What is the dosage of Ninlaro?

Ninlaro is available in 3 dosages, including 4 mg Cap, 3 mg Cap and 2.3 mg Cap

What does Ninlaro treat?

Ninlaro treats Multiple Myeloma

What is Ninlaro made of?

Ninlaro contains ixazomib which is a Proteasome Inhibitor

How is Ninlaro administered?

Ninlaro is administered as a Oral Pill

What is Ninlaro mechanism of action?

Ninlaro mechanism of action is Proteasome Inhibitors

Ninlaro

(ixazomib)

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Dosage & 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.

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Ninlaro Prescribing Information

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

Limitations of Use: NINLARO is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials [see Warnings and Precautions (5.9) and Clinical Studies (14.2, 14.3)].

Dosing and Administration Guidelines

NINLARO in combination with lenalidomide and dexamethasone

The recommended starting dose of NINLARO 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 through 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.

Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone ✔ Take medicine
28-Day Cycle (a 4-week cycle)
	Week 1		Week 2		Week 3		Week 4
	Day 1	Days 2-7	Day 8	Days 9-14	Day 15	Days 16-21	Day 22	Days 23-28
NINLARO	✔		✔		✔
Lenalidomide	✔	✔ Daily	✔	✔ Daily	✔	✔ Daily
Dexamethasone	✔		✔		✔		✔

For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.

NINLARO should be taken once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. 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 overdosage has led to deaths [see Overdosage (10)].

NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (12.3)]. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (16)].

If 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 the missed dose.

If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose.

Prior to initiating a new cycle of therapy:

Absolute neutrophil count should be at least 1,000/mm3
Platelet count should be at least 75,000/mm3
Non-hematologic toxicities should, at the healthcare provider's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower

Treatment should be continued until disease progression or unacceptable toxicity.

Concomitant Medications

Consider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1)].

Dosage Modification Guidelines

The NINLARO dose reduction steps are presented in Table 2 and the dosage modification guidelines are provided in Table 3.

Table 2: NINLARO Dose Reductions due to Adverse Reactions
* Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis [see Dosage and Administration (2.3, 2.4)].
Recommended starting dose *	First reduction to	Second reduction to	Discontinue
4 mg	3 mg	2.3 mg	Discontinue

An alternating dose modification approach is recommended for NINLARO and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 3. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide.

Table 3: Dosage Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone
* For additional occurrences, alternate dose modification of lenalidomide and NINLARO † Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03
Hematological Toxicities	Recommended Actions
Thrombocytopenia (Platelet Count)
Platelet count less than 30,000/mm3	Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose. If platelet count falls to less than 30,000/mm3 again, withhold NINLARO and lenalidomide until platelet count is at least 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 less than 500/mm3	Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 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 less than 500/mm3 again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. *
Non-Hematological Toxicities	Recommended Actions
Rash
Grade † 2 or 3	Withhold lenalidomide until rash recovers to Grade 1 or lower. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information. If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade 1 or lower. 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 or lower 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 healthcare provider's discretion, generally recover to patient's baseline condition or Grade 1 or lower prior to resuming NINLARO. Following recovery, resume NINLARO at the next lower dose.
Grade 4 Peripheral Neuropathy	Discontinue treatment regimen.
Other Non-Hematological Toxicities
Other Grade 3 or 4 Non-Hematological Toxicities	Withhold NINLARO. Toxicities should, at the healthcare provider's discretion, generally recover to patient's baseline condition or Grade 1 or lower prior to resuming NINLARO. If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.

Dosage in Patients with Hepatic Impairment

Reduce the starting dose of NINLARO to 3 mg in patients with moderate (total bilirubin greater than 1.5-3 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Dosage in Patients with Renal Impairment

Reduce the starting dose of NINLARO to 3 mg in patients with severe renal impairment (creatinine clearance less than 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 Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

Pregnancy

Risk Summary

Based on its mechanism of action [see Clinical Pharmacology (12.1)] and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a pregnant woman. There are no available data on NINLARO use in pregnant women to evaluate drug-associated risk. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus.

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

Animal Data

In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) at doses that were also maternally toxic (≥0.3 mg/kg). Exposures in the rabbit at 0.3 mg/kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability, and increased post-implantation losses at 0.6 mg/kg. Exposures in rats at the dose of 0.6 mg/kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg.

Lactation

Risk Summary

There are no data on the presence of ixazomib or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions from NINLARO in a breastfed infant, advise women not to breastfeed during treatment with NINLARO and for 90 days after the last dose.

Females and Males of Reproductive Potential

NINLARO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating NINLARO.

Contraception

Females

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days after the last dose. Dexamethasone is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters. Because NINLARO is administered with dexamethasone, the risk for reduced efficacy of contraceptives needs to be considered [see Drug Interactions (7.1)].

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days after the last dose.

Pediatric Use

Safety and effectiveness of NINLARO have not been established in pediatric patients.

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.

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 [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

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 [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

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 [see Adverse Reactions (6.1)]. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. The rate of platelet transfusions was 10% in the NINLARO regimen and 7% in the placebo regimen.

Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications [see Dosage and Administration (2.2)] and platelet transfusions as per standard medical guidelines.

Gastrointestinal Toxicities

Diarrhea, constipation, nausea, and vomiting have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 52% of patients in the NINLARO regimen and 43% in the placebo regimen, constipation in 35% and 28%, respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen [see Adverse Reactions (6.1)]. Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

Peripheral Neuropathy

The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens.

The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2)].

Peripheral Edema

Peripheral edema was reported in 27% and 21% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 6% in the placebo regimen).

Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively [see Adverse Reactions (6.1)]. Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

Cutaneous Reactions

Rash was reported in 27% of patients in the NINLARO regimen and 16% of patients in the placebo regimen. The majority of the rash adverse reactions were Grade 1 (15% in the NINLARO regimen and 9% in the placebo regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Serious adverse reactions of rash were reported in <1% of patients in the NINLARO regimen. The most common type of rash reported in both regimens included maculo-papular and macular rash. Rash resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher [see Dosage and Administration (2.2)].

Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO [see Adverse Reactions (6.1, 6.2)]. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated.

Thrombotic Microangiopathy

Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.

Hepatotoxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients treated with NINLARO [see Adverse Reactions (6.1)]. Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

Embryo-Fetal Toxicity

NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animal studies. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1, 8.3)].

Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting

In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials [see Clinical Studies (14.2)].