rituximab during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with rituximab and for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the Safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia)

The overall safety profile of rituximab 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 rituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were IRRs 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 rituximab.

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 trials in patients with CLL

The most frequent reported or observed serious adverse drug reactions were:

• IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
• Infections, see section 4.4.
• Cardiovascular events, see section 4.4.

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with „+“ where the frequency count was based only on severe (> grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported

1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below

3 see also section haematologic adverse reactions below

4 see also section infusion-related reactions below. Rarely fatal cases reported

5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituxima therapy

6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions

7 includes fatal cases

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

Description of selected adverse reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, 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 infusions and is <1% of patients by the eighth cycle of rituximab-containing treatment.

Infections

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab 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 rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoetic 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 (progressive multifocal leukoencephalopathy (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 rituximab in combination with

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 v disturbance, headache, seizures and altered mental status, with or without associated h diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases 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 ob d in patients receiving

rituximab for treatment of non-Hodgkin’s lymphoma. In the majority o e cases, rituximab was

administered with chemotherapy.

Skin and subcutaneous tissue disorders

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

pulations – rituximab monotherapy

s (> 65 years):

ce of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared er 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 rituximab was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).

Patient subpopulations – rituximab combination therapy

Elderly patients (^ 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.

Summary of the safety profile (rheumatoid arthritis)

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is summarised in the sections below. In clinical trials more than 3,100 patients received at least o treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2,400 patients received two or more courses of treatment with over 1,000 havin received 5 or more courses. The safety information collected during post-marketing experience reflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 × 1,000 mg of rituximab separated by an interval of two we

methotrexate (10–25 mg/week). Rituximab infusions were administered a of 100 mg methylprednisolone; patients also received treatment with oral

Tabulated list of adverse reactions

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with 733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the postmarketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a se IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of rituximab. Patients with a history of a serious infusion reactio therapy for RA were excluded from entry. The incidence, types and severity of IRRs with that observed historically. No serious IRRs were observed.

Infections

The overall rate of infection was approximately 94 per 100 patient years i patients. The infections were predominately mild to moderate and cons respiratory tract infections and urinary tract infections. The incidence

or required IV antibiotics, was approximately 4 per 100 patient did not show any significant increase following multiple co tract infections (including pneumonia) have been report in the rituximab-arms compared to control arms.

Cardiovascular adverse reactions

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treated patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

of posterior reversible encephalopathy syndrome (PRES) reversible posterior

ncephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

ance, headache, seizures and altered mental status, with or without associated hypertension. A agnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Neutropenia

Events of neutropenia were observed with rituximab treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and

Rituximab (n=99)

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149–470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3–15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. 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 recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy. V’

Hepatitis B reactivation

A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the postmarketing setting.

Hypogammaglobu­linaemia

Hypogammaglobu­linaemia (IgA, IgG or IgM below the lower limit o granulomatosis with polyangiitis and microscopic polyangiitis patient months, in the active-controlled, randomised, double-blind, multicent

rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 2 cyclophosphamide group. There was no increased rate in patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the rituximab group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in rituximab-treated patients. The effect of multiple rituximab courses on the development of neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been studied in clinical trials.

Skin and subcutaneous tissue disorders

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

Reportingof 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 via the national reporting system listed in Appendix V.

4.9 Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab 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

5.1 Pharmacodynamic properties

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia itial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of rituximab as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI95% 41% – 56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT.

Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to rituximab. A statistically significant correlation was noted between response rates and bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.

Initial treatment, weekly for 8 doses

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bu lesion > 10 cm in diameter), low grade or follicular B cell NHL received 3 intravenous infusion weekly for four doses. The ORR was 36 % (CI95% 21 33%) with a median TTP for responding patients of 9.6 months (range 4.5

Results from three other randomised trials using rituximab in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-a) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key

ronic lymphocytic leukaemia

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.

Table 6 Treatment of relapsed/refractory chronic lymphocytic leukaemia – overview

of efficacy results for rituximab plus FC vs. FC alone (25.3 months medi 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;

Results from other supportive studies using rituximab 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 rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical benefit (including CR) and are supportive for rituximab 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 follicular lymphoma and chronic lymphocytic leukaemia. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis

(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day) for 3–6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s gra­nulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR) at 6 months (Table 7).

Efficacy was observed both for patients with newly diagnosed disease and for patien disease (Table 8).

Table 7

Rituximab (n

Complete remis;

months by disease status

Table 8

imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared with four in the cyclophosphami­de group.

Retreatment with rituximab

Based upon investigator judgment, 15 patients received a second course of rituximab therapy for treatment of relapse of disease activity which occurred between 6 and 18 months after the first course of rituximab. The limited data from the present trial preclude any conclusions regarding the efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses (i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent relapse. The efficacy and safety of rituximab in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 mo None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevan HACA formation in rituximab-treated patients is unclear.

