Ninlaro

Oral Administration

Take once a week on the same day and at approximately the same time for the first 3 weeks of a 4-week cycle

Taken at least 1 hr before or at least 2 hr after food

Swallow capsule whole with water; do not crush, chew, or open (see Storage and Chemotherapy Handling)

Missed or vomited dose

• If a dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hr away
• A missed dose should not be taken within 72 hr 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; resume dosing at the time of the next scheduled dose

Storage

Store at room temperature; not to exceed 30°C (86°F)

Do not freeze

Store capsules in original packaging until immediately prior to use

Chemotherapy handling and disposal

• Ixazomib is cytotoxic
• Capsules should not be opened or crushed
• 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
• Any unused medicinal product or waste material should be disposed in accordance with local requirements

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Other drugs may interact with ixazomib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your combination chemotherapy will be given in a 28-day treatment cycle. You will take ixazomib once per week during the first 3 weeks of each cycle. Your other medicines may be taken daily or only once per week.

Follow your doctor's dosing instructions very carefully. Your doctor will determine how long to treat you with ixazomib.

Take ixazomib on an empty stomach, at least 1 hour before or 2 hours after a meal.

Do not take your dexamethasone dose at the same time you take ixazomib. Dexamethasone should be taken with food and ixazomib should be taken without food.

Take this medicine with a full glass of water. Do not crush, chew, break, or open the capsule. Swallow it whole.

If you vomit shortly after taking an ixazomib capsule, do not take another one. Wait until your next scheduled dose and take the regular amount of medicine at that time.

Do not use a broken ixazomib capsule. The medicine inside the capsule can be dangerous if it gets in your eyes or on your skin. If this occurs, wash your skin with soap and water or rinse your eyes with water. Ask your doctor or pharmacist how to safely handle and dispose of a broken capsule.

You may need frequent medical tests to be sure this medicine is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Store at room temperature away from moisture and heat. Do not freeze. Keep each capsule in the blister pack until you are ready to take a dose. Store blister packs in their original carton.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 72 hours (3 days) away. Do not take extra medicine to make up the missed dose.

Ninlaro may cause serious side effects, including:

• Low platelet counts (thrombocytopenia). Low platelet counts are common with Ninlaro, and can sometimes be serious. You may need platelet transfusions if your counts are too low. Tell your healthcare provider if you have any signs of low platelet counts, including bleeding and easy bruising.
• Stomach and intestinal (gastrointestinal) problems. Diarrhea, constipation, nausea, and vomiting are common with Ninlaro, and can sometimes be severe. Call your healthcare provider if you get any of these symptoms and they do not go away during treatment with Ninlaro. Your healthcare provider may prescribe medicine to help treat your symptoms.
• Nerve problems. Nerve problems are common with Ninlaro and may also be severe. Tell your healthcare provider if you get any new or worsening symptoms, including:
  • tingling
  • numbness
  • pain
  • a burning feeling in your feet or hands
  • weakness in your arms or legs
• Swelling. Swelling is common with Ninlaro and can sometimes be severe. Tell your healthcare provider if you develop swelling in your arms, hands, legs, ankles, or feet, or if you gain weight from swelling.
• Skin reactions. Tell your healthcare provider if you get a new or worsening rash.
• Liver problems. Tell your healthcare provider if you get these signs of a liver problem:
  • yellowing of your skin or the whites of your eyes
  • pain in your right upper stomach-area Back pain is also common with Ninlaro.

These are not all the possible side effects of Ninlaro. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 

Other drugs may interact with ixazomib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

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

• It is used to treat multiple myeloma.

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 [see Data]. Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with Ninlaro.

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

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.

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 [see Nonclinical Toxicology (13.1)].

Pediatric Use

Safety and effectiveness 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)].

Ninlaro (ixazomib) is an antineoplastic agent. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- and the structural formula is:

The molecular formula for ixazomib citrate is C20H23BCl2N2O9 and its molecular weight is 517.12. Ixazomib citrate has one chiral center and is the R-stereoisomer. The solubility of ixazomib citