Ninlaro

Therapeutic indication

Adult patients with multiple myeloma who have received at least one prior therapy

Mechanism of action

Ixazomib is an oral, highly selective and reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.

Therapeutic Indication

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

Reimbursement Modalities

Since October 2017 NINLARO is reimbursed under ehealth chapter IV – 8900000 for the treatment in combination with Lenalidomide and Dexamethasone of adult patients with multiple myeloma who show disease progression and who have received at least one prior therapy.
The prior treatment should at least include 1 hematopoietic stem cell transplant, unless the patient does not meet transplant criteria. All treatments administered in the framework of a stem cell transplant are considered as one treatment, including the stem cell transplant.
The specialty is not reimbursed if it is administered to patients who have had at least 2 prior treatments, for which they have shown disease progression on a lenalomide-containing combination therapy.

Administration and Dosage

NINLARO is for oral use and should be taken at approximately the same time at least 1 hour before or at least 2 hours after food. The capsule should be swallowed whole with water. It should not be crushed, chewed, or opened.

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 (starting dose 4 mg)	a		a		a
Lenalidomide (starting dose 25mg)	a	aDaily	a	aDaily	a	aDaily
Dexamethasone (starting dose 40 mg)	a		a		a		a
a= intake of medicinal product

For additional information regarding lenalidomide and dexamethasone, refer to the SmPC for these medicinal products.

Prior to initiating a new cycle of therapy:
- Absolute neutrophil count should be ≥ 1,000/mm³- Platelet count should be ≥ 75,000/mm³- Non‑haematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤ Grade 1

Treatment should be continued until disease progression or unacceptable toxicity. Treatment with NINLARO 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.

Delayed or missed doses
In the event that a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 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 modification

NINLARO dose reduction steps

Recommended starting dose*	First reduction to	Second reduction to	Discontinue
4 mg	3 mg	2.3 mg	Discontinue

*Recommended reduced dose of 3 mg in the presence of moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease (ESRD) requiring dialysis.

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 ≥ 30,000/mm³. Following recovery, resume lenalidomide at the next lower dose according to its SmPC and resume NINLARO at its most recent dose. If platelet count falls to < 30,000/mm³ again, withhold NINLARO and lenalidomide until platelet count ≥ 30,000/mm³. Following recovery, 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 absolute neutrophil count is ≥ 500/mm³. Consider adding G‑CSF as per clinical guidelines. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose. If absolute neutrophil count falls to < 500/mm³ again, withhold NINLARO and lenalidomide until absolute neutrophil count is ≥ 500/mm³. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Non-haematological toxicities	Recommended actions
Rash
Grade^† 2 or 3	Withhold lenalidomide until rash recovers to ≤ Grade 1. Following recovery, resume lenalidomide at the next lower dose according to its SmPC. If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to ≤ Grade 1. Following recovery, 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 ≤ Grade 1 without pain or patient's baseline. Following recovery, resume NINLARO at its most recent dose.
Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy		Withhold NINLARO. Toxicities should, at the physician’s discretion, generally recover to patient’s baseline condition or ≤ Grade 1 prior to resuming NINLARO. Following recovery, 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 physician’s discretion, generally recover to patient’s baseline condition or at most Grade 1 prior to resuming NINLARO. If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.

*For additional occurrences, alternate dose modification of lenalidomide and NINLARO
^†Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03

Dose adjustments for special patient populations

Elderly	No dose adjustment of NINLARO is required for patients over 65 years of age.
Hepatic Impairment	Mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1‑1.5 x ULN and any AST) : No dose adjustment of NINLARO is required . Moderate to severe hepatic impairment (total bilirubin > 1.5-3 x ULN to total bilirubin > 3 x ULN) : The reduced dose of 3 mg NINLARO is recommended.
Renal impairment	Mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min): No dose adjustment of NINLARO is required for patients with mild or moderate renal impairment. Severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis): The reduced dose of 3 mg is recommended. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis. Refer to the lenalidomide SmPC 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.

NINLARO Concomitant medicinal products
Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation.

Thromboprophylaxis is recommended in patients being treated with NINLARO in combination with lenalidomide and dexamethasone, and should be based on an assessment of the patient’s underlying risks and clinical status.

For other concomitant medicinal products that may be required, refer to the current lenalidomide and dexamethasone SmPC.

NINLARO Drug Interactions

CYP-inducers (carbamazepine, phenytoin, rifampicin and St. John’s Wort (Hypericum perforatum))
Oral contraceptives

NINLARO Contraindications

Hypersensitivity to the active substance or to any of the excipients:
Capsule contents Capsule Shell Printing Ink
Microcrystalline cellulose Gelatin Shellac
Magnesium stearate Titanium Dioxide (E171) Propylene glycol
Talc Red iron oxide (E172) Potassium Hydroxide
Black iron oxide (E172)

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

NINLARO Special warnings and precautions for use

As NINLARO is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional special warnings and precautions for use.

Thrombocytopenia	Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. 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 SmPC. Thrombocytopenia can be managed with dose modifications and platelet transfusions as per standard medical guidelines.
Gastrointestinal toxicities	Diarrhoea, constipation, nausea and vomiting have been reported with NINLARO, occasionally requiring use of antiemetic and antidiarrheal medicinal products and supportive care. The dose should be adjusted for severe (Grade 3-4) symptoms. In case of severe gastrointestinal events, monitoring of serum potassium level is recommended.
Peripheral neuropathy	Peripheral neuropathy has been reported with NINLARO. The patient should be monitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification.
Peripheral oedema	Peripheral oedema has been reported with NINLARO. 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 NINLARO for Grade 3 or 4 symptoms.
Cutaneous reactions	Rash has been reported with NINLARO. Rash should be managed with supportive care or with dose modification if Grade 2 or higher
Hepatotoxicity	Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have been uncommonly reported with NINLARO. Hepatic enzymes should be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms.
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. Women of childbearing potential must use highly effective contraception while taking NINLARO and for 90 days after stopping treatment. 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 seizure, 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. John’s Wort (Hypericum perforatum), should be avoided. Closely monitor patients for disease control if co-administration with a strong CYP3A inducer cannot be avoided

NINLARO Adverse reactions

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR): 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); 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.

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	Uncommon
Herpes zoster	Common	Common
Blood and lymphatic system disorders
Thrombocytopenia*	Very common	Very common	Common
Neutropenia*	Very common	Very common	Common
Nervous system disorders
Peripheral neuropathies*	Very common	Common
Gastrointestinal disorders
Diarrhoea	Very common	Common
Nausea	Very common	Common
Vomiting	Very common	Uncommon
Constipation	Very common	Uncommon
Skin and subcutaneous tissue disorders
Rash*	Very common	Common
Musculoskeletal and connective tissue disorders
Back pain	Very common	Uncommon
General disorders and administration site conditions
Oedema peripheral	Very common	Common