5.2 Pharmacokinetic properties

Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab doses ranged from 100 to 500 mg/m2), the typical populati timates of nonspecific

clearance (CL1), specific clearance (CL2) likely contributed by B tumour burden, and

central compartment volume of distribution (V1) were 0.14 L/day, 0. /day, and 2.7 L, respectively. The estimated median terminal elimination half-l f rituximab was 22 days (range,

6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability in CL2 of rituximab i ata from 161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. However, a large component of inter-individual

for CD19-positive cell counts and tumour lesion size. HOP therapy. This variability in V1 (27.1% and 19.0%) m2) and concurrent CHOP therapy, respectively, were rmance status had no effect on the pharmacokinetics of ose adjustment of rituximab with any of the tested covariates l reduction in its pharmacokinetic variability.

intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4 L naive to rituximab, yielded a mean Cmax following the fourth

ge, 77.5 to 996.6 ^g/mL). Rituximab was detectable in the serum of completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusi i, s panning from a mean of 243 ^g/mL (range, 16 – 582 ^g/mL) after the first infusion to 550 ige, 171 – 1177 ^g/mL) after the eighth infusion.

pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in ombination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 ^g/mL (range, 97 – 764 ^g/mL) after the fifth 500 mg/ m2 infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51

• L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.

  re ng first /mL for 2

  /mL for the2 x minal elimination for the 2 × 1000

  
  

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 5 and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacok dose proportional over the limited dose range studied. Mean Cmax for serum rituxim infusion ranged from 157 to 171 ^g/mL for 2 × 500 mg dose and ranged from 298 × 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 500 mg dose and ranged from 355 to 404 ^g/mL for the 2 × 1000 mg dose. Me; n.

half-life ranged from 15 to 16 days for the 2 × 500 mg dose group and 17 to 21 da mg dose group. Mean Cmax was 16 to 19% higher following secon infusion for both doses.

The pharmacokinetics of rituximab were assessed following tw of 500 mg and 1000 mg

upon re-treatment in the second course. Mean Cmax for serum ab following first infusion was 170 to 175 ^g/mL for 2 × 500 mg dose and 317 to 370 ^g/r. L r 2 × 1000 mg dose. Cmax following second infusion, was 207 ^g/mL for the 2 × 500 mg dose and ranged from 377 to 386 ^g/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the 2 × 1000 mg dose.

PK parameters for rituximab were comparable over the two treatment courses.

nti-TNF inadequate responder population, following the ks apart), were similar with a mean maximum serum

rminal half-life of 19.2 days.

Granulomatosis with polyangiif

Based on the populatio acokinetic analysis of data in 97 patients with granulomatosis with polyangiitis and micr opic polyangiitis who received 375 mg/m2 rituximab once weekly for four doses, the estimated terminal elimination half-life was 23 days (range, 9 to 49 days).

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these patients appear similar to what has been observed in rheumatoid arthritis patients.

mab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in nomolgus 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 immunisation.

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 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.

• 6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Tri-sodium citrate dihydrate

Polysorbate 80

Water for injections

• 6.2 Incompati­bilities

  e bags or infusion sets

  
  

No incompatibilities between rituximab and polyvinyl chloride or po have been observed.

6.3 Shelf life

Unopened vial

4 years

Diluted product

The prepared infusion solution of rituximab is at 2 °C – 8 °C and subsequently 12 hours at ro

6.6 Special precautions for disposal and other handling

Rituzena is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Aseptically withdraw the necessary amount of Rituzena, and dilute to a calculated concentration of 1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9 mg/mL (0.9%) solution for injection or 5 % D-Glucose in water. For mixing the solution, gently invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.

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

EU/1/17/1206/001

Celltrion Healthcare Hungary Kft.

1062 Budapest

Vaci ut 1–3. WestEnd Office Building B torony

Hungary

Date of first authorisation: 13 July 2017 Date of latest renewal:

Detailed information on this medicin Agency

10. DATE OF REVISION OF THE TEXT

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF T

7. MARKETING AUTHORISATION HOLDER

ORISATION

lable on the website of the European Medicines

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

CELLTRION Inc.,

20 Academy-ro 51 beon-gil

Yeonsu-gu, Incheon, 22014, Republic of Korea

Name and address of the manufacturers responsible for batch release

Biotec Services International Ltd.

Biotec House, Central Park, Western Avenue

Bridgend Industrial Estate

Bridgend, CF31 3RT, UK

• B. CONDITIONS OR RESTRICTIONS

  DING SUPPLY AND USE

  
  

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

REQUIREMENTS OF THE MARKETING

Periodic safety

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

Additional risk minimisation measures

The Patient Alert Ca elements:

• The to carry the card at all times and to show the card to all treating health ssionals

g on the risk of infections and PML, including the symptoms e need for patients to contact their health care professional if symptoms occur

Ecology indications:

he MAH must ensure that all physicians who are expected to prescribe Rituzena are rovided with the following:

roduct information

hysician information

• The Physician information about Rituzena should contain the following key elements: Information that the product should be administered as IV only to avoid administration route errors.

The Physician information and Patient information must be agreed with the National Competent Authorities prior to distribution and Patient Alert Card should be included as

Store in a refrigerator. Keep the container in the outer carton, in order to protect from light.

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

  ling Braille accepted.>

  IDENTIFIER – 2D BARCODE

  PLY

  ILLE

  
  

Celltrion Healthcare Hungary Kft.

1062 Budapest

Vaci ut 1–3. WestEnd Office Building B torony

Hungary

• 12. MARKETING AUTHORISATION NUMBER(S)

  EU/1/17/1206/002

  
  

  13. BATCH NUMBER

  
  

  Lot

  
  

  15. INSTRUCTIONS ON US

  
  

  16. INFORMATIO

  
  

  ■ Justification for n

  17.

  <

  PC:

  SN:

  NN:

  
  

14. GENERAL CLASSIFICATION e carrying the unique identifier included.>

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Celltrion Healthcare Hungary Kft.

1062 Budapest

Vaci ut 1–3. WestEnd Office Building B torony

Hungary

12. MARKETING AUTHORISATION NUMBER(S)

14. GENERAL CLASSIFICATION F

■Justification for not includ

UNIQUE IDENTIFIER – HUMAN READABLE DATA

Package leaflet: Information for the patient

Rituzena 100 mg concentrate for solution for infusion

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• If you get any side effects talk to your doctor, pharmacist or nurse. This inc

side effects not listed in this leaflet. See section 4.

What Rituzena is and what it is used for

What you need to know before you use Rituzena

How to use Rituzena

Possible side effects

How to store Rituzena

Contents of the pack and other information

What Rituzena is and what it is used for

What Rituzena is

Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When sticking to the surface of this cell, rituximab causes the cell to die.

What Rituzena is used for

Rituzena may be used for the tr prescribe Rituzena for the treat

a) Non-Hodgkin’s L

This is a disease of the

a

tissue (part of the immune system) that affects B-Lymphocytes. or with other medicines called “chemotherapy”.

b) Chroni

Chronic lymp

B-lymphocyte

leukaemia

leukaemia (CLL) is the most common form of adult leukaemia. CLL affects which originate in the bone marrow and develop in the lymph nodes. Patients with any abnormal lymphocytes, which accumulate mainly in the bone marrow and blood. ese abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in

Granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called Wegener’s gra­nulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well.

2. What you need to know before you use Rituzena

Do not take Rituzena if:

• you are allergic to rituximab, other proteins which are like rituximab, or any of the other ingredients of this medicine (listed in section 6)
• you have a severe active infection at the moment
• you have a weak immune system
• you have severe heart failure or severe uncontrolled heart disease and have granulomatosis with polyangiitis or microscopic polyangiitis.

Do not have Rituzena if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before you are given Rituzena.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Rituzena if:

you have ever had or might now have a hepatitis infection. This is because in a fe Rituzena could cause hepatitis B to become active again, which can be fatal in very rare cases. Patients who have ever had hepatitis B infection will be carefully checked by their doctor for signs of this infection.

you have ever had heart problems (such as angina, palpitations or heart failure) or breathing problems.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena. Your doctor may need to take special care during your treatment with Rituzena.

If you have granulomatosis with polyangiitis or mic

if you think you may have an infection, even a mil

by Rituzena help to fight infection and you should wait until the infection has passed before you are given Rituzena. Also please tell your doctor if you have had a lot of infections in the past or suffer from severe infections.

if you think you may need any vaccinations in the near future, including vaccinations for travel to other countries. Some vaccines should not be given at the same time as Rituzena or in the months after you receive Rituzena. Your doctor will check if you should have any vaccines before you receive Rituze

Children and adolescents

Talk to your doctor, pha nurse before you are given this medicine if you, or your child,

are under 18 years of ag s is because there is not much information about the use of Rituzena in children and young people.

Other medicines and Rituzena

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because Rituzena can affect the way some other medicines work. Also some other medicines can ay Rituzena works.

icular, tell your doctor:

if you are taking medicines for high blood pressure. You may be asked not to take these other medicines 12 hours before you are given Rituzena. This is because some people have a fall in their blood pressure while they are being given Rituzena.

if you have ever taken medicines which affect your immune system – such as chemotherapy or immune-suppressive medicines.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena.

Pregnancy and breast-feeding

Driving and using machines

It is not known whether Rituzena has an effect on you being able to drive or use any tools or machines.

How it is given

Rituzena will be given to you by a doctor or nurse who is experienced in the use They will watch you closely while you are being given this medicine. This is i side effects.

You will always be given Rituzena as a drip (intravenous infusion).

Medicines given before each Rituzena administration

Before you are given Rituzena, you will be given other medici reduce possible side effects.

