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Ninlaro

Generic Name: Ixazomib
Class: Antineoplastic Agents
Chemical Name: 2 - [(1R) - 1 - [[2 - [(2,5 - Dichlorobenzoyl)amino]acetyl]amino] - 3 - methylbutyl] - 5 - oxo - 1,3,2 - Dioxaborolane - 4,4 - diacetic acid
Molecular Formula: C20H23BCl2N2O9
CAS Number: 1239908-20-3

Introduction

Antineoplastic agent; inhibitor of 20S proteasome.1 2 5 6 7 8 9

Uses for Ninlaro

Multiple Myeloma

Used in combination with lenalidomide and dexamethasone for previously treated (≥1 prior therapy) multiple myeloma (designated an orphan drug for this use).1 10

Ninlaro Dosage and Administration

General

  • Confirm that ANC is ≥1000/mm3 and platelet count ≥75,000/mm3 before initiating a new cycle of therapy; at clinician's discretion, generally allow nonhematologic toxicity to resolve to baseline or grade 1 or less.1

  • Consult manufacturers' labeling for additional information regarding lenalidomide and dexamethasone.1

  • If capsule breakage occurs, avoid direct contact of contents with skin or eyes.1 If contact occurs, wash skin thoroughly with soap and water; flush eyes thoroughly with water.1

Administration

Oral Administration

Administer orally once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.1

Administer orally at least 1 hour before or at least 2 hours after food.1

Do not administer ixazomib and dexamethasone simultaneously on days when both drugs are scheduled; administer dexamethasone with food and give ixazomib on an empty stomach.1

Swallow capsules whole with water; do not crush, chew, or open.1

If vomiting occurs following administration, do not repeat the dose.1 Resume therapy at time of next scheduled dose.1

If a dose is delayed or missed, administer the dose only if there are at least 72 hours until the next scheduled dose.1 Do not administer a missed dose within 72 hours of the next scheduled dose; do not double the dose to make up for the missed dose.1

Dosage

Available as ixazomib citrate; dosage expressed in terms of ixazomib.1

Adults

Multiple Myeloma
Oral

Recommended initial dosage in each 28-day cycle: Ixazomib 4 mg once weekly on days 1, 8, and 15 in combination with lenalidomide 25 mg once daily on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22.1 3

Continue treatment until disease progression or unacceptable toxicity occurs.1

Consult manufacturer's labeling for lenalidomide and dexamethasone for additional information.1

Dosage Modification for Toxicity
Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.1 Up to 2 dosage reductions for toxicity may be made.1

If dosage reduction from 4 mg once weekly is necessary, initially reduce dosage to 3 mg once weekly.1 If further dosage reduction is necessary, reduce dosage to 2.3 mg once weekly.1 Dosages <2.3 mg once weekly not recommended.1

Neutropenia
Oral

If ANC <500/mm3, withhold ixazomib and lenalidomide until ANC is ≥500/mm3.1 Consider addition of granulocyte colony-stimulating factors based on clinical guidelines.1

When ANC returns to ≥500/mm3, reduce lenalidomide by 1 dose level according to manufacturer's labeling; resume ixazomib at previous dosage.1 If ANC <500/mm3 recurs, withhold ixazomib and lenalidomide until ANC ≥500/mm3; reduce ixazomib by 1 dose level (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg); resume lenalidomide at previous dosage.1

For additional occurrences of neutropenia, alternate dosage modifications between ixazomib and lenalidomide.1 Following a second dosage reduction of ixazomib, discontinue treatment if ANC <500/mm3 recurs.1

Thrombocytopenia
Oral

If platelet count <30,000/mm3, withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3.1

When platelet count returns to ≥30,000/mm3, resume ixazomib at previous dosage; resume lenalidomide at 1 dose level lower than the previous dosage according to manufacturer's labeling.1 If platelet count <30,000/mm3 recurs, withhold ixazomib and lenalidomide until platelet count is ≥30,000/mm3; resume ixazomib at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg); resume lenalidomide at previous dosage.1

For additional occurrences of thrombocytopenia, alternate dosage modifications between ixazomib and lenalidomide.1 Following a second dosage reduction of ixazomib, discontinue treatment if platelet count <30,000/mm3 recurs.1

Peripheral Neuropathy
Oral

If grade 1 with pain or grade 2 peripheral neuropathy occurs, withhold ixazomib until toxicity resolves to grade 1 or less without pain or to baseline;1 resume ixazomib at the previous dosage.1 Discontinue treatment if grade 1 with pain or grade 2 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1

If grade 2 with pain or grade 3 peripheral neuropathy occurs, withhold ixazomib; generally (at clinician's discretion) allow toxicity to resolve to baseline or grade 1 or less prior to resuming therapy.1 Resume ixazomib at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg).1

Discontinue treatment if grade 2 with pain or grade 3 peripheral neuropathy occurs following a second dosage reduction of ixazomib.1

If any grade 4 peripheral neuropathy occurs, discontinue treatment.1

Dermatologic Toxicity
Oral

If grade 2 or 3 rash occurs, withhold lenalidomide until rash resolves to grade 1 or less;1 resume lenalidomide at 1 dose level lower than the previous dosage according to manufacturer's labeling.1

If grade 2 or 3 rash recurs, withhold ixazomib and lenalidomide until rash resolves to grade 1 or less;1 resume ixazomib at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg); resume lenalidomide at the previous dosage.1

For additional occurrences of rash, alternate dosage modifications between ixazomib and lenalidomide.1 Discontinue treatment if grade 2 or 3 rash occurs following a second dosage reduction of ixazomib.1

Discontinue treatment if any grade 4 rash occurs.1

Other Nonhematologic Toxicity
Oral

If other grade 3 or 4 nonhematologic toxicity occurs, withhold ixazomib; generally (at clinician's discretion) allow toxicity to resolve to baseline or grade 1 or less.1 If nonhematologic toxicity is attributable to ixazomib, resume therapy at 1 dose level lower than the previous dosage (i.e., a dose of 4 mg reduced to 3 mg or a dose of 3 mg reduced to 2.3 mg).1

Discontinue treatment if grade 3 or 4 nonhematologic toxicity occurs following a second dosage reduction of ixazomib.1

Special Populations

Hepatic Impairment

Reduce initial dosage of ixazomib to 3 mg weekly in patients with moderate (total bilirubin >1.5 to 3 times the ULN) or severe (total bilirubin >3 times the ULN) hepatic impairment.1 Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.1

Renal Impairment

Reduce initial dosage of ixazomib to 3 mg weekly in patients with severe renal impairment (Clcr <30 mL/minute) or in patients with end-stage renal disease (ESRD) requiring dialysis.1 Ixazomib is not dialyzable; administer without regard to timing of dialysis.1 Refer to manufacturer's labeling for lenalidomide for specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no special dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Ninlaro

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Thrombocytopenia

Thrombocytopenia reported frequently.1 Platelet nadirs usually occur on days 14–21 of each 28-day cycle and resolve to baseline by beginning of next cycle.1

Monitor platelet counts at least monthly.1 Consider more frequent monitoring during the first 3 treatment cycles.1 Manage thrombocytopenia with dosage modifications and platelet transfusions according to standard of care.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

GI Toxicity

GI toxicity reported (e.g., diarrhea, constipation, nausea, vomiting), requiring occasional use of antidiarrheal or antiemetic drugs and/or supportive care.1 Modify dosage in patients experiencing grade 3 or 4 GI toxicity.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Neuropathy

Peripheral neuropathy (usually sensory neuropathy and mostly grade 1 or 2) reported.1

Monitor patients for symptoms of peripheral neuropathy; dosage modifications may be required in those experiencing new or worsening symptoms.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Peripheral Edema

Peripheral edema (mostly grade 1 or 2) reported.1 Assess for underlying causes and provide supportive care, as needed.1 Adjust dosage of ixazomib for grade 3 or 4 symptoms, and modify dosing of dexamethasone based on manufacturer's labeling.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Dermatologic Reactions

Rash (mostly grade 1 or 2) reported.1 Maculopapular and macular rash reported most frequently.1 Manage with supportive care or with dosage modification if grade 2 or greater.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatotoxicity

Hepatotoxicity reported (e.g., drug-induced hepatic injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, hepatotoxicity).1 Monitor hepatic enzymes regularly; adjust dosage in patients experiencing grade 3 or 4 toxicity.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity demonstrated in animals.1

