FDA

Ninlaro

Approved 20 Nov 2015OralCapsule

The FDA lists this product in 3 strengths and forms.

Indications

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. 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. ( 1 ) 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.

( 1 ) 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) ] .

Contraindications

None. None. ( 4 )

Warnings and precautions

Thrombocytopenia : Monitor platelet counts at least monthly during treatment and adjust dosing, as needed. ( 2.2 , 5.1 ) Gastrointestinal Toxicities : Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed. ( 2.2 , 5.2 ) Peripheral Neuropathy : Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed. ( 2.2 , 5.3 ) Peripheral Edema : Monitor for fluid retention. Investigate for underlying causes, when appropriate.

Adjust dosing, as needed. ( 2.2 , 5.4 ) Cutaneous Reactions : Monitor patients for rash and adjust dosing, as needed. ( 2.2 , 5.5 ) Thrombotic Microangiopathy : Monitor for signs and symptoms. Discontinue NINLARO if suspected. ( 5.6 ) Hepatotoxicity : Monitor hepatic enzymes during treatment. ( 5.7 ) Embryo-Fetal Toxicity : NINLARO can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective non-hormonal contraception.

( 5.8 , 8.1 , 8.3 ) Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting : Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials. ( 5.9 )

5.1Thrombocytopenia

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.

At a glance

Brand name: Ninlaro
Active substance: ixazomib citrate
Route: Oral
Dosage form: Capsule
Applicant: Takeda Pharms USA
Status: Prescription
FDA approval: 20 Nov 2015
Application: NDA208462-001

Indications

Warnings and precautions

5.1Thrombocytopenia

Adverse reactions

The following adverse reactions are described in detail in other sections of the prescribing information: Thrombocytopenia [see Warnings and Precautions (5.1) ] Gastrointestinal Toxicities [see Warnings and Precautions (5.2) ] Peripheral Neuropathy [see Warnings and Precautions (5.3) ] Peripheral Edema [see Warnings and Precautions (5.4) ] Cutaneous Reactions [see Warnings and Precautions (5.5) ] Thrombotic Microangiopathy [see Warnings and Precautions (5.6) ] Hepatotoxicity [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥20%) are thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-617-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=361) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=359).

The most frequently reported adverse reactions (≥20% with a difference of ≥5% compared to placebo) in the NINLARO regimen were thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. Serious adverse reactions reported in ≥2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%) and bronchitis (2%). One or more of the three drugs was permanently discontinued in 4% of patients reporting peripheral neuropathy, 3% of patients reporting diarrhea and 2% of patients reporting thrombocytopenia.

Permanent discontinuation of NINLARO due to an adverse reaction occurred in 10% of patients. Table 4 summarizes the non-hematologic adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo regimen. Table 4: Non-Hematologic Adverse Reactions Occurring in ≥5% of Patients with a ≥5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4) System Organ Class / Preferred Term NINLARO + Lenalidomide and Dexamethasone N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0.

Gastrointestinal disorders Diarrhea 52 10 0 43 3 0 Constipation 35 <1 0 28 <1 0 Nausea 32 2 0 23 0 0 Vomiting 26 1 0 13 <1 0 Nervous system disorders Peripheral neuropathies Represents a pooling of preferred terms 32 2 0 24 2 0 Musculoskeletal and connective tissue disorders Back pain At the time of the final analysis, these adverse reactions no longer met the criterion for a ≥5% difference between the NINLARO regimen and the placebo regimen. 27 <1 0 24 3 0 Infections and infestations Upper respiratory tract infection 27 1 0 23 1 0 Bronchitis 22 2 0 17 2 <1 Skin and subcutaneous tissue disorders Rash 27 3 0 16 2 0 General disorders and administration site conditions Edema peripheral 27 2 0 21 1 0 Table 5 represents pooled information from adverse event and laboratory data.

Table 5: Thrombocytopenia and Neutropenia NINLARO + Lenalidomide and Dexamethasone N=361 Placebo + Lenalidomide and Dexamethasone N=359 % % Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 85 30 67 14 Neutropenia 74 34 70 37 Herpes Zoster Herpes zoster was reported in 6% of patients in the NINLARO regimen and 3% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the healthcare provider's discretion.

Patients treated in the NINLARO regimen who received antiviral prophylaxis had a lower incidence (1%) of herpes zoster infection compared to patients who did not receive prophylaxis (10%). Eye Disorders Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 38% in patients in the NINLARO regimen. The most common adverse reactions of the eyes were cataract (15%), conjunctivitis (9%), blurred vision (7%), and dry eye (6%).

Other Clinical Trials Experience The following serious adverse reactions have each been reported at a frequency of <1% in patients treated with NINLARO: acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NINLARO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Angioedema Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis

Ninlaro

Indications

Contraindications

Warnings and precautions

5.1Thrombocytopenia

At a glance

Two medicines in one question?

Ninlaro

Indications

Contraindications

Warnings and precautions

5.1Thrombocytopenia

At a glance

Two medicines in one question?

5.2Gastrointestinal Toxicities

5.3Peripheral Neuropathy

5.4Peripheral Edema

5.5Cutaneous Reactions

5.6Thrombotic Microangiopathy

5.7Hepatotoxicity

5.8Embryo-Fetal Toxicity

5.9Increased Mortality in Patients Treated with

Interactions

7.1Strong CYP3A Inducers

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information