If you are being treated for non-

If you are having Rituzena alone Rituzena will be given to you onc

for chronic lymphocytic leukaemia

na in combination with chemotherapy, you will receive Rituzena

re being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena uses four separate infusions given at weekly intervals. A corticosteroid

ill usually be given by injection before the start of Rituzena treatment. Corticosteroid iven by mouth may be started at any time by your doctor to treat your condition.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of these reactions have been fatal.

Infusion reactions

During or within the first 2 hours of the first infusion you may develop fever, chills and shivering. Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness, headache, breathing difficulties, tongue or throat swelling, itchy or runny nose, vomiting, flushing or palpitations, heart attack or low number of platelets. If you have heart disease or angina, these infusion reactions might get worse. Tell the person giving you the infusion immediately if you develop any of these symptoms, as the infusion may need to be slowed down or stopped. You may require additional treatment such as an antihistamine or paracetamol. When these symptoms go away, or improve, the infusion can be continued. These reactions are less likely to happen after the second infusion. Your doctor may decide to stop your Rituzena treatment if these reactions are serious.

Infections

• fever, cough, sore throat, burning pain when passing urine or feeling weak or g nwell
• memory loss, trouble thinking, difficulty walking or sight loss – these may be c ery rare, serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or PML).

You might get infections more easily during your treatment with Rituzena.

These are often colds, but there have been cases of pneumonia or urina ections. These are listed below under “Other side effects”.

Skin reactions

Very rarely, severe blistering skin conditions that can be life-threatening may occur. Redness, often associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital areas or the eyelids, and fever may be present. Tell your doctor immediately if you have any of these symptoms.

Other side effects include:

Very common side effects (may affect an 1 in 10 people):

bacterial or viral infection hitis

low number of white bloo s sometimes with fever, or low number of blood cells called “platelets”

feeling sick (nausea)

bald spots on the scalp, chills, headache

lower immunity – because of lower levels of anti-bodies called “immunoglobulin­s” (IgG)

in the blood which help protect against infection

(may affect up to 1 in 10 people):

fections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, ngal infections, infections of unknown origin, sinus inflammation, hepatitis B w number of red blood cells (anaemia), low number of all blood cells

allergic reactions (hypersensitivity) high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme “lactate dehydrogenase (LDH)” in the blood, low calcium levels in the blood unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin feeling, reduced sense of touch feeling restless, problems falling asleep,

becoming very red in the face and other areas of the skin as a consequence of dilation of the blood vessels

feeling dizzy or anxious

producing more tears, tear duct problems, inflamed eye (conjunctivitis) ringing sound in the ears, ear pain

heart problems – such as heart attack and uneven or fast heart rate

high or low blood pressure (low blood pressure especially when standing upright) tightening of the muscles in the airways which causes wheezing (bronchospasm), inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny nose

being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat and mouth, problems swallowing, constipation, indigestion eating disorders: not eating enough, leading to weight loss hives, increased sweating, night sweats

muscle problems – such as tight muscles, joint or muscle pain, back and neck pain general discomfort or feeling uneasy or tired, shaking, signs of flu multiple-organ failure.

Uncommon side effects (may affect up to 1 in 100 people):

• blood clotting problems, decrease of red blood cell production and increase of re cell destruction (aplastic haemolytic anaemia), swollen or enlarged lymph no
• low mood and loss of interest or enjoyment in doing things, feeling nervous
• taste problems – such as changes in the way things taste
• heart problems – such as reduced heart rate or chest pain (angina)
• asthma, too little oxygen reaching the body organs
• swelling of the stomach.

Very rare side effects (may affect up to 1 in 10,000 people):

• short term increase in the amount of some types of anti-b immunoglobulins – IgM), chemical disturbances in the b dying cancer cells
• nerve damage in arms and legs, paralysed face
• heart failure

inflammation of blood vessels including those leading to skin symptoms

respiratory failure

damage to the intestinal wall (perforation)

severe skin problems causing blisters that can be life-threatening. Redness, often associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital areas or the eyelids, and fever may be present.

kidney failure

severe vision loss

Not known (it is not kno ften these side effects happen):

• a reduction in blood cells which does not happen straight away
• reduced platelets number just after the infusion – this can be reversed, but can be fatal in rare cases
• heari , loss of other senses

being treated for granulomatosis with polyangiitis or microscopic polyangiitis

infections, such as chest infections, urinary tract infections (pain on passing water), colds and herpes infections

allergic reactions that are most likely to occur during an infusion, but can occur up to 24-hours after infusion

diarrhoea

coughing or shortness of breath

nose bleeds

raised blood pressure

painful joints or back

muscle twitches or shakiness

feeling dizzy

tremors (shakiness, often in the hands)

• difficulty sleeping (insomnia)
• swelling of the hands or ankles

Common side effects (may affect up to 1 in 10 people):

• indigestion
• constipation
• skin rashes, including acne or spots
• flushing or redness of the skin
• blocked nose
• tight or painful muscles
• pain in the muscles or in the hands or feet
• low number of red blood cells (anaemia)
• low numbers of platelets in the blood
• an increase in the amount of potassium in the blood
• changes in the rhythm of the heart, or the heart beating faster than normal

Very rare side effects (may affect up to 1 in 10,000 people):

• severe blistering skin conditions that can be life-threatening. Redness, often associated

with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital areas or the eyelids, and fever may be present.

recurrence of a previous Hepatitis B infection

Rituzena may also cause changes in laboratory tests carried out by your doctor.

