Mabthera

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MABTHERA®

Composition:

Active substance: rituximab;

1 vial contains rituximab 1400 mg/11.7 mL.

Excipients: recombinant human hyaluronidase (rHuPH20), L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, L-methionine, polysorbate 80, water for injections.

Medicinal form. Solution for injection.

Main physicochemical properties: the product is a transparent or opalescent, colorless or slightly yellow liquid.

Pharmacotherapeutic group.

Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. CD20 (cluster of differentiation 20) inhibitors.

ATC code L01FA01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Rituximab is a genetically engineered chimeric monoclonal antibody of mouse/human origin, which is a glycosylated immunoglobulin with constant regions of human IgG1 and variable regions of mouse light and heavy chains. The antibodies are produced by a mammalian cell suspension culture (Chinese hamster ovary cells) and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal techniques.

The subcutaneous formulation of MabThera® contains recombinant human hyaluronidase (rHuPH20), an enzyme used to enhance the diffusion and absorption of substances when administered subcutaneously in combination.

Rituximab specifically binds to the transmembrane CD20 antigen, a non-glycosylated phosphoprotein expressed on precursor B-lymphocytes (pre-B) and mature B-lymphocytes. This antigen is expressed on more than 95% of all B-cells in non-Hodgkin's lymphomas.

CD20 is found on both normal and malignant B-cells, but it is absent on hematopoietic stem cells, B-cell precursors, normal plasma cells, and other healthy tissues. This antigen does not internalize upon antibody binding and does not migrate from the cell surface. CD20 does not circulate in blood plasma as a free antigen and therefore does not compete with the antibody for binding.

The Fab domain of rituximab binds to the CD20 antigen on B-lymphocytes, while the Fc domain is capable of effector immune functions and participates in B-cell lysis. The likely mechanism of effector-mediated cell lysis includes complement-dependent cytotoxicity mediated by C1q binding, as well as antibody-dependent cellular cytotoxicity mediated by one or more Fcγ receptors on the surface of granulocytes, macrophages, and natural killer (NK) cells. It has also been demonstrated that rituximab, upon binding to the CD20 antigen on B-lymphocytes, induces cell death via apoptosis.

After administration of the first dose of MabThera®, peripheral B-cell counts decreased to below-normal levels. In patients receiving treatment for hematologic malignancies, B-cell recovery occurs within 6 months after treatment, with return to normal levels achieved within 12 months after completion of therapy; however, in some patients, the duration of B-cell recovery may be longer (on average up to 23 months after induction therapy). In patients with rheumatoid arthritis, rapid depletion of the B-cell population in peripheral blood was observed after two 1000 mg infusions of MabThera® administered 14 days apart. B-cell counts in peripheral blood began to increase by week 24, and signs of population recovery were observed in most patients by week 40, regardless of whether MabThera® was administered as monotherapy or in combination with methotrexate.

Immunogenicity

Data from the development program for the subcutaneous formulation of MabThera® indicate that the formation of anti-rituximab antibodies following subcutaneous administration is comparable to that observed after intravenous administration. In the SABRINA (BO22334) study, the frequency of treatment-induced or treatment-enhanced formation of anti-rituximab antibodies was low and similar between the subcutaneous and intravenous groups (1.9% vs. 2%, respectively). The frequency of treatment-induced or treatment-enhanced formation of anti-rHuPH20 antibodies was 8% in the intravenous group compared to 15% in the subcutaneous group, and neutralizing antibodies were not detected in any patient with positive test results for anti-rHuPH20 antibodies.

The overall number of patients in whom anti-rHuPH20 antibodies were detected remained similar during the observation period in both cohorts. The clinical significance of developing anti-rituximab or anti-rHuPH20 antibodies after treatment with subcutaneous MabThera® is unknown.

No apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety and efficacy was observed.

Pharmacokinetics.

Absorption

The pharmacokinetics of rituximab after subcutaneous administration of a single dose of MabThera® at 375 mg/m², 625 mg/m², and 800 mg/m² was comparable to that after intravenous administration of MabThera® at 375 mg/m² in patients with follicular lymphoma. After subcutaneous administration, rituximab is slowly absorbed and reaches peak concentration approximately 3 days after administration. Based on population pharmacokinetic analysis, the absolute bioavailability was 71%. Rituximab exposure increased in a dose-proportional manner following subcutaneous administration in doses ranging from 375 mg/m² to 800 mg/m². Pharmacokinetic parameters such as clearance, volume of distribution, and half-life were comparable between the two formulations of MabThera®.

Study BP22333 (SparkThera)

A two-stage Phase Ib study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the subcutaneous formulation of MabThera® administered to patients with follicular lymphoma as part of maintenance therapy. During Stage 2, MabThera® subcutaneous was administered at a fixed dose of 1400 mg during maintenance therapy following at least one course of treatment with intravenous MabThera® in patients with follicular lymphoma who responded to prior induction therapy with intravenous MabThera®.

A comparison of predicted mean maximum concentrations of subcutaneous MabThera® and intravenous MabThera® is presented in Table 1.

Table 1. Study BP22333 (SparkThera): Absorption – Pharmacokinetic parameters of subcutaneous MabThera® compared with intravenous MabThera®

	Mabthera® for subcutaneous administration	Mabthera® for intravenous administration
Projected mean maximum concentration (q2m), mcg/mL	201	209
Projected mean maximum concentration (q3m), mcg/mL	189	184

The median time to reach maximum concentration (Tmax) following administration of MabThera® for subcutaneous use was approximately 3 days, compared to the Tmax achieved at the end or near the end of the infusion of the intravenous formulation of MabThera®.

Study BO22334 (SABRINA)

MabThera® for subcutaneous use was administered at a fixed dose of 1400 mg subcutaneously over 6 cycles during the induction treatment phase every 3 weeks following an initial course of MabThera® for intravenous use in previously untreated patients with follicular lymphoma, in combination with chemotherapy. The maximum serum concentration of rituximab after 7 cycles was similar between the two treatment groups, with geometric means (CV%) of 250.63 (19.01) µg/mL and 236.82 (29.41) µg/mL for the intravenous and subcutaneous formulations, respectively, resulting in a geometric mean ratio (Cmax, subcutaneous formulation/Cmax, intravenous formulation) of 0.941 (90% confidence interval: 0.872, 1.015).

Distribution/Elimination

Geometric mean trough concentrations and geometric mean AUCτ values from studies BPP22333 and BO22334 are presented in Table 2.

Table 2. Distribution/Elimination – Pharmacokinetic parameters of MabThera® for subcutaneous use compared to MabThera® for intravenous use

Study BP22333 (SparkThera)
Drug formulation	Geometric mean minimum concentration (q2m), µg/mL	Geometric mean minimum concentration (q3m), µg/mL	Geometric mean AUCτ cycle 2 (q2m), µg×day/mL	Geometric mean AUCτ cycle 2 (q3m), µg×day/mL
Rituximab for subcutaneous injection	32.2	12.1	5430	5320
Rituximab for intravenous infusion	25.9	10.9	4012	3947
Study BO22334 (SABRINA)
Drug formulation	Geometric mean minimum concentration prior to start of 8th cycle, µg/mL		Geometric mean AUC after 7 cycles, µg×day/mL
Rituximab for subcutaneous injection	134.6		3778
Rituximab for intravenous infusion	83.1		2734

Based on the population pharmacokinetic analysis in 403 patients with follicular lymphoma who received MabThera® administered subcutaneously and/or intravenously as single or multiple infusions either as monotherapy or in combination with chemotherapy, the population estimates of non-specific clearance (CL1), specific clearance (CL2)—likely occurring via B-cells or tumor mass—and volume of distribution in the central compartment (V1) were 0.194 L/day, 0.535 L/day, and 4.37 L, respectively. The calculated median terminal half-life of subcutaneously administered MabThera® was 29.7 days (range: 9.9 to 91.2 days). The analysis dataset included 6003 measured samples from 403 patients who received subcutaneous and/or intravenous MabThera® in studies BP22333 (3736 samples from 277 patients) and BO22334 (2267 samples from 126 patients). Twenty-nine (0.48%) post-dose observations (all from study BP22333) were below the lower limit of quantification. There were no missing covariate values except for baseline B-cell counts. Baseline tumor burden data were available only in study BO22334.

Special populations

In the clinical study BO22334, a relationship was observed between body size and the exposure ratio following 7 cycles of subcutaneously administered rituximab (1400 mg administered every 3 weeks) compared to intravenously administered rituximab (375 mg/m² administered every 3 weeks), with corresponding minimum concentration (Cmin) ratios of 2.29, 1.31, and 1.41 in patients with small, medium, and large body surface area, respectively (small body surface area ≤ 1.70 m²; 1.70 m² < medium body surface area < 1.90 m²; large body surface area ≥ 1.90 m²). The corresponding AUCτ ratios were 1.66, 1.17, and 1.32.

Clinically significant effects of age and sex on the pharmacokinetics of rituximab were not observed.

Anti-rituximab antibodies were detected in only 13 patients and did not lead to any clinically significant increase in steady-state clearance.

Clinical characteristics.

Indications.

Non-Hodgkin's lymphomas (NHL)

Treatment of previously untreated follicular lymphoma stage III–IV, in combination with chemotherapy.

Maintenance therapy for follicular lymphoma following response to induction therapy.

Treatment of CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).

Contraindications.

Hypersensitivity to the active substance or to mouse proteins, hyaluronidase, or to any of the excipients (see section "Composition").

Active severe infections (see section "Special precautions").

Marked immunodeficiency.

Interaction with other medicinal products and other types of interactions.

Currently, data on possible interactions between medicinal products and MabThera® are limited.

There is no evidence that concomitant administration of drugs with MabThera® affects the pharmacokinetics of fludarabine or cyclophosphamide. Furthermore, no significant influence of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab has been observed.

In patients with titers of human anti-mouse antibodies or antibodies to the medicinal product, allergic reactions or hypersensitivity reactions may occur when using other diagnostic or therapeutic monoclonal antibodies.

Special precautions for use.

Traceability

To improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly documented. The information provided in this section applies to the subcutaneous formulation of MabThera® used for the approved indications of treatment of non-Hodgkin's lymphoma (dose 1400 mg) and treatment of chronic lymphocytic leukemia (dose 1600 mg). Information on other indications can be found in the Summary of Product Characteristics for MabThera® for intravenous administration.

The use of subcutaneously administered MabThera® as monotherapy in patients with stage III–IV follicular lymphoma who are chemotherapy-resistant or in second or later relapse after chemotherapy is not recommended, as the safety of weekly subcutaneous administration has not been established.

Progressive multifocal leukoencephalopathy (PML)

Treatment with MabThera® may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients should be monitored regularly for any new or worsening neurological symptoms that may indicate PML. If PML is suspected, further treatment should be suspended until PML has been ruled out. Clinicians should evaluate patients to determine whether symptoms suggest neurological dysfunction and, if so, whether these symptoms could indicate PML. Neurological consultation should be considered as clinically indicated.

If there is any uncertainty, additional diagnostic testing may be appropriate, including MRI scanning (preferably with contrast), analysis of cerebrospinal fluid for John Cunningham (JC) virus DNA, and repeat neurological evaluation.

Physicians must pay special attention to symptoms that may indicate PML but which the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms). Patients should also be advised to inform their family members or caregivers about their treatment, as these individuals may notice symptoms the patient has not recognized.

If PML develops in a patient, treatment with MabThera® must be permanently discontinued.

In immunocompromised patients with PML, stabilization or improvement of the condition has been observed after immune system recovery. It is currently unknown whether early detection of PML and discontinuation of MabThera® therapy may lead to similar stabilization or improvement.

Infusion reactions / administration-related reactions

Treatment with MabThera® is associated with infusion reactions/administration-related reactions, which may be related to cytokine release and/or other chemical mediators. Cytokine release syndrome may clinically resemble acute hypersensitivity reactions.

The reactions described below include cytokine release syndrome, tumor lysis syndrome, and anaphylactic and hypersensitivity reactions. These reactions are not specifically related to the route of administration of MabThera® and may occur with either formulation.

Severe infusion reactions with fatal outcomes have been reported during post-marketing use of the intravenous formulation of MabThera®. These reactions occurred within 30 minutes to 2 hours after the start of the first intravenous infusion of MabThera®. They were characterized by pulmonary symptoms and, in some cases, included rapid tumor lysis and signs of tumor lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema, and other symptoms (see section "Adverse reactions").

Severe cytokine release syndrome is characterized by marked dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be accompanied by some features of tumor lysis syndrome, such as hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, elevated lactate dehydrogenase (LDH) levels, and may also lead to acute respiratory failure and death. Acute respiratory failure may be associated with findings such as interstitial infiltration or pulmonary edema, detectable by chest X-ray. The syndrome often manifests within one to two hours after the start of the first infusion. Patients with a history of respiratory insufficiency or tumor infiltration of the lungs are at higher risk of an unfavorable clinical outcome and therefore require heightened caution during treatment. In case of severe cytokine release syndrome, infusion should be immediately interrupted (see section "Dosage and administration") and intensive symptomatic treatment initiated. Because clinical symptoms may worsen after initial improvement, such patients require careful monitoring until tumor lysis syndrome and pulmonary infiltration are resolved or excluded. In rare cases, resuming treatment after complete symptom resolution has led to recurrence of severe cytokine release syndrome.

Treatment of patients with a high tumor burden or a large number of circulating malignant cells (≥25 × 10⁹/L) (e.g., patients with CLL), who are at increased risk of particularly severe cytokine release syndrome, should be conducted with extreme caution. Such patients require especially close monitoring throughout the first infusion. If, during the first or any subsequent cycle, lymphocyte count remains >25 × 10⁹/L in such patients, consideration should be given to reducing the infusion rate or splitting the dose over two days.

Anaphylactic and other hypersensitivity reactions have been reported after intravenous administration of protein-based medicinal products. Unlike cytokine release syndrome, true hypersensitivity reactions develop within minutes after the start of infusion. Medicinal products for the treatment of hypersensitivity reactions, such as epinephrine (adrenaline), antihistamines, and glucocorticoids, should be readily available for immediate use in case of an allergic reaction during MabThera® administration. Clinical manifestations of anaphylaxis may resemble those of cytokine release syndrome (described above). Hypersensitivity-related reactions have been reported less frequently than cytokine release-related reactions.

Other reactions observed in some cases include myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia.

Since arterial hypotension may occur during MabThera® infusion, consideration should be given to withholding antihypertensive medications for 12 hours before MabThera® infusion.

Infusion-related adverse reactions of all types were observed in 77% of patients receiving MabThera® treatment (including cytokine release syndrome associated with arterial hypotension and bronchospasm in 10% of patients) (see section "Adverse reactions"). These symptoms are usually reversible upon interruption of MabThera® infusion and administration of antipyretics, antihistamines, and, in some cases, oxygen, intravenous saline, bronchodilators, and glucocorticoids if necessary. Severe reactions are described above in this subsection.

In clinical trials, administration-related reactions occurred in up to 50% of patients receiving MabThera® for subcutaneous administration. Reactions occurring within 24 hours after subcutaneous injection were mainly erythema, pruritus, rash, and injection site reactions such as pain, swelling, and redness; these reactions were mostly mild or moderate in severity (Grade 1 or 2) and transient.

Local skin reactions were very common in patients receiving subcutaneously administered MabThera® in clinical trials. Symptoms included pain, swelling, induration, bleeding, erythema, pruritus, and rash (see section "Adverse reactions").

Some local skin reactions occurred more than 24 hours after subcutaneous administration of MabThera®. The majority of local skin reactions observed after subcutaneous administration of MabThera® were mild or moderate in severity and resolved without specific treatment.

Before initiating subcutaneous injection of MabThera®, all patients must have received at least one full dose of intravenously administered MabThera®. The highest risk of administration-related reactions generally occurs during the first cycle. Starting treatment with intravenous MabThera® allows better control of infusion-related reactions by slowing or stopping the intravenous infusion.

If a patient has not received one full intravenous dose of MabThera® before switching to subcutaneous administration, the next cycle should continue with intravenous MabThera® until a full intravenous dose has been administered. Therefore, switching patients to subcutaneous MabThera® is possible only from the second or subsequent treatment cycles.

As with intravenous MabThera®, subcutaneous administration of MabThera® should be performed under the close supervision of an experienced physician in a setting where full resuscitation measures are immediately available. Premedication (antipyretic/antihistamine) should be administered before each MabThera® infusion. Consideration should be given to premedication with glucocorticoids.

Patients should be monitored for at least 15 minutes after subcutaneous administration of MabThera®. Patients at increased risk of hypersensitivity reactions may require a longer observation period.

Patients should be instructed to seek immediate medical attention if symptoms suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after administration.

Cardiac disorders

In patients receiving MabThera®, angina pectoris, cardiac arrhythmias (including atrial flutter and atrial fibrillation), heart failure, and/or myocardial infarction have been observed. Therefore, patients with a history of cardiac disease and/or prior cardiotoxic chemotherapy require careful monitoring.

Hematotoxicity

Although MabThera® does not have myelosuppressive effects when used as monotherapy, caution should be exercised when administering treatment to patients with neutrophil counts <1.5 × 10⁹/L and/or platelet counts <75 × 10⁹/L, as experience in this population is limited. MabThera® has been used to treat 21 patients who underwent autologous bone marrow transplantation and other high-risk groups for bone marrow suppression, without observed myelotoxic effects.

Complete blood counts, including neutrophil and platelet counts, should be performed regularly during MabThera® therapy.

In studies of MabThera® use in patients with Waldenström's macroglobulinemia, transient increases in serum IgM levels were observed after initiation of treatment, which may be associated with increased blood viscosity and related symptoms. Transient increases in IgM levels were usually reversible, returning to baseline or lower within 4 months.

Infections

Serious infections, including fatal cases, may occur during MabThera® therapy (see section "Adverse reactions"). MabThera® should not be administered to patients with active severe infections (e.g., tuberculosis, sepsis, and opportunistic infections; see section "Contraindications").

Physicians should exercise caution when considering MabThera® use in patients with recurrent or chronic infections in their medical history or underlying conditions that increase susceptibility to severe infections (see section "Adverse reactions").

Cases of hepatitis B reactivation have been reported in individuals receiving MabThera®, including cases of fulminant hepatitis with fatal outcomes. Most of these patients were also receiving cytotoxic chemotherapy. Screening for hepatitis B virus (HBV) should be performed in all patients before starting MabThera® therapy. Testing should include at minimum HBsAg and HBcAb, and may be supplemented with other appropriate markers according to local guidelines. MabThera® should not be used in patients with active hepatitis B. Patients with positive serological tests for hepatitis B virus (HBsAg or HBcAb) should consult with liver disease specialists before starting treatment. These patients should be monitored according to local medical standards to prevent hepatitis B virus reactivation.

During post-marketing use of MabThera® in NHL, very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported (see section "Adverse reactions"). Most patients received rituximab in combination with chemotherapy or as part of hematopoietic stem cell transplantation programs.

After rituximab administration, cases of enteroviral meningoencephalitis, including fatal cases, have been reported.

False-negative results in serological infection tests.
Due to the risk of false-negative serological test results for infections, alternative diagnostic methods should be considered if symptoms suggestive of rare infectious diseases occur, including West Nile virus and neuroborreliosis.

Immunization

The safety of live viral vaccines after MabThera® therapy has not been studied in patients with NHL; therefore, vaccination with live viral vaccines is not recommended. Patients who have received MabThera® may receive vaccines that do not contain live viruses. However, the response to non-live vaccines may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received intravenous MabThera® as monotherapy had a lower response rate to tetanus toxoid vaccination (16% vs. 81%) and to the neoantigen keyhole limpet hemocyanin (KLH) (4% vs. 69% for antibody titer increase >2-fold) compared to healthy untreated volunteers.

Antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) measured prior to therapy were maintained for up to 6 months after MabThera® treatment.

Skin reactions

Severe skin reactions, such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, have been reported, some of which were fatal (see section "Adverse reactions"). If such skin reactions occur and are suspected to be related to MabThera® administration, treatment should be permanently discontinued.

Use during pregnancy or breastfeeding.

Contraception in men and women

Given the prolonged persistence of rituximab in patients with B-cell depletion, women of childbearing potential should use effective contraception during treatment and for 12 months after completion of MabThera® therapy.

Pregnancy

It is known that IgG immunoglobulins cross the placental barrier.

B-cell levels in infants whose mothers received MabThera® during pregnancy have not been studied in clinical trials. Adequate and well-controlled studies in pregnant women are lacking, although reports exist of transient B-cell depletion and lymphopenia in some infants whose mothers received MabThera® during pregnancy. Similar effects have been observed in animal studies. For these reasons, MabThera® should not be administered to pregnant women unless the potential benefit outweighs the potential risk.

Breastfeeding

Limited data on the excretion of rituximab in breast milk indicate very low concentrations of rituximab in breast milk (relative infant dose less than 0.4%). Several cases of follow-up of breastfed infants describe normal growth and development up to 2 years of age. However, since these data are limited and long-term outcomes in breastfed infants remain unknown, breastfeeding is not recommended during rituximab treatment and optimally for 6 months after rituximab treatment.

Fertility

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

Ability to drive and use machines.

Studies on the effect of MabThera® on the ability to drive or operate machinery have not been conducted; however, its pharmacological action and currently reported adverse reactions suggest no or negligible effect of MabThera® on the ability to drive or operate machinery.

Administration and Dosage

MabThera® must be administered under the close supervision of an experienced physician in settings where full resuscitation measures can be immediately performed (see section "Special Precautions").

Premedication (antipyretic, e.g., paracetamol, and antihistamine, e.g., diphenhydramine) must be administered before each administration of MabThera®.

Consider premedication with glucocorticoids if MabThera® is not used in combination with chemotherapy regimens that include glucocorticoids.

Dosage

The recommended dose of MabThera® for subcutaneous administration in adults is 1400 mg (fixed dose) as a subcutaneous injection, regardless of body surface area. The 1400 mg dose is intended for subcutaneous administration only in patients with non-Hodgkin's lymphoma (NHL).

Before initiating treatment with subcutaneously administered MabThera®, all patients must first receive one full dose of intravenously administered MabThera® (see section "Special Precautions").

If a patient has not received one full intravenous dose of MabThera® prior to switching to subcutaneous MabThera®, the next cycle should continue with intravenous MabThera® until a full intravenous dose has been administered. Therefore, switching patients to subcutaneous MabThera® is only possible starting from the second or subsequent treatment cycles.

It is important to check the product label to ensure that the correct formulation (intravenous or subcutaneous) and dose prescribed by the physician are being used.

MabThera® for subcutaneous administration is not intended for intravenous use and must be administered exclusively as a subcutaneous injection. The subcutaneous formulation of MabThera® must only be given as a subcutaneous injection.

Follicular Non-Hodgkin’s Lymphoma

Combination Therapy

The recommended dose of MabThera® in combination with chemotherapy for induction therapy in previously untreated patients or in patients with relapsed/refractory follicular lymphoma who have not previously received treatment is: first cycle – MabThera® administered intravenously at a dose of 375 mg/m² body surface area, followed by subcutaneous MabThera® at a fixed dose of 1400 mg per cycle, with a total treatment duration of up to 8 cycles.

MabThera® should be administered on Day 1 of each chemotherapy cycle, after administration of the glucocorticoid component of chemotherapy, if included in the treatment regimen.

Maintenance Therapy

Previously Untreated Follicular Lymphoma

The recommended dose of MabThera® for subcutaneous administration as maintenance therapy in patients with previously untreated follicular lymphoma who have achieved a clinical response to induction therapy is: 1400 mg every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum duration of two years (a total of 12 administrations).

Relapsed/Refractory Follicular Lymphoma

The recommended dose of MabThera® for subcutaneous administration as maintenance therapy in patients with relapsed/refractory follicular lymphoma who have achieved a clinical response to induction therapy is: 1400 mg every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum duration of two years (a total of 8 administrations).

Diffuse Large B-cell Non-Hodgkin’s Lymphoma

MabThera® should be used in combination with chemotherapy according to the CHOP regimen. The recommended dosage is: first cycle – MabThera® administered intravenously at a dose of 375 mg/m² body surface area, followed by subcutaneous MabThera® at a fixed dose of 1400 mg per cycle, with a total treatment duration of up to 8 cycles.

MabThera® should be administered on Day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the CHOP regimen.

The safety and efficacy of MabThera® in combination with other chemotherapeutic agents for the treatment of diffuse large B-cell non-Hodgkin’s lymphoma have not been established.

Dose Adjustment During Treatment

Dose reduction of MabThera® is not recommended. If MabThera® is used in combination with chemotherapy, standard approaches to dose reduction of chemotherapeutic agents should be followed (see section "Adverse Reactions").

Special Precautions for Disposal or Other Handling of the Medicinal Product

MabThera® is supplied in sterile, preservative-free, pyrogen-free, single-use vials. A sterile needle and syringe should be used to prepare MabThera® for administration. The following recommendations for the use and disposal of syringes and other sharp medical devices must be strictly observed:

• Needles and syringes must never be reused.
• All used needles and syringes must be placed in sharps containers (single-use, puncture-resistant containers).

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

Special Populations

Children

The safety and efficacy of MabThera® in children have not been established. There are no available data.

Elderly Patients

Dose adjustment in patients aged over 65 years is not required.

Administration Method

Subcutaneous Injections

The 1400 mg subcutaneous formulation of MabThera® must be administered exclusively as a subcutaneous injection over approximately 5 minutes. The subcutaneous injection needle should be attached to the syringe immediately before administration to avoid needle contamination.

The subcutaneous injection should be administered subcutaneously into the abdominal wall. The product must not be injected into areas of skin with redness, bruising, pain, induration, nevi, or scars.

There are no data on administration at other body sites; therefore, injections should only be given in the abdominal wall.

During treatment with subcutaneously administered MabThera®, other subcutaneously administered medicinal products should preferably be administered at different injection sites.

If an injection is interrupted, it may be continued at the same site or at another site, if possible.

Storage Precautions After First Opening of the Vial

After transferring the subcutaneous solution from the vial into the syringe, the physical and chemical stability of the product remains stable for 48 hours at 2–8°C and subsequently for 8 hours at 30°C, provided it is stored under ambient daylight conditions.

From a microbiological standpoint, the product should be used immediately. If not used immediately, preparation should be carried out under controlled and validated aseptic conditions. The user is responsible for the storage time and conditions of the product prior to administration.

Overdose

Clinical experience with doses exceeding the approved doses of intravenously administered MabThera® in humans is limited. The highest intravenous dose studied in humans to date is 5000 mg (2250 mg/m²), investigated in a dose-escalation study in patients with chronic lymphocytic leukemia. No additional safety signals were identified.

In case of overdose, the infusion should be stopped immediately and the patient should be closely monitored.

In the SABRINA (BO22334) study of subcutaneously administered MabThera®, three patients inadvertently received up to 2780 mg of subcutaneous rituximab administered intravenously, without occurrence of adverse effects. In cases of overdose or administration error, patients should be closely monitored.

During post-marketing surveillance, five cases of overdose with MabThera® have been reported. In three cases, no adverse events were reported. The two adverse events reported were influenza-like symptoms at a rituximab dose of 1.8 g and respiratory failure with fatal outcome at a rituximab dose of 2 g.

Adverse Reactions

The information provided in this section pertains to the use of MabThera® in oncology. For autoimmune diseases, refer to the instructions for medical use of MabThera® for intravenous administration.

Safety Profile Summary

During the development program, the safety profile of the subcutaneous formulation of MabThera® was comparable to that of the intravenous formulation, except for skin reactions at the injection site. Skin reactions at the injection site, including injection site reactions, were very common in patients receiving the subcutaneous formulation of MabThera®. In the phase 3 SABRINA study (BO22334), skin reactions were reported in up to 20% of patients receiving MabThera® subcutaneously. The most common local skin reactions in the subcutaneous MabThera® group were erythema at the injection site (13%), pain at the injection site (7%), and swelling at the injection site (4%). Reactions observed after subcutaneous administration were mild to moderate in severity, except for one patient who experienced a single episode of grade 3 rash at the injection site following the first subcutaneous administration of MabThera® (cycle 2). Local skin reactions of any grade in the subcutaneous MabThera® group were most frequent during the first cycle of subcutaneous administration (cycle 2) and the second administration, with decreasing frequency during subsequent injections.

Adverse reactions reported with subcutaneous MabThera®

The risk of acute reactions associated with the subcutaneous formulation of MabThera® was evaluated in two open-label studies involving patients with follicular lymphoma during induction and maintenance therapy (SABRINA [BO22334]) and during maintenance therapy alone (SparkThera [BP22333]). In the SABRINA study, severe administration-related reactions (≥ grade 3) were observed in two (2%) patients after administration of the subcutaneous formulation of MabThera®. These were grade 3 reactions: injection site rash and dry mouth. In the SparkThera study, no severe administration-related reactions were reported.

Adverse reactions reported with intravenous MabThera®

Patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL)

The overall safety profile of MabThera® in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia is based on data from clinical trials and post-marketing surveillance. These patients received MabThera® either as monotherapy (for induction therapy or maintenance therapy following induction) or in combination with chemotherapy.

The most common adverse reactions (ARs) in patients receiving MabThera® were infusion-related reactions, which occurred in the majority of patients during the first infusion.

The frequency of infusion-related symptoms significantly decreases with subsequent infusions and is less than 1% after the eighth dose of MabThera®.

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

Serious drug reactions most commonly observed were:

• Infusion-related reactions (including cytokine release syndrome, tumor lysis syndrome); see section "Special Warnings and Precautions".
• Infections; see section "Special Warnings and Precautions".
• Cardiovascular events; see section "Special Warnings and Precautions".

Other serious ARs reported include hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML) (see section "Special Warnings and Precautions").

The frequency of adverse reactions reported with MabThera® administered alone or in combination with chemotherapy is shown in Table 3. Within each frequency group, adverse reactions are listed in descending order of severity. Frequency is 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 available data).

Adverse reactions identified only during post-marketing surveillance, for which frequency cannot be estimated, are categorized as "Frequency not known."

Table 3. Adverse reactions reported during clinical trials or post-marketing surveillance in patients with NHL and CLL receiving MabThera® as monotherapy/maintenance therapy or in combination with chemotherapy

System organ class	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations	Bacterial infections, viral infections, +bronchitis	Sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown etiology, +acute bronchitis, +sinusitis, hepatitis B1		Severe viral infection2		Enteroviral meningoencephalitis2,3
Blood and lymphatic system disorders	Neutropenia, leukopenia, +febrile neutropenia, +thrombocytopenia	Anemia, +pancytopenia, +granulocytopenia	Coagulation disorders, aplastic anemia, hemolytic anemia, lymphadenopathy		Transient increase in serum IgM levels4	Late-onset neutropenia4
Immune system disorders	Infusion-related reactions4, angioedema	Hypersensitivity		Anaphylaxis	Tumor lysis syndrome, cytokine release syndrome5, serum sickness	Infusion-related acute reversible thrombocytopenia5
Metabolism and nutrition disorders		Hypoglycemia, weight decreased, peripheral edema, facial edema, increased LDH, hypocalcemia
Psychiatric disorders			Depression, restlessness
Nervous system disorders		Paraesthesia, hypoaesthesia, irritability, insomnia, vasodilation, dizziness, anxiety	Dysgeusia		Peripheral neuropathy, facial nerve paralysis6	Cranial nerve neuropathy, loss of other senses6
Eye disorders		Tear film disorders, conjunctivitis			Severe vision loss6
Ear and labyrinth disorders		Tinnitus, ear pain				Hearing loss6
Cardiac disorders		+Myocardial infarction5, 7, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder	+Left ventricular dysfunction, +supraventricular tachycardia, +ventricular tachycardia, +angina pectoris, +myocardial ischemia, bradycardia	Severe cardiac events5, 7	Heart failure5, 7
Vascular disorders		Arterial hypertension, orthostatic hypotension, arterial hypotension			Vasculitis (mainly cutaneous), leukocytoclastic vasculitis
Respiratory, thoracic and mediastinal disorders		Bronchospasm5, respiratory disorder, chest pain, dyspnea, increased cough, rhinitis	Bronchial asthma, obliterative bronchiolitis, lung disorders, hypoxia	Interstitial lung disease8	Respiratory failure5	Lung infiltrates
Gastrointestinal disorders	Nausea	Vomiting, diarrhea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, loss of appetite, throat mucosal irritation	Abdominal distension		Perforation of stomach or intestine8
Skin and subcutaneous tissue disorders	Pruritus, rash, +alopecia	Urticaria, sweating, night sweats, +skin disorders			Severe bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)8
Musculoskeletal and connective tissue disorders		Increased muscle tone, myalgia, arthralgia, back pain, neck pain, pain
Renal and urinary disorders					Renal failure5
General disorders and administration site conditions	Pyrexia, chills, asthenia, headache	Tumor pain, flushing, malaise, influenza-like syndrome, +weakness, +tremor, +multi-organ failure4	Infusion site pain
Investigations	Decreased IgG levels

For each reaction, the frequency was calculated including reactions of all severity grades (from mild to severe), except for reactions marked with "+", for which the frequency was calculated considering only severe reactions (≥ grade 3 according to the National Cancer Institute's [NCI] Common Toxicity Criteria). Only the highest observed frequency from the studies is shown.

1 Including infusion reactions and primary infections; frequency observed with R-FC regimen in relapsed/refractory CLL.

2 See also the section "Infections" below.

3 Observed during post-marketing use.

4 See also the section "Blood-related adverse reactions" below.

5 See also information on infusion-related reactions below. In rare cases, fatal events have been reported.

6 Symptoms of cranial neuropathy. Observed at various times over several months following completion of MabThera® therapy.

7 Observed predominantly in patients with prior cardiac disease and/or cardiotoxic chemotherapy, and primarily associated with infusion-related reactions.

8 Including cases with fatal outcome.

Adverse reactions reported during clinical trials where the frequency in the MabThera® treatment group was the same or lower compared to control groups: hematologic toxicity, neutropenic infection, urinary tract infection, sensory disorder, hyperthermia.

During clinical trials of intravenous MabThera®, infusion-related symptoms were observed in more than 50% of patients; these occurred predominantly during the first infusion, usually within the first two hours. These symptoms most commonly included fever, chills, and shivering. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, weakness, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnea, dyspepsia, asthenia, and signs of tumor lysis syndrome. Severe infusion reactions (such as bronchospasm, hypotension) occurred in approximately 12% of cases. Other reactions reported in isolated cases included myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia. Exacerbation of pre-existing cardiac conditions, such as angina or congestive heart failure, or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary edema, multi-organ failure, tumor lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were observed at a lower frequency or with unknown frequency. The incidence of infusion-related symptoms significantly decreased with subsequent infusions and was less than 1% of patients by the eighth treatment cycle containing MabThera®.

Description of selected adverse reactions

Infections

MabThera® causes B-cell depletion in approximately 70–80% of patients, but only in a minority of patients was MabThera® treatment associated with decreased serum immunoglobulin levels.

Cases of localized candidiasis and herpes zoster occurred more frequently in patient groups receiving MabThera® in randomized trials. Severe infections developed in approximately 4% of patients receiving MabThera® monotherapy. A higher incidence of infections overall, including grade 3 or 4 infections, was observed during two-year maintenance therapy with MabThera® compared to the observation group. No cumulative infection-related toxicity was observed during the two-year treatment period. Additionally, other serious viral infections—first occurrence, reactivation, or exacerbation—some with fatal outcomes, have been reported with MabThera® treatment. Most patients received MabThera® in combination with chemotherapy or within hematopoietic stem cell transplantation programs. Examples of such serious viral infections include those caused by herpes viruses (cytomegalovirus, varicella-zoster virus, herpes simplex virus), John Cunningham virus (JCV) (progressive multifocal leukoencephalopathy [PML]), enterovirus (meningoencephalitis), and hepatitis C virus (see section "Special precautions"). Fatal cases of PML, occurring after disease progression and retreatment, were also observed during clinical trials. Cases of hepatitis B reactivation have been reported, most occurring in patients receiving MabThera® in combination with cytotoxic chemotherapy. Progression of Kaposi's sarcoma was observed in patients with pre-existing Kaposi's sarcoma receiving rituximab. These cases occurred during off-label use, and most patients were HIV-positive.

Blood-related adverse reactions

In clinical trials of MabThera® monotherapy administered over 4 weeks, blood count abnormalities were observed in a minority of patients and were usually mild and reversible.

Severe neutropenia (grade 3/4) occurred in 4.2% of patients, anemia in 1.1%, and thrombocytopenia in 1.7%. During two-year maintenance therapy with MabThera®, leukopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4%, grade 3/4) were reported more frequently than in the observation group. The frequency of thrombocytopenia was low (<1%, grade 3/4) in all treatment groups. In trials of MabThera® in combination with chemotherapy, grade 3/4 leukopenia (R-CHOP 88% vs. CHOP 79%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%) were generally observed more frequently compared to chemotherapy alone. However, the higher frequency of neutropenia in patients receiving MabThera® with chemotherapy was not associated with a higher frequency of infections and invasive events compared to patients receiving chemotherapy alone. No significant differences were reported regarding anemia. Isolated cases of late-onset neutropenia developing more than four weeks after the last MabThera® infusion have been reported.

In MabThera® trials involving patients with Waldenström's macroglobulinemia, transient increases in serum IgM levels were observed after initiation of treatment, which may be associated with increased blood viscosity and related symptoms. The transient IgM increase usually returned to at least baseline levels within 4 months.

Cardiovascular reactions

Cardiovascular reactions during MabThera® monotherapy clinical trials were observed in 18.8% of patients, most commonly hypotension and hypertension. Cases of grade 3 or 4 arrhythmias (including ventricular and supraventricular tachycardia) and angina occurred during infusions. During maintenance therapy, the frequency of grade 3/4 cardiac disorders was comparable between MabThera®-treated patients and the observation group. Cardiac events were reported as serious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular dysfunction, myocardial ischemia) in 3% of patients receiving MabThera®, compared to <1% in the observation group. In trials of MabThera® in combination with chemotherapy, the frequency of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP treatment group (14 patients, 6.9%) compared to the CHOP group (3 patients, 1.5%). All these arrhythmias occurred either during MabThera® infusion or were associated with precipitating conditions such as fever, infection, acute myocardial infarction, or pre-existing respiratory and cardiovascular diseases. No differences between R-CHOP and CHOP treatment groups were observed regarding the frequency of grade 3 and 4 cardiac events, including heart failure, myocardial disorders, and manifestations of ischemic heart disease.

Respiratory system

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

Neurological disorders

During treatment, acute thromboembolic cerebrovascular events occurred in four patients (2%) who received induction therapy with up to 8 cycles of R-CHOP and had cardiovascular risk factors, during the first treatment cycle. No differences between treatment groups were observed regarding the frequency of other thromboembolic events. For comparison, three patients (1.5%) in the CHOP group experienced cerebrovascular events during the follow-up period.

Cases of reversible posterior encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome have been reported. Symptoms included visual disturbances, headache, seizures, and altered mental status, with or without hypertension. Diagnosis of reversible posterior encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome requires confirmation by brain imaging. In reported cases, identifiable risk factors for reversible posterior encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome were present, including the patient's underlying disease, hypertension, immunosuppressive therapy, and/or chemotherapy.

Gastrointestinal disorders

In some patients receiving MabThera® for the treatment of non-Hodgkin's lymphoma, gastrointestinal perforation was observed, sometimes with fatal outcome. In most such cases, MabThera® was administered in combination with chemotherapy.

IgG levels

In clinical trials evaluating MabThera® maintenance therapy in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) after induction therapy in both the observation and MabThera® treatment groups. In the observation group, median IgG levels subsequently increased, reaching values above the LLN, but remained unchanged in the MabThera® treatment group. The proportion of patients with IgG levels below the LLN was approximately 60% in the MabThera® group throughout the 2-year treatment period, whereas a decrease was observed in the observation group (36% after 2 years).

Skin and subcutaneous tissue disorders

Very rare cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported, some with fatal outcomes.

Patient subpopulations: MabThera® monotherapy

Older patients (≥ 65 years):

The frequency of adverse reactions (ARs) of all severity grades and grade 3/4 ARs in older patients was similar to that in younger patients (<65 years).

Massive lymphadenopathy

In patients with massive lymph node involvement, the frequency of grade 3/4 ARs was higher than in those without massive lymphadenopathy (25.6% vs. 15.4%). The frequency of ARs of all grades was similar in both patient groups.

Retreatment

The proportion of patients reporting ARs during retreatment with additional courses of MabThera® was similar to the proportion reporting ARs during initial treatment (ARs of all grades and grade 3/4).

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at 2 to 8°C in the original packaging to protect from light. Keep out of reach of children. Do not freeze.

Incompatibilities

No incompatibilities were observed between subcutaneously administered MabThera® and syringe materials made of polypropylene or polycarbonate, or with stainless steel needles and polyethylene conical Luer-lock adapters.

Packaging

1400 mg/11.7 mL in a vial; 1 vial per cardboard box.

Prescription status

Prescription only.

Manufacturer

F. Hoffmann-La Roche Ltd

Manufacturer's address and location of operations:

Wurmisweg, 4303 Kaiseraugst, Switzerland