DRUG INTERACTIONS-

­ Strong CYP3A inducers: Avoid concomitant use with NINLARO.

38/15 PRODUCT DETAILS 

Drug Name-                NINLARO

Active Ingredient-      Ixazomib

FDA approved use-    To treat people with multiple myeloma

Approved date         11/16/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use                             NINLARO safely and effectively.

See full prescribing information for NINLARO. NINLARO® (ixazomib) capsules, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

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

ADVERSE REACTIONS--

­ The most common adverse reactions (= 20%) are diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain.

CONTRAINDICATIONS---

­ None.

WARNINGS AND PRECAUTIONS-

 Thrombocytopenia: Monitor platelet counts at least monthly during treatment and adjust dosing, as needed.

Gastrointestinal Toxicities: Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed.

Peripheral Neuropathy: Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed.

Peripheral Edema: Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed

Cutaneous Reactions: Monitor patients for rash and adjust dosing, as needed.

Hepatotoxicity: Monitor hepatic enzymes during treatment.

 Embryo-Fetal Toxicity: NINLARO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION-

 Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle.

Dose should be taken at least one hour before or at least two hours after food. (2.1) ------

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 4 mg, 3 mg, and 2.3 mg

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dosing Instructions -                                                                                                      Instruct patients to take NINLARO exactly as prescribed. ? Advise patients to take NINLARO once a week on the same day and at approximately the same time for the first three weeks of a four week cycle.

 Advise patients to take NINLARO at least one hour before or at least two hours after food.

 Advise patients that NINLARO and dexamethasone should not be taken at the same time, because dexamethasone should be taken with food and NINLARO should not be taken with food.

 Advise patients to swallow the capsule whole with water. The capsule should not be crushed, chewed or opened. 

Advise patients that direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes.

If contact occurs with the skin, wash thoroughly with soap and water. If contact occurs with the eyes, flush thoroughly with water.

 If a patient misses a dose, advise them to take the missed dose as long as the next scheduled dose is = 72 hours away.

Advise patients not to take a missed dose if it is within 72 hours of their next scheduled dose.

 If a patient vomits after taking a dose, advise them not to repeat the dose but resume dosing at the time of the next scheduled dose. ?

Advise patients to store capsules in original packaging, and not to remove the capsule from the packaging until just prior to taking NINLARO. [see Dosage and Administration

] Thrombocytopenia Advise patients that they may experience low platelet counts (thrombocytopenia).

Signs of thrombocytopenia may include bleeding and easy bruising.

Gastrointestinal Toxicities- Advise patients they may experience diarrhea, constipation, nausea and vomiting and to contact their physician if these adverse reactions persist. 

Peripheral Neuropathy- Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs.

Peripheral Edema -Advise patients to contact their physicians if they experience unusual swelling of their extremities or weight gain due to swelling

Cutaneous Reactions- Advise patients to contact their physicians if they experience new or worsening rash 

Hepatotoxicity- Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain 

Pregnancy Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO and for 90 days following the final dose.

Advise patients to contact their physicians immediately if they or their female partner become pregnant during treatment or within 90 days of the final dose

Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking and before starting any new medications.

Distributed and Marketed by: Takeda Pharmaceutical Company Limited Cambridge, MA 02139 NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. ©2015 Millennium Pharmaceuticals, Inc. For more information, you may also go to www.NINLARO.com or call 1-844-617-6468. Item Code: 101155/1

CLINICAL PHARMACOLOGY

1. Mechanism of Action Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome

. Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model.

2. Pharmacodynamics Cardiac Electrophysiology NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients.

3 Pharmacokinetics Absorption After oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in a dose proportional manner over a dose range of 0.2 to 10.6 mg. A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration

 Distribution-                                                                                                                    Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L

. Elimination-                                                                                                               Based on a population PK analysis, systemic clearance was approximately 1.9 L/hr with interindividual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold.

Metabolism-                                                                                                                    After oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism for ixazomib.

Excretion-                                                                                                                        After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.

Specific Populations Age, Sex, Race There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2 ), or race on the clearance of ixazomib based on population PK analysis.

Hepatic Impairment -                                                                                                     The PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin = ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and any AST) based on population PK analysis.

Renal Impairment-                                                                                                               The PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance = 30 mL/min) based on population PK analysis.

Drug Interactions Effect of Other Drugs on NINLARO Strong CYP3A Inducers Co-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug Interactions (7.1)]

Strong CYP3A Inhibitors Co-administration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib. Reference ID: 3849755 Page 14 of 23

Strong CYP1A2 Inhibitors Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib based on a population PK analysis.

Effect of NINLARO on Other Drugs Ixazomib is neither a reversible nor a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib 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 Ixazomib is a low affinity substrate of P-gp. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATPs. Ixazomib 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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy-

Women should avoid becoming pregnant while being treated with NINLARO.

Risk Summary -                                                                                                       NINLARO can cause fetal harm when administered to a pregnant woman.

There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher then those observed in patients receiving the recommended dose 

Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO. Reference ID: 3849755 Page 10 of 23

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data

2. Lactation Risk Summary-                                                                                             It is not known whether NINLARO or its metabolites are present in human milk. Many drugs are present in human milk and as a result, there could be a potential for adverse events in nursing infants. Advise women to discontinue nursing

3 Females and Males of Reproductive Potential Contraception-                             Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment. Infertility

Fertility studies were not conducted with NINLARO; however there were no effects on reproductive organs in either males or females in nonclinical studies in rats and dogs 

4 Pediatric Use -                                                                                                        Safety and effectiveness have not been established in pediatric patients.

5. Geriatric Use -                                                                                                            Of the total number of subjects in clinical studies of NINLARO, 55% were 65 and over, while 17% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Reference ID: 3849755 Page 11 of 23

6. Hepatic Impairment-                                                                                                     In patients with moderate or severe hepatic impairment, the mean AUC increased by 20% when compared to patients with normal hepatic function. Reduce the starting dose of NINLARO in patients with moderate or severe hepatic impairment 

7. Renal Impairment In patients with severe renal impairment or ESRD requiring dialysis, the mean AUC increased by 39% when compared to patients with normal renal function

. Reduce the starting dose of NINLARO in patients with severe renal impairment or ESRD requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis

 OVERDOSAGE There is no known specific antidote for NINLARO overdose. In the event of an overdose, monitor the patient for adverse reactions [see Adverse Reactions (6.1)] and provide appropriate supportive care.