Reporting of side effects

If you get any side effects talk to your doctor, pharmacist o nur >e. This includes any side effects not listed in this leaflet. You can also report side effects direc

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. aVZ

How to store Rituzena

Keep this medicine out of the si

expiry date which is stated on the carton and the vial after EXP. ay of that month.

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

ay any medicines via wastewater or household waste. Ask your pharmacist how edicines that you no longer use. These measures will help protect the

6. Contents of the pack and other information The active ingredient in Rituzena is called rituximab. The vial contains 100 mg of rituximab. Each mL of concentrate contains 10 mg of rituximab.

• The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 and water for injections.

What Rituzena looks like and contents of the pack

Marketing Authorisation Holder

Manufacturer

België/Belgique/Belgien

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Lietuva

EGIS PHARMACEUTICALS PLC atstovybé

Tel: +370 5 231 4658

Efc^rapufl

EGIS Bulgaria EOOD

Ten.: + 359 2 987 6040

Česká republi

EGIS Praha, Tel: +420 22

Luxembourg/Luxemburg

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Magyarország

Egis Gyógyszergyár Zrt.

Tel.: + 36 1 803 5555

Danmark

Orion Pharma A/S

Tlf: + 45 86 14 00 00

Malta

Medical Logistics Ltd.

Tel: +356 2755 9990

tschland

dipharma GmbH

Tel: +49 (0) 69 506029–000

Nederland

Mundipharma Pharmaceuticals B.V

Tel: + 31 33 450 8270

Eesti

Orion Pharma Eesti OÜ

Tel: + 372 6 644 550

Norge

Orion Pharma AS

Tlf: + 47 40 00 42 10

EXÀàôa

BIANES A.E.

Tql: +30 210 8009111 – 120

Espana

Kern Pharma, S.L.

Tel: +34 93 700 2525

Polska

EGIS Polska Sp. z o.o.

Tel.: + 48 22 417 9200

France

Laboratoires Biogaran

Tél: +33 (0) 800 970 109

Hrvatska

Oktal Pharma d.o.o.

Tel: +385 1 6595 777

Ireland

Mundipharma Pharmaceuticals Limited

Tel: +353 1 2063800

island

Vistor hf.

Simi: +354 535 7000

Romania

Egis Pharmaceuticals PLC Romania

Tel: + 40 21 412 0017

Slovenija

OPH Oktal Pharma d.o.o.

Tel: +386 1 519 29 22

Slovenska republika

EGIS SLOVAKIA sp

Tel: +421 2 3240 942

Italia

Mundipharma Pharmaceuticals Srl

Tel: +39 02 31 82 88 1

Suomi/F

Orion Ph Puh/Tel:

Latvija

EGIS Pharmaceuticals PLC pärstävniec

Tel: +371 67613859

Sveri

on Pharma AB : + 46 8 623 64 40

Package leaflet: Information for the patient

Rituzena 500 mg concentrate for solution for infusion

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

• 7. What Rituzena is and what it is used for

• 8. What you need to know before you use Rituzena

• 9. How to use Rituzena

• 10. Possible side effects

• 11. How to store Rituzena

• 12. Contents of the pack and other information

  7.

  
  

What Rituzena is and what it is used

Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When sticking to the surface of this cell, rituximab causes the cell to die.

What Rituzena is used for

Rituzena may be used for the treatment of several different conditions in adults. Your doctor may prescribe Rituzena for the treatment of:

d) Non-Hodgkin’s Lymphoma

This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes.

Rituzena can be given alone or with other medicines called “chemotherapy”.

e) Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood. The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in combination with chemotherapy destroys these cells.

f) Granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called Wegener’s gra­nulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well.

B-lymphocytes are involved in the cause of these conditions.

8. What you need to know before you use Rituzena you are allergic to rituximab, other proteins which are like rituximab, or any of the other ingredients of this medicine (listed in section 6)

• you have a severe active infection at the moment
• you have a weak immune system
• you have severe heart failure or severe uncontrolled heart disease and have granulomatosis with polyangiitis or microscopic polyangiitis.

Do not have Rituzena if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before you are given Rituzena.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Rituzena if:

you have ever had or might now have a hepatitis infection. This is becau

Rituzena could cause hepatitis B to become active again, which can Patients who have ever had hepatitis B infection will be carefully signs of this infection.

you have ever had heart problems (such as angina, palpitations problems.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena. Your doctor may need to take special care during your treatment with Rituzena.