If used during pregnancy, or patient becomes pregnant, apprise of potential fetal hazard.1 Women of childbearing potential and men who are partners of such women must use effective contraception during treatment and for 90 days following discontinuance of the drug.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether ixazomib or its metabolites are distributed into milk.1 Discontinue nursing.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In clinical trials, 55% of patients were ≥65 years of age; 17% were ≥75 years of age.1 No overall differences in safety or efficacy observed between geriatric patients and younger adults; other clinical experience has not demonstrated differences in responses between geriatric and younger patients.1 However, greater sensitivity of some older patients cannot be ruled out.1

Hepatic Impairment

Pharmacokinetics similar in patients with normal hepatic function and in those with mild hepatic impairment (total bilirubin less than or equal to the ULN and AST concentrations greater than the ULN, or total bilirubin >1 to 1.5 times the ULN with any AST concentration).1 Mean AUC increased substantially in those with moderate or severe hepatic impairment compared with patients with normal hepatic function.1

Reduce initial dosage in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pharmacokinetics similar in patients with normal renal function and in those with mild (Clcr 60–89 mL/minute) or moderate (Clcr 30–59 mL/minute) renal impairment.1 Mean AUC increased substantially in patients with severe renal impairment or ESRD requiring dialysis compared with those with normal renal function.1

Reduce initial dosage in patients with severe renal impairment or ESRD requiring dialysis.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Thrombocytopenia,1 rash,1 upper respiratory tract infection,1 back pain,1 vomiting,1 peripheral edema,1 nausea,1 peripheral neuropathy,1 constipation,1 diarrhea.1

Interactions for Ninlaro

Low-affinity substrate of P-glycoprotein (P-gp); not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, or hepatic organic anion transport protein (OATP).1

Not a reversible or time-dependent inhibitor of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.1 Not expected to cause interactions via CYP inhibition.1

Not an inhibitor of P-gp, BCRP, MRP2, OATP 1B1 or 1B3, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1 or 3, or multidrug and toxin extrusion (MATE) 1 or MATE2K transporters.1 Not expected to cause transporter-mediated pharmacokinetic interactions.1

Not an inducer of CYP1A2, 2B6, or 3A4/5 or corresponding immunoreactive protein concentrations.1 Not expected to cause interactions via CYP induction.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP1A2 inhibitors: No clinically important change in the systemic exposure of ixazomib.1

Potent CYP3A inducers: Possible decreased systemic exposure of ixazomib.4 Avoid concomitant use.1

Specific Drugs

Drug

Interaction

Comments

Carbamazepine

Possible decreased systemic exposure of ixazomib4

Avoid concomitant use1

Clarithromycin

No clinically important effect on systemic exposure of ixazomib1

Phenytoin

Possible decreased systemic exposure of ixazomib4

Avoid concomitant use1

Rifampin

Decreased peak plasma concentration and AUC of ixazomib1

Avoid concomitant use1

St. John's wort (Hypericum perforatum)

Possible decreased systemic exposure of ixazomib4

Avoid concomitant use1

Ninlaro Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 58%.1

Median time to peak plasma concentration is 1 hour.1

Systemic exposure increases in a dose-proportional manner over a dosage range of 0.2–10.6 mg; accumulation is twofold following weekly oral dosing.1

Food

High-fat meal decreases AUC and peak plasma concentration by 28 and 69%, respectively.1

Special Populations

In patients with moderate or severe hepatic impairment, mean AUC increased by 20% compared with those having normal hepatic function.1

In patients with severe renal impairment or ESRD requiring dialysis, mean AUC increased by 39% compared with those having normal renal function.1

Distribution

Extent

Distributes into RBCs with a blood-to-plasma ratio of 10.1

Plasma Protein Binding

99%.1

Elimination

Metabolism

Ixazomib citrate (a prodrug) is rapidly hydrolyzed to ixazomib (active metabolite).1 Metabolized by multiple CYP isoenzymes and through non-CYP-dependent pathways; in vitro studies reveal that no specific isoenzyme principally contributes to metabolism of drug at clinically relevant concentrations.1 Principally metabolized by CYP3A4 (42%) and 1A2 (26%) at higher than clinical concentrations.1

Elimination Route

Urinary (62%) and fecal (22%) elimination.1

<3.5% of dose recovered in urine as unchanged drug.1

Not removed by hemodialysis.1

Half-life

9.5 days.1

Stability

Storage

Oral

Capsules

15–30°C in original carton until immediately prior to use; do not expose to temperatures >30°C.1 Do not freeze.1

