DARZALEX SC

1 Dosing Considerations It is important to check the product labels to ensure that the appropriate formulation (SC or IV) is being given to the patient, as described. • Darzalex SC should be administered under the supervision of a healthcare professional experienced in the treatment of cancer.

• Do not administer intravenously. Darzalex SC is for subcutaneous use only. Darzalex SC has different dosage and administration instructions than Darzalex intravenous daratumumab. 4 Administration). 4 Administration). 2 Recommended Dose and Dosage Adjustment Recommended Dose for Multiple Myeloma The recommended dose of Darzalex SC is 1800 mg administered subcutaneously, over approximately 3-5 minutes.

See Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6 for the recommended dosing schedules when Darzalex SC is administered as monotherapy or as part of a combination. 0 Darzalex SC (daratumumab injection) Page 7 of 144 Dosing Schedule: Combination therapy with bortezomib/lenalidomide/dexamethasone (4-week cycle regimen) The dosing schedule in Table 1 is for combination therapy with bortezomib, lenalidomide and dexamethasone (4-week cycle regimens) for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

Table 1:

Dosing schedule for Darzalex SC in combination with bortezomib, lenalidomide and dexamethasone ([VRd]; 4-week cycle dosing regimen) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16a every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 17 to 24b every two weeks (total of 4 doses) Maintenance Week 25 onwards until disease progressionc every four weeks a First dose of the every-2-week dosing schedule is given at Week 9 b Week 17 corresponds to re-initiation of treatment following recovery from ASCT c Discontinue Darzalex SC for patients who have achieved MRD negativity that is sustained for 12 months and have been treated on maintenance for at least 24 months.

For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14 CLINICAL TRIALS, and consult the corresponding Product Monographs. Combination therapy with bortezomib/lenalidomide/dexamethasone (3-week cycle regimen) The dosing schedule in Table 2 is for combination therapy with bortezomib, lenalidomide and dexamethasone (3-week cycle regimens) for the treatment of patients with newly diagnosed multiple myeloma who are not candidates for ASCT.

0 Darzalex SC (daratumumab injection) Page 8 of 144 a First dose of the every-3-week dosing schedule is given at Week 7 b First dose of the every-4-week dosing schedule is given at Week 25 For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14 CLINICAL TRIALS, and consult the corresponding Product Monographs.

g. lenalidomide or pomalidomide) and for monotherapy as follows: - combination therapy with lenalidomide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).

- combination therapy with lenalidomide and low-dose dexamethasone for patients with multiple myeloma who have received at least one prior therapy. - combination therapy with pomalidomide and dexamethasone for patients with multiple myeloma who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor.

- monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD.

Table 3:

Dosing schedule for Darzalex SC monotherapy and in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone (4-week cycle dosing regimens) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24a every two weeks (total of 8 doses) Week 25 onwards until disease progressionb every four weeks a First dose of the every 2-week-dosing schedule is given at Week 9 b First dose of the every 4-week-dosing schedule is given at Week 25 For dosing instructions for medicinal products administered in combination with Darzalex SC, see 14 CLINICAL TRIALS, and consult the corresponding Product Monographs.

0 Darzalex SC (daratumumab injection) Page 9 of 144 The Darzalex SC dosing schedule in Table 4 is for combination therapy with carfilzomib and dexamethasone (4-week regimen) for patients with relapsed multiple myeloma who have received one to three prior lines of therapy: Table 4: Dosing schedule for Darzalex SC in combination with carfilzomib and dexamethasone, (4-week cycle dosing regimens) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24a every two weeks (total of 8 doses) Week 25 onwards until disease progressionb every four weeks a First dose of the every 2-week-dosing schedule is given at Week 9 b First dose of the every 4-week-dosing schedule is given at Week 25 In the CANDOR Study of Darzalex in combination with carfilzomib and […]

). Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV were not studied.

Monitor patients with cardiac involvement of AL amyloidosis more frequently for cardiac adverse reaction and administer supportive care as appropriate. Hematologic Neutropenia/Thrombocytopenia Darzalex SC alone or in combination with other medications increases neutropenia.

In lower body weight patients receiving Darzalex SC, further increases in the rate of neutropenia and thrombocytopenia, including higher rates of Grade 3-4 events, were observed. When used in combination with background therapy, Darzalex SC increases neutropenia and thrombocytopenia induced by the background therapy (see 8 ADVERSE REACTIONS).

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Darzalex SC dose delay may be required to allow recovery of blood cell counts (neutrophils or platelets).

No dose reduction is recommended. Consider supportive care with transfusions or growth factors as needed. 0 Darzalex SC (daratumumab injection) Page 16 of 144 Administration-Related Reactions Darzalex SC can cause severe and/or serious administration-related reactions (ARRs), including anaphylactic reactions.

In clinical trials with Darzalex SC in patients with multiple myeloma (n=1253) or light chain (AL) amyloidosis (n=193), ARRs (defined as administration-related systemic reactions) were reported in approximately 7% of patients. Most ARRs occurred following the first injection and were Grade 1-2.

ARRs occurring with subsequent injections were seen in 1% of patients. Severe ARRs occurred in 1% of patients treated with Darzalex SC. 08-83 hours). The majority of ARRs occurred on the day of treatment. Delayed ARRs have occurred in 1% of patients.

Signs and symptoms of ARRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing as well as pyrexia, chest pain, pruritis, chills, vomiting, nausea, hypotension, and blurred vision.

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia and ocular adverse events (including choroidal effusion, acute myopia and acute angle closure glaucoma) (see 8 ADVERSE REACTIONS). Pre medicate patients with antihistamines, antipyretics and corticosteroids to reduce the risk of ARRs prior to treatment with Darzalex SC.

