Ruxience

4). g. paracetamol and diphenhydramine, should always be given before each administration of Ruxience. Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if Ruxience is not given in combination with glucocorticoid-containing chemotherapy.

In paediatric patients with non-Hodgkin’s lymphoma, premedication with paracetamol and H1 antihistamine (= diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of the infusion of Ruxience. In addition, prednisone should be given as indicated in Table 1.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL 4 patients whose lymphocyte counts are > 25 x 109/L, it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with Ruxience to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris In patients with rheumatoid arthritis, GPA or MPA or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of Ruxience to decrease the incidence and severity of infusion-related reactions (IRRs).

In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Ruxience (the last dose of methylprednisolone may be given on the same day as the first infusion of Ruxience).

This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after the 4-week induction course of Ruxience treatment. Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for adult and paediatric patients with GPA/MPA and adult patients with PV during and following Ruxience treatment, as appropriate according to local clinical practice guidelines.

In paediatric patients with GPA or MPA, prior to the first Ruxience IV infusion, methylprednisolone should be given IV for three daily doses of 30 mg/kg/day (not to exceed 1 g/day) to treat severe vasculitis symptoms. Up to three additional daily doses of 30 mg/kg IV methylprednisolone can be given prior to the first Ruxience infusion.

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults Summary of the safety profile 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 reactions 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.

4. 4. 4. ). Tabulated list of adverse reactions The frequencies of adverse reactions reported with rituximab alone or in combination with chemotherapy are summarised in Table 3. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness. The adverse reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes.

16 Table 3 Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with rituximab monotherapy/maintenance or in combination with chemotherapy MedDRA System Organ Class Very Common Common Uncommon Rare Very Rare Not Known Infections and infestations bacterial infections, viral infections, +bronchitis sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 serious viral infection2, pneumocystis jirovecii PML enteroviral meningoenceph alitis2 and 3 Blood and lymphatic system disorders neutropenia, leucopenia, +febrile neutropenia, +thrombocytopen ia anaemia, +pancytopenia, +granulocytopenia coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenop athy transient increase in serum IgM levels4 late neutropenia4 Immune system disorders infusion-related reactions5, angioedema hypersensitivity anaphylaxis tumour lysis syndrome, cytokine release syndrome5, serum sickness infusion-related acute reversible thrombocytope nia5 Metabolism and nutrition disorders hyperglycaemia, weight decrease, oedema peripheral, face oedema, increased LDH, hypocalcaemia Psychiatric disorders depression, nervousness Nervous system disorders paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety dysgeusia peripheral neuropathy, facial nerve palsy6 cranial neuropathy, loss of other senses6 Eye disorders lacrimation disorder, conjunctivitis severe vision loss6 Ear and labyrinth disorders tinnitus, ear pain hearing loss6 Cardiac disorders +myocardial infarction5 and 7, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder +left ventricular failure, +supraventric ular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia severe cardiac disorders5 and 7 heart failure5 and 7 17 MedDRA System Organ Class Very Common Common Uncommon Rare Very Rare Not Known Vascular disorders hypertension, orthostatic hypotension, hypotension vasculitis (predominate ly cutaneous), leukocytoclas tic vasculitis Respiratory, thoracic and mediastinal disorders bronchospasm5, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis asthma, bronchiolitis obliterans, lung disorder, hypoxia interstitial lung disease8 respiratory failure5 lung infiltration Gastrointestin al disorders nausea vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation abdominal enlargement gastro-intesti nal perforation8 Skin and subcutaneous tissue disorders pruritus, rash, +alopecia urticaria, sweating, night sweats, +skin disorder severe bullous skin reactions, Stevens-John son syndrome, toxic epidermal necrolysis (Lyell’s syndrome)8 Musculoskelet al and connective tissue disorders hypertonia, myalgia, arthralgia, back pain, neck pain, pain Renal and urinary disorders renal failure5 General disorders and administration site conditions fever, chills, asthenia, headache tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure5 infusion site pain Investigations decreased IgG levels 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.

Traceability In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. Progressive multifocal leukoencephalopathy All patients treated with Ruxience for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris 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 progressive multifocal leukoencephalopathy (PML). Very rare cases of fatal PML have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) and vasculitis] and during post-marketing use of rituximab in NHL and CLL (where the majority of patients had received rituximab in combination with chemotherapy or as part of haematopoietic stem cell transplant).

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. 10 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.

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 Ruxience must be permanently discontinued.

1. 4). Patients in a severely immunocompromised state. 4 regarding other cardiovascular diseases).