Actions

  • Ixazomib citrate is a prodrug of ixazomib, a boron-containing selective inhibitor of the 20S proteasome.1 2 5 6 7 8 9

  • Reversibly binds the β5 subunit of the 20S proteasome, inhibiting its chymotrypsin-like activity.1 2

  • In vitro, induces caspase-mediated apoptosis9 of multiple myeloma cell lines and demonstrated cytotoxicity against myeloma cells from patients who relapsed following previous therapies (e.g., bortezomib, lenalidomide, dexamethasone).1 5

  • Demonstrates synergistic cytotoxic effects with lenalidomide in multiple myeloma cell lines; demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model in vivo.1 6

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information carefully before starting ixazomib and before each treatment.1

  • Importance of instructing patients to take ixazomib exactly as prescribed at least 1 hour before or 2 hours after food.1 Advise patients to swallow capsules whole with water and to not crush, chew, or open the capsules.1

  • Importance of advising patients to take ixazomib once weekly on the same day and at approximately the same time for the first 3 weeks of each 4-week cycle.1

  • Importance of advising patients not to administer ixazomib and dexamethasone simultaneously; dexamethasone is administered with food, while ixazomib is given on an empty stomach.1

  • Importance of informing patients that if a dose is missed, to take the dose as soon as possible if there are at least 72 hours until next scheduled dose.1 Advise patients not to take the missed dose if it is within 72 hours of next scheduled dose.1

  • If vomiting occurs following administration, inform patients not to repeat the dose but to resume dosing at time of next scheduled dose.1

  • Advise patients to avoid direct contact with capsule contents.1 If direct contact with skin or eyes occurs, wash skin thoroughly with soap and water; flush eyes thoroughly with water.1

  • Importance of advising patients to store capsules in original carton until time of use.1

  • Risk of thrombocytopenia.1 Importance of advising patients of the signs or symptoms of thrombocytopenia (e.g., bleeding, easy bruising).1

  • Risk of GI toxicity.1 Importance of advising patients to report persistent diarrhea, constipation, nausea, vomiting to their clinician.1

  • Risk of peripheral neuropathy.1 Importance of advising patients to report new or worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation in feet or hands, weakness in arms or legs) to their clinician.1

  • Risk of peripheral edema.1 Importance of advising patients to report unusual swelling of their extremities or weight gain from swelling to their clinician.1

  • Risk of cutaneous reactions.1 Importance of advising patients to report new or worsening rash to their clinician.1

  • Risk of hepatotoxicity.1 Importance of advising patients to report jaundice or right upper quadrant abdominal pain to their clinician.1

  • Risk of fetal harm.1 Importance of informing women of childbearing potential and men who are partners of such women to use effective contraception during treatment and for 90 days following discontinuance of the drug.1 Importance of immediately informing clinician if the patient or their partner becomes pregnant during treatment or within 90 days of the last dose.1

  • Importance of advising patients to discontinue nursing while receiving ixazomib.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ixazomib Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

2.3 mg (of ixazomib)

Ninlaro

Takeda

3 mg (of ixazomib)

Ninlaro

Takeda

4 mg (of ixazomib)

Ninlaro

Takeda

AHFS DI Essentials. © Copyright 2016, Selected Revisions November 1, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Takeda Pharmaceutical Company Limited. Ninlaro (ixazomib) capsules prescribing information. Cambridge, MA; 2015 Nov.

2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Medical Review. From FDA website.

3. A phase 3 study comparing oral ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma. From ClinicalTrials.gov Registry. Accessed 2016 Mar 8.

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Clinical Pharmacology and Biopharmaceutics Review(s). From FDA website.

5. Chauhan D, Tian Z, Zhou B et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 2011; 17:5311-21. [PubMed 21724551]

6. Kumar SK, Bensinger WI, Zimmerman TM et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014; 124:1047-55. [PubMed 24904120]

7. Moreau P. Oral therapy for multiple myeloma: ixazomib arriving soon. Blood. 2014; 124:986-7. [PubMed 25124778]

8. Muz B, Ghazarian RN, Ou M et al. Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Devel Ther. 2016; 10:217-26. [PubMed 26811670]

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number208462Orig1s000: Pharmacology Review(s). From FDA website.

10. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Mar 8.

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