Patients should be monitored and counselled regarding ARRs, especially during and following the first and second injections. If an anaphylactic reaction or life threatening (Grade 4) reactions occur, institute appropriate emergency care and permanently discontinue Darzalex SC.

To reduce the risk of delayed ARRs, administer oral corticosteroids to all patients after each injection of Darzalex SC. g. inhaled corticosteroids, short and long acting bronchodilators) for patients with a history of chronic obstructive pulmonary disease to manage respiratory complications should they occur.

Pre- and post-injection medications may vary when Darzalex SC is used in combination therapy. If ocular symptoms occur, interrupt Darzalex SC and seek immediate ophthalmologic evaluation prior to restarting Darzalex SC (see 4 DOSAGE AND ADMINISTRATION).

Hypogammaglobulinemia Hypogammaglobulinemia can occur in patients treated with Darzalex SC. Immunoglobulin levels should be monitored during treatment with Darzalex SC. In patients with low immunoglobulin levels, pre-emptive measures according to local guidelines such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be considered.

0 Darzalex SC (daratumumab injection) Page 17 of 144 that could be severe, life-threatening and/or fatal, compared with those treated with background therapies alone (see 8 ADVERSE REACTIONS). Patients should be monitored for signs and symptoms of infection and treated promptly.

Hepatitis B Virus Reactivation Hepatitis B Virus (HBV) reactivation, in some cases fatal, has been reported in patients treated with daratumumab. HBV screening should be performed in all patients before initiation of treatment with Darzalex SC.

For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of Darzalex SC treatment. Manage patients according to current clinical guidelines.

Consider consulting a hepatitis disease expert as clinically indicated. In patients who develop reactivation of HBV while on Darzalex SC, suspend treatment with Darzalex SC and any concomitant steroids, chemotherapy, and institute appropriate treatment.

Resumption of Darzalex SC treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV. Monitoring and Laboratory Tests Interference with indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test.

Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab dose. […]

). For information concerning medicinal products given in combination with Darzalex SC, consult the corresponding Product Monographs. 0x109/L. g. G-CSF) should be considered, according to local guidelines (see 7 WARNINGS AND PRECAUTIONS).

0x109/L (see 7 WARNINGS AND PRECAUTIONS). 03. 3 Reconstitution Not applicable. 4 Administration Recommended Concomitant Medications: Pre-injection medication: For all patients, to reduce the risk of administration-related reactions administer the following pre-medications approximately 1-3 hours prior to every dose of Darzalex SC: Combination therapy: • Administer 20 mg dexamethasone (or equivalent) prior to every Darzalex SC dose.

When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-medication on Darzalex SC injection days (see 14 CLINICAL TRIALS). • Dexamethasone is given orally or intravenously prior to Darzalex SC injections.

g. prednisone) should not be taken on Darzalex SC injection days when patients have received dexamethasone as a pre- medication. 0 Darzalex SC (daratumumab injection) Page 12 of 144 • Antipyretics (oral paracetamol/acetaminophen 650 to 1000 mg).

• Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent). Monotherapy: • corticosteroid (methylprednisolone 100 mg, or equivalent dose of an intermediate-acting or long-acting corticosteroid) given intravenously or orally • oral antipyretics (acetaminophen 650 to 1000 mg), plus • oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent).

, methylprednisolone 60 mg IV).

Post-injection medication:

Administer post-injection medication to reduce the risk of delayed administration-related reactions as follows: Combination therapy: • Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent the day after Darzalex SC injection.

g. dexamethasone or prednisone) is administered the day after Darzalex SC injection, additional post- injection medications may not be needed (see 14 CLINICAL TRIALS). Monotherapy: • Administer oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid (intermediate or long-acting) in accordance with local standards) to patients the first and second day after each injection of Darzalex SC (beginning the day after the injection).

If the patient experiences no major systemic administration-related reactions (ARRs) after the first three injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued. Additionally, for patients with a history of chronic obstructive pulmonary disease, consider the use of post-injection medications including bronchodilators (short and long acting), and inhaled corticosteroids.

Following the first four injections, if the patient experiences no major systemic administration-related reactions, these inhaled post-injection medications may be discontinued. 0 Darzalex SC (daratumumab injection) Page 13 of 144 Prophylaxis for herpes zoster virus reactivation: Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

Instructions for Use, Handling, and Disposal To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Darzalex SC and not intravenous Darzalex. Darzalex SC is not intended for intravenous administration and should be administered via subcutaneous injection only.

Darzalex SC is for single use only and is ready to use without dilution. • Darzalex SC is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles.

• Darzalex SC should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use if opaque particles, discolouration or other foreign particles are present.

• Remove the Darzalex SC vial from refrigerated storage [2°C-8°C] and equilibrate to ambient temperature [15°C-30°C]. The unpunctured vial may be stored at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight.

Do not shake. • Prepare the dosing syringe in aseptic conditions. • To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection. Storage of prepared syringe • If the syringe containing Darzalex SC is not used immediately, store the Darzalex SC solution for up to 24 hours refrigerated followed by up to 12 hours at 15°C-25°C and ambient light.

• Discard if stored more than 24 hours of being refrigerated or more than 12 hours of being at 15°C-25°C. • If stored in the refrigerator, allow the solution to come to ambient temperature before administration. 5 cm to the right or left of the navel over approximately 3-5 minutes.

Do not inject Darzalex SC at other sites of the body as […]

Darzalex SC is contraindicated for patients with a history of severe hypersensitivity to daratumumab or who are hypersensitive to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.