If you have granulomatosis with polyangiitis or microscopic polyangiitis also tell your doctor

• if you think you may have an infection, even a mild one like a cold. The cells that are affected by Rituzena help to fight infectio ou should wait until the infection has passed before you are given Rituzena. Also please t r doctor if you have had a lot of infections in the past or

ny vaccinations in the near future, including vaccinations for travel ines should not be given at the same time as Rituzena or in the tuzena. Your doctor will check if you should have any vaccines

Children and a

Talk to your doc armacist or nurse before you are given this medicine if you, or your child,

are under 18 years of age. This is because there is not much information about the use of Rituzena in children and young people.

icines and Rituzena

octor, pharmacist or nurse if you are taking, have recently taken or might take any other ines. This includes medicines obtained without a prescription and herbal medicines. This is cause Rituzena can affect the way some other medicines work. Also some other medicines can affect the way Rituzena works.

In particular, tell your doctor:

• if you are taking medicines for high blood pressure. You may be asked not to take these other medicines 12 hours before you are given Rituzena. This is because some people have a fall in their blood pressure while they are being given Rituzena.
• if you have ever taken medicines which affect your immune system – such as chemotherapy or

immune-suppressive medicines.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena.

Pregnancy and breast-feeding

You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are planning to become pregnant. This is because Rituzena can transfer across the placenta and may affect your baby.

If you can get pregnant, you and your partner must use an effective method of contraception while using Rituzena. You must also do this for 12 months after your last treatment with Rituzena.

Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months after your last treatment with Rituzena. This is because Rituzena may pass into breast milk.

Driving and using machines

It is not known whether Rituzena has an effect on you being able to drive or use any tools or machines.

9. How Rituzena is given

Rituzena will be given to you by a doctor or nurse who is experienced in the use of this treatment. They will watch you closely while you are being given this medicine. This is in case you get any side effects.

You will always be given Rituzena as a drip (intravenous infusion).

Medicines given before each Rituzena administration

Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or reduce possible side effects.

How much and how often you will receive your treatment

If you are being treated for

If you are having Rituzena al Rituzena will be given to yo

gkin’s Lymphoma

g treated for chronic lymphocytic leukaemia

When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena infusion. Your doctor will decide if you should receive other treatment at the same time.

• f) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid medicine given by mouth may be started at any time by your doctor to treat your condition.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

10. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of these reactions have been fatal.

Infusion reactions

During or within the first 2 hours of the first infusion you may develop fever, chills and shivering. Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness, headache, breathing difficulties, tongue or throat swelling, itchy or runny nose, vomiting, flushing or palpitations, heart attack or low number of platelets. If you have heart disease or angina, these infusion reactions might get worse. Tell the person giving you the infusion immediately if you develop any of these symptoms, as the infusion may need to be slowed down or stopped. You may require additional treatment such as an antihistamine or paracetamol. When these symptoms go away, or improve, the infusion can be continued. These reactions are less likely to happen aft second infusion. Your doctor may decide to stop your Rituzena treatment if these reactions a serious.

Infections

• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare,

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or PML).

You might get infections more easily during your treatment with Rituzena.

These are often colds, but there have been cases of pneumonia or urinary infections. These are listed below under “Other side effects”.

Skin reactions

Very rarely, severe blistering skin conditions tha associated with blisters, may appear on the ski the genital areas or the eyelids, and fever any of these symptoms.

-Hodgkin’s Lymphoma or chronic lymphocytic leukaemia

Very common side effects (may affect more than 1 in 10 people):

• bacterial or viral infections, bronchitis
• low number of white blood cells sometimes with fever, or low number of blood cells called “platelets”
• feeling sick (nausea)

ts on the scalp, chills, headache

munity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) ood which help protect against infection n side effects (may affect up to 1 in 10 people):

infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, fungal infections, infections of unknown origin, sinus inflammation, hepatitis B low number of red blood cells (anaemia), low number of all blood cells allergic reactions (hypersensitivity)

high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme “lactate dehydrogenase (LDH)” in the blood, low calcium levels in the blood unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin feeling, reduced sense of touch

feeling restless, problems falling asleep,

becoming very red in the face and other areas of the skin as a consequence of dilation of the blood vessels

If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

• painful joints or back
• muscle twitches or shakiness
• feeling dizzy
• tremors (shakiness, often in the hands)
• difficulty sleeping (insomnia)
• swelling of the hands or ankles

Common side effects (may affect up to 1 in 10 people):

• indigestion
• constipation
• skin rashes, including acne or spots
• flushing or redness of the skin
• blocked nose
• tight or painful muscles
• pain in the muscles or in the hands or feet
• low number of red blood cells (anaemia)
• low numbers of platelets in the blood
• an increase in the amount of potassium in the blood
• changes in the rhythm of the heart, or the heart beating faster than normal

Very rare side effects (may affect up to 1 in 10,000 people):

• severe blistering skin conditions that can be life-threatening. Redness, often associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital areas or the eyelids, and fever may be present.
• recurrence of a previous Hepatitis B infection

11. How to store Rituzena

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The expiry date refers to the last day of that month.

