Ninlaro 2.3 mg. 3 mg & 4 mg Hard capsule.

NINLARO in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with recurrent or relapsed multiple myeloma who have received at least one prior therapy.

Treatment must be initiated and monitored under the supervision of a medical practitioner experienced in the management of multiple myeloma.

Posology

The recommended starting dose of ixazomib is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 to 21 of a 28-day treatment cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle.

Dosing Schedule: NINLARO taken with lenalidomide and dexamethasone

28-Day Cycle (a 4-week cycle)

• Week 1
• Week 2
• Week 3
• Week 4

Day 1 Days 2 to 7 Day 8 Days 9 to 14 Day 15 Days 16 to 21 Day 22 Days 23 to 28

NINLARO ✔ ✔ ✔

Lenalidomide ✔ ✔ Daily ✔ ✔ Daily ✔ ✔ Daily

Dexamethasone ✔ ✔ ✔ ✔ ✔ intake of medicinal product

For additional information regarding lenalidomide and dexamethasone, refer to the professional information for these medical products.

Prior to initiating a new cycle of therapy:

• Absolute neutrophil count should be u2265 1 000/mm3
• Platelet count should be u2265 75 000/mm3
• Non-haematologic toxicities should, at the medical practitioneru2019s discretion, generally have reversed to patientu2019s baseline condition or u2264 Grade 1

Treatment should be continued until disease progression or unacceptable toxicity. Treatment with ixazomib in combination with lenalidomide and dexamethasone for longer than 24 cycles should be based on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond 24 cycles are limited (see 5.1 Pharmacodynamic properties).

Delayed or missed doses

In the event that an ixazomib dose is delayed or missed, the dose should be taken only if the next scheduled dose is u2265 72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for a missed dose. If a patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the time of the next scheduled dose.

Dose modifications

The NINLARO dose reduction steps are provided in Table 1 and the dose modification guidelines are provided in Table 2.

Table 1: NINLARO dose reduction steps

Recommended starting dose* First reduction to Second reduction to Discontinue

4 mg 3 mg 2,3 mg

*Recommended lower dose of one 3 mg capsule in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease (ESRD) requiring dialysis.

An alternating dose modification approach is recommended for NINLARO and lenalidomide for overlapping toxicities of thrombocytopaenia, neutropenia and rash. For these toxicities, the first dose modification step is to withhold/reduce lenalidomide. Refer to the lenalidomide professional information for the dose reduction steps for these toxicities.

Table 2: Dose modifications guidelines for NINLARO in combination with lenalidomide and dexamethasone

Haematological toxicities

Recommended actions

Thrombocytopenia (platelet count) Platelet count < 30 000/mm3

• Withhold NINLARO and lenalidomide until platelet count u2265 30 000/mm3.
• Following reversal, resume lenalidomide at the next lower dose according to its professional information and resume NINLARO at its most recent dose.
• If platelet count falls to < 30 000/mm3 again, withhold NINLARO and lenalidomide until platelet count u2265 30 000/mm3.
• Following reversal, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Neutropenia (absolute neutrophil count) Absolute neutrophil count < 500/mm3

• Withhold NINLARO and lenalidomide until platelet count u2265 500/mm3. Consider adding G-CSF (Growth Factor Support) as per clinical guidelines.
• Following reversal, resume lenalidomide at the next lower dose according to its professional information and resume NINLARO at its most recent dose.
• If absolute neutrophil count falls to < 500/mm3 again, withhold NINLARO and lenalidomide until platelet count u2265 500/mm3.
• Following reversal, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Non-Haematological Toxicities

Recommended actions

Rash Grade u2020 2 or 3

• Withhold lenalidomide until rash recovers to u2264 Grade 1.
• Following reversal, resume lenalidomide at the next lower dose according to its professional information.
• If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to u2264 Grade 1.
• Following reversal, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose*

Grade 4 Discontinue treatment regimen.

Peripheral Neuropathy Grade 1 peripheral neuropathy with Pain or Grade 2 peripheral neuropathy

• Withhold NINLARO until peripheral neuropathy recovers to u2264 Grade 1 without pain or patient's baseline.
• Following reversal, resume NINLARO at its most recent dose.