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

tDoothnrot throw away any medicines via wastewater or household waste. Ask your pharmacist how ow away medicines that you no longer use. These measures will help protect the environment.

12. Contents of the pack and other information The active ingredient in Rituzena is called rituximab. The vial contains 500 mg of rituximab. Each mL of concentrate contains 10 mg of rituximab.

The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 andwater for injections.What Rituzena looks like and contents of the packRituzena is a clear, colourless solution, supplied as a concentrate for solution for infusion in a glass vial. Pack of 1 vial.Marketing Authorisation HolderCelltrion Healthcare Hungary Kft.1062 BudapestVáci út 1-3. WestEnd Office Building B toronyHungaryManufacturerBiotec Services International Ltd.Biotec House, Central Park, Western AvenueBridgend Industrial EstateBridgend, CF31 3RT, UKAndUnits 2100, 2110, 2010, 2120, 2130 and 2500Phase 18, Central ParkBridgend Industrial EstateBridgend, CF31 3TY, UKMillmount Healthcare Ltd.Block 7, City North Business Campus, Stamullen, Co. Meath K32 YD60, IrelandFor any information about this me Authorisation Holder:België/Belgique/BelgienMundipharma CVATél/Tel: + 32 15 45 1180se contact the local representative of the MarketingLietuvaEGIS PHARMACEUTICALS PLC atstovybéTel: +370 5 231 4658Efc^rapuflEGIS BulgariTea.: + 35Česká040a, spol. s r.o227 129 111Luxembourg/LuxemburgMundipharma CVATél/Tel: + 32 15 45 1180MagyarországEgis Gyógyszergyár Zrt.Tel.: + 36 1 803 5555anmarkrion Pharma A/STlf: + 45 86 14 00 00MaltaMedical Logistics Ltd.Tel: +356 2755 9990DeutschlandNederlandMundipharma GmbHTel: +49 (0) 69 506029-000Mundipharma Pharmaceuticals B.V Tel: + 31 33 450 8270

Eesti

Orion Pharma Eesti OÜ

Tel: + 372 6 644 550

Norge

Orion Pharma AS

Tlf: + 47 40 00 42 10

EMûôa

BLANES A.E.

Tql: +30 210 8009111 – 120

Espana

Kern Pharma, S.L.

Tel: +34 93 700 2525

Polska

EGIS Polska Sp. z o.o.

Tel.: + 48 22 417 9200

France

Laboratoires Biogaran

Tél: +33 (0) 800 970 109

Portugal

PharmaKERN Portugal – Produtos Farmacêuti Sociedade Unipessoal, Lda.

Tel: +351 214 200 290

Hrvatska

Oktal Pharma d.o.o.

Tel: +385 1 6595 777

Romania

Egis Pharmaceuticals PLC Ro

Tel: + 40 21 412 0017

Ireland

Mundipharma Pharmaceuticals Limited

Tel: +353 1 2063800

island

Vistor hf.

Simi: +354 535 7000

Italia

Mundipharma Pharmaceuticals Srl

Tel: +39 02 31 82 88 1

Slovenska r

EGIS SL Tel: +

Latvija

EGIS Pharmaceuticals PLC pärstävniec

Tel: +371 67613859

Package leaflet: Information for the patient

Rituzena 500 mg concentrate for solution for infusion

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

• 7. What Rituzena is and what it is used for

• 8. What you need to know before you use Rituzena

• 9. How to use Rituzena

• 10. Possible side effects

• 11. How to store Rituzena

• 12. Contents of the pack and other information

  7.

  
  

What Rituzena is and what it is used

Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When sticking to the surface of this cell, rituximab causes the cell to die.

What Rituzena is used for

Rituzena may be used for the treatment of several different conditions in adults. Your doctor may prescribe Rituzena for the treatment of:

• d) Non-Hodgkin’s Lymphoma

This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes.

Rituzena can be given alone or with other medicines called “chemotherapy”.

• e) Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood. The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in combination with chemotherapy destroys these cells.

• f) Granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called Wegener’s gra­nulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well.

B-lymphocytes are involved in the cause of these conditions.

8. What you need to know before you use Rituzena you are allergic to rituximab, other proteins which are like rituximab, or any of the other ingredients of this medicine (listed in section 6)

• you have a severe active infection at the moment
• you have a weak immune system
• you have severe heart failure or severe uncontrolled heart disease and have granulomatosis with polyangiitis or microscopic polyangiitis.

Do not have Rituzena if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before you are given Rituzena.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Rituzena if:

you have ever had or might now have a hepatitis infection. This is becau

Rituzena could cause hepatitis B to become active again, which can Patients who have ever had hepatitis B infection will be carefully signs of this infection.

you have ever had heart problems (such as angina, palpitations problems.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena. Your doctor may need to take special care during your treatment with Rituzena.

If you have granulomatosis with polyangiitis or microscopic polyangiitis also tell your doctor

• if you think you may have an infection, even a mild one like a cold. The cells that are affected by Rituzena help to fight infectio ou should wait until the infection has passed before you are given Rituzena. Also please t r doctor if you have had a lot of infections in the past or

ny vaccinations in the near future, including vaccinations for travel ines should not be given at the same time as Rituzena or in the tuzena. Your doctor will check if you should have any vaccines

Children and a

Talk to your doc armacist or nurse before you are given this medicine if you, or your child,

are under 18 years of age. This is because there is not much information about the use of Rituzena in children and young people.

icines and Rituzena

octor, pharmacist or nurse if you are taking, have recently taken or might take any other ines. This includes medicines obtained without a prescription and herbal medicines. This is cause Rituzena can affect the way some other medicines work. Also some other medicines can affect the way Rituzena works.

In particular, tell your doctor:

• if you are taking medicines for high blood pressure. You may be asked not to take these other medicines 12 hours before you are given Rituzena. This is because some people have a fall in their blood pressure while they are being given Rituzena.
• if you have ever taken medicines which affect your immune system – such as chemotherapy or

immune-suppressive medicines.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before you are given Rituzena.

Pregnancy and breast-feeding

You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are planning to become pregnant. This is because Rituzena can transfer across the placenta and may affect your baby.

If you can get pregnant, you and your partner must use an effective method of contraception while using Rituzena. You must also do this for 12 months after your last treatment with Rituzena.

Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months after your last treatment with Rituzena. This is because Rituzena may pass into breast milk.

Driving and using machines

It is not known whether Rituzena has an effect on you being able to drive or use any tools or machines.

• 9. How Rituzena is given

  Rituzena will be given to you by a doctor or nurse who is experienced in the use of this treatment. They will watch you closely while you are being given this medicine. This is in case you get any side effects.

You will always be given Rituzena as a drip (intravenous infusion).

Medicines given before each Rituzena administration

Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or reduce possible side effects.

How much and how often you will receive your treatment

g treated for chronic lymphocytic leukaemia

When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena infusion. Your doctor will decide if you should receive other treatment at the same time.

• f) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid medicine given by mouth may be started at any time by your doctor to treat your condition.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

10. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of these reactions have been fatal.

Infusion reactions

During or within the first 2 hours of the first infusion you may develop fever, chills and shivering. Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness, headache, breathing difficulties, tongue or throat swelling, itchy or runny nose, vomiting, flushing or palpitations, heart attack or low number of platelets. If you have heart disease or angina, these infusion reactions might get worse. Tell the person giving you the infusion immediately if you develop any of these symptoms, as the infusion may need to be slowed down or stopped. You may require additional treatment such as an antihistamine or paracetamol. When these symptoms go away, or improve, the infusion can be continued. These reactions are less likely to happen aft second infusion. Your doctor may decide to stop your Rituzena treatment if these reactions a serious.

Infections

• fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell
• memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare,

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or PML).

You might get infections more easily during your treatment with Rituzena.

These are often colds, but there have been cases of pneumonia or urinary infections. These are listed below under “Other side effects”.

Skin reactions

Very rarely, severe blistering skin conditions tha associated with blisters, may appear on the ski the genital areas or the eyelids, and fever any of these symptoms.

-Hodgkin’s Lymphoma or chronic lymphocytic leukaemia

Very common side effects (may affect more than 1 in 10 people):

• bacterial or viral infections, bronchitis
• low number of white blood cells sometimes with fever, or low number of blood cells called “platelets”
• feeling sick (nausea)

ts on the scalp, chills, headache

munity – because of lower levels of anti-bodies called “immunoglobulins” (IgG) ood which help protect against infection n side effects (may affect up to 1 in 10 people):

infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections, fungal infections, infections of unknown origin, sinus inflammation, hepatitis B low number of red blood cells (anaemia), low number of all blood cells allergic reactions (hypersensitivity)

high blood sugar level, weight loss, swelling in the face and body, high levels of the enzyme “lactate dehydrogenase (LDH)” in the blood, low calcium levels in the blood unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping skin feeling, reduced sense of touch

feeling restless, problems falling asleep,

becoming very red in the face and other areas of the skin as a consequence of dilation of the blood vessels

• painful joints or back
• muscle twitches or shakiness
• feeling dizzy
• tremors (shakiness, often in the hands)
• difficulty sleeping (insomnia)
• swelling of the hands or ankles

Common side effects (may affect up to 1 in 10 people):

• indigestion
• constipation
• skin rashes, including acne or spots
• flushing or redness of the skin
• blocked nose
• tight or painful muscles
• pain in the muscles or in the hands or feet
• low number of red blood cells (anaemia)
• low numbers of platelets in the blood
• an increase in the amount of potassium in the blood
• changes in the rhythm of the heart, or the heart beating faster than normal

Very rare side effects (may affect up to 1 in 10,000 people):

• severe blistering skin conditions that can be life-threatening. Redness, often associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth, the genital areas or the eyelids, and fever may be present.
• recurrence of a previous Hepatitis B infection