Grade 2 peripheral neuropathy with Pain or Grade 3 peripheral neuropathy

• Withhold NINLARO. Toxicities should, at the medical practitioneru2019s discretion, generally recover to patientu2019s baseline condition or u2264 Grade 1 prior to resuming NINLARO.
• Following reversal, resume NINLARO at the next lower dose.

Grade 4 Peripheral Neuropathy Discontinue treatment regimen.

Other Non-Haematological Toxicities

Other Grade 3 or 4 non-haematological toxicities

• Withhold NINLARO. Toxicities should, at the medical practitioneru2019s discretion, generally recover to patientu2019s baseline condition or u2264 Grade 1 prior to resuming NINLARO.
• If attributable to NINLARO, resume NINLARO at the next lower dose following reversal.

*For additional occurrences, alternate dose modification of lenalidomide and NINLARO

u2020 Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03

Concomitant medicinal products

Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation. Patients included in studies with NINLARO who received antiviral prophylaxis had a lower incidence of herpes zoster infection compared to patients who did not receive prophylaxis.

Thromboprophylaxis is recommended in patients being treated with NINLARO in combination with lenalidomide and dexamethasone and should be based on an assessment of the patientu2019s underlying risks and clinical status. For other concomitant medicinal products that may be required, refer to the current lenalidomide and dexamethasone professional information.

Special Patient Populations

Elderly

No dose adjustment of NINLARO is required for patients over 65 years of age. Discontinuations in patients > 75 years of age were reported in 13 patients (28 %) in the NINLARO regimen and 10 patients (16 %) in the placebo regimen. Cardiac dysrhythmias in patients > 75 years of age were observed in 10 patients (21 %) in the NINLARO regimen and 9 patients (15 %) in the placebo regimen.

Hepatic impairment

No dose adjustment of NINLARO is required for patients with mild hepatic impairment (total bilirubin u2264 upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 u2013 1, 5 x ULN and any AST). The reduced dose of 3 mg is recommended for patients with moderate (total bilirubin > 1, 5 - 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment. (see section 5.2 Pharmacokinetic properties).

Renal impairment

No dose adjustment of NINLARO is required for patients with mild or moderate renal impairment (creatinine clearance u2265 30 mL/min). The reduced dose of 3 mg is recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis (see section 5.2 Pharmacokinetic properties). Refer to the lenalidomide professional information for dosing recommendations in patients with renal impairment.

Paediatric population

The safety and efficacy of NINLARO in children below 18 years of age have not been established. No data are available.

Method of administration

NINLARO is for oral use. The absorption of NINLARO is decreased after a fatty meal. NINLARO should be taken at approximately the same time on days 1, 8, and 15 of each treatment cycle at least 1 hour before or at least 2 hours after food (see section 5.2 Pharmacokinetic properties). The capsule should be swallowed whole with water. It should not be crushed, chewed, or opened (see section 6.6 Special precautions for disposal and other handling).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (List of excipients).

As NINLARO is administered in combination with lenalidomide and dexamethasone, refer to the professional information for these medicinal products for additional contraindications.

As NINLARO is administered in combination with lenalidomide and dexamethasone, Thrombocytopaenia has been reported with NINLARO (see section 4.8 Undesirable effects) with platelet nadirs typically occurring between Days 14 - 21 of each 28 - day cycle and reverse to baseline by the start of the next cycle (see section 4.8 Undesirable effects). Platelet counts should be monitored at least monthly during NINLARO treatment. More frequent monitoring should be considered during the first three cycles as per the lenalidomide professional information. Thrombocytopaenia can be managed with dose modifications (see section 4.2 Posology and method of administration) and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities

Diarrhoea, constipation, nausea and vomiting have been reported with NINLARO, that may require use of antiemetic and anti-diarrhoeal medicinal products and supportive care (see section 4.8 Undesirable effects). The dose should be adjusted downwards for severe (Grade 3 - 4) symptoms (see 4.2 Posology and method of administration). In case of severe gastrointestinal events, monitoring of serum potassium level is recommended and dose reduction or discontinuation of treatment may be necessary.

Peripheral neuropathy

Peripheral neuropathy has been reported with NINLARO (see section 4.8 Undesirable effects). The patient should be monitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification (see section 4.2 Posology and method of administration).

Peripheral oedema

Peripheral oedema has been reported with NINLARO (see section 4.8 Undesirable effects). The patient should be evaluated for underlying causes and provide supportive care, as necessary. The dose of dexamethasone should be adjusted per its prescribing information or ixazomib for Grade 3 or 4 symptoms (see section 4.2 Posology and method of administration).

Cutaneous reactions

Rash has been reported with NINLARO (see section 4.8 Undesirable effects). Rash should be managed with supportive care or with dose modification if Grade 2 or higher (see 4.2 Posology and method of administration). Severe cutaneous adverse reactions (SCARs) including Toxic epidermal necrolysis (TEN) and Stevens - Johnson syndrome (SJS) which can be life-threatening or fatal have also been rarely reported in association with ixazomib treatment (see section 4.8 Undesirable effects). At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, ixazomib should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of ixazomib, treatment with ixazomib must not be restarted in this patient at any time.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP), have been reported in patients who received ixazomib. Some of these events have been fatal. Signs and symptoms of TMA should be monitored for. If the diagnosis is suspected, stop ixazomib and evaluate patients for possible TMA. If the diagnosis of TMA is excluded, ixazomib can be restarted. The safety of reinitiating ixazomib therapy in patients previously experiencing TMA is not known.

Hepatotoxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have been uncommonly reported with NINLARO (see section 4.8 Undesirable effects). Hepatic enzymes should be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms (see section 4.2 Posology and method of administration).

Pregnancy

Women should avoid becoming pregnant while being treated with NINLARO. If NINLARO is used during pregnancy or if the patient becomes pregnant while taking NINLARO, the patient should be apprised of the potential hazard to the foetus. (See section section 4.3). Women of childbearing potential must use highly effective contraception while taking NINLARO and for 90 days after stopping treatment (see section 4.5 Interactions with other medicinal products and 4.6 Fertility, pregnancy and lactation). Women using hormonal contraceptives should additionally use a barrier method of contraception.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) has occurred in patients receiving NINLARO. PRES is a rare, reversible, neurological disorder which can present with seizures, hypertension, headache, altered consciousness, and visual disturbances. Brain imaging, preferably Magnetic Resonance Imaging, is used to confirm the diagnosis. In patients developing PRES, discontinue NINLARO.

Strong CYP3A inducers

Strong inducers may reduce the efficacy of NINLARO therefore the concomitant use of strong CYP3A inducers such as carbamazepine, phenytoin, rifampicin and St. Johnu2019s Wort (Hypericum perforatum), should be avoided (see section 4.5 Interactions with other medicinal products and section 5.2 Pre-clinical safety data). Closely monitor patients for disease control if co-administration with a strong CYP3A inducer cannot be avoided.

Pharmacokinetic interactions

CYP inhibitors

Co-administration of NINLARO with clarithromycin, a strong CYP3A inhibitor, did not result in a clinically meaningful change in the systemic exposure of NINLARO. NINLARO Cmax was decreased by 4 % and AUC was increased by 11 %. Therefore, no dose modification is required for NINLARO with co-administration of strong CYP3A inhibitors.

Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of NINLARO based on the results of a population pharmacokinetic (PK) analysis. Therefore, no dose modification is required for NINLARO with co-administration of strong CYP1A2 inhibitors.

CYP inducers

Co-administration of NINLARO with rifampicin decreased ixazomib Cmax by 54 % and AUC by 74 %. Therefore, co-administration of strong CYP3A inducers with NINLARO is not recommended (see 4.4 Special warnings and precautions for use).

Effect of ixazomib on other medicinal products

NINLARO is not a reversible or a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. NINLARO did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.

Transporter-based interactions

NINLARO is a low affinity substrate of P-gp. NINLARO is not a substrate of BCRP, MRP2 or hepatic OATPs. NINLARO is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.

Oral contraceptives

When NINLARO is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of oral contraceptives needs to be considered. Women using hormonal contraceptives should additionally use a barrier method of contraception.

NINLARO use is contraindicated in pregnancy (See section 4.3)

Women of childbearing potential/Contraception in males and females

Male and female patients who are able to have children must use effective contraceptive measures during and for 90 days following treatment. NINLARO is contraindicated in women of childbearing potential not using contraception. When NINLARO is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of oral contraceptives needs to be considered. Therefore, women using oral hormonal contraceptives should additionally use a barrier method of contraception.

Pregnancy

NINLARO is contraindicated during pregnancy as it can cause foetal harm when administered to a pregnant woman. Therefore, women should avoid becoming pregnant while being treated with NINLARO. Studies in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data). NINLARO is given in combination with lenalidomide. Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect in humans is expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Please refer to the current lenalidomide professional information.

Breast-feeding

Mothers taking NINLARO must not breastfeed their infants. See section 4.3

Fertility

Fertility studies have not been conducted with NINLARO (see section 5.3 Preclinical safety data).

Fatigue and dizziness have been observed in clinical trials. Patients should be advised not to drive or operate machines if they experience any of these symptoms.

As NINLARO is administered in combination with lenalidomide and dexamethasone, refer to the professional information for these medicinal products for additional undesirable effects.

Summary of the safety profile

The data presented below is the pooled safety data from the pivotal, Phase 3, global C16010 study (n = 720) and the double-blind, placebo-controlled C16010 China Continuation Study (n = 115). The most frequently reported adverse reactions (u2265 20 %) across 418 patients treated within the ixazomib regimen and 417 patients within the placebo regimen were diarrhoea (47 % vs. 38 %), thrombocytopaenia (41 % vs. 24 %), neutropenia (37 % vs. 36 %), constipation (31 % vs. 24 %), upper respiratory tract infection (28 % vs. 24 %), peripheral neuropathy (28 % vs. 22 %), nausea (28 % vs. 20 %), back pain (25 % vs. 21 %), rash (25 % vs. 15 %), peripheral oedema (24 % vs. 19 %), vomiting (23 % vs. 12 %) and bronchitis (20 % vs. 15 %). Serious adverse reactions reported in u2265 2 % of patients included diarrhoea (3 %), thrombocytopaenia (2 %) and bronchitis (2 %).

Tabulated list of adverse reactions

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR): very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions in patients treated with NINLARO in combination with lenalidomide and dexamethasone (all Grades, grade 3 and grade 4)

System Organ Class/Adverse reaction Adverse Reactions (All Grades) Grade 3 Adverse Reactions Grade 4 Adverse Reactions

Infections and infestations Upper respiratory tract infection Very Common Common Bronchitis Very Common Common Herpes zoster Common Common

Blood and lymphatic system disorders Thrombocytopaenia* Very Common Very Common Common Neutropaenia* Very Common Very Common Common Thrombotic microangiopathy Rare Rare

Thrombotic thrombocytopenic purpurau2020 Rare Rare Rare

Immune system disorders Anaphylactic reaction u2020 Rare Very rare Very rare Angioedema u2020 Rare Rare

Metabolism and nutrition disorders Tumour lysis syndrome u2020 Rare Rare Rare

Nervous system disorders Peripheral neuropathies* Very Common Common Posterior reversible encephalopathy disorders* u2020 Rare Rare Rare Transverse myelitis u2020 Rare Rare

Gastro-intestinal disorders Diarrhoea Very Common Common Constipation Very Common Uncommon Nausea Very Common Common Vomiting Very Common Uncommon

Skin and subcutaneous tissue disorders Rash* Very Common Common Stevens - Johnson syndrome u2020 Rare Rare Acute febrile neutrophilic dermatosis Rare Rare Toxic epidermal necrolysisu2020 Rare Rare

Musculoskeletal and connective tissue disorders Back pain Very Common Uncommon Arthralgia Very common Common

General disorders and administration site conditions Oedema peripheral Very Common Common Pyrexia Very common Uncommon

Note: ADRs included as preferred terms are based on MedDRA version 23.0. *Represents a pooling of preferred terms. u2020Reported outside of the Phase 3 studies

Description of selected adverse reactions

Discontinuations For each adverse reaction, one or more of the three medicinal products was discontinued in u2264 1 % of patients in the ixazomib regimen. Thrombocytopaenia Two percent of patients in both the ixazomib regimen and in the placebo regimen had a platelet count u2264 10 000/mm3 during treatment. Less than 1 % of patients in both regimens had a platelet count u2264 5 000/mm3 during treatment. Thrombocytopaenia resulted in discontinuation of one or more of the three medicinal products in <2 % of patients in the ixazomib regimen and 3 % of patients in the placebo regimen. Thrombocytopaenia did not result in an increase in haemorrhagic events or platelet transfusions.

Gastrointestinal toxicities Diarrhoea resulted in discontinuation of one or more of the three medicinal products in 2 % of patients in the ixazomib regimen and 1 % of patients in the placebo regimen.

Rash Rash occurred in 25 % of patients in the ixazomib regimen compared to 15 % of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Grade 3 rash was reported in 3 % of patients in the ixazomib regimen compared to 2 % of patients in the placebo regimen. Rash resulted in discontinuation of one or more of the three medicinal products in < 1 % of patients in both regimens.

Peripheral neuropathy Peripheral neuropathy occurred in 28 % of patients in the ixazomib regimen compared to 22 % of patients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in 2 % of patients in the ixazomib regimen compared to 1 % in the placebo regimen. The most commonly reported reaction was peripheral sensory neuropathy (21 % and 15 % in the ixazomib and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<3 %). Peripheral neuropathy resulted in discontinuation of one or more of the three medicinal products in 3 % of patients in the ixazomib regimen compared to <1 % of patients in the placebo regimen.

Eye disorders Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 34 % in patients in the ixazomib regimen and 28 % of patients in the placebo regimen. The most common adverse reactions were blurred vision (6 % in the ixazomib regimen and 5 % in the placebo regimen), dry eye (6 % in the ixazomib regimen and 1 % in the placebo regimen), conjunctivitis (8 % in the ixazomib regimen and 2 % in the placebo regimen) and cataract (13 % in the ixazomib regimen and 17 % in the placebo regimen). Grade 3 adverse reactions were reported in 6 % of patients the ixazomib regimen and 8 % of patients in the placebo regimen.

Other adverse reactions In the pooled dataset from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, placebo-controlled, C16010 China Continuation Study (n=115), the following adverse reactions occurred with a similar rate between the ixazomib and placebo regimens: fatigue (28 % vs. 26 %), decreased appetite (13 % vs. 11 %), hypotension (5 % vs. 4 %), heart failure u2020 (5 % each), arrhythmia u2020 (17 % vs. 16 %), and liver impairment including enzyme changes u2020 (11 % vs. 9 %). The frequency of severe (Grade 3 - 4) events of hypokalaemia was higher in the ixazomib regimen (5 %) than the placebo regimen (< 2 %). Fungal and viral pneumonia resulting in fatal outcome were rarely reported (less than 1 %) in patients given the ixazomib, lenalidomide and dexamethasone combination.

u2020 Standardised MedDRA Queries (SMQs)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Additionally, suspected adverse reactions can be reported to [email protected]

Overdose has been reported in patients taking NINLARO. Symptoms of overdose are generally consistent with the known risks of NINLARO (see section 4.8). Overdose of 12 mg (taken at one time) has resulted in serious adverse events, such as severe nausea, aspiration pneumonia, multiple organ failure and death. There is no known specific antidote for ixazomib overdose. In the event of an overdose, monitor the patient closely for adverse reactions (see section 4.8 Undesirable effects) and provide appropriate supportive care. Ixazomib is not dialyzable (see section 5.2). Overdoses were most common in patients starting treatment with NINLARO. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Instruct patients to take the recommended dosage as directed because overdose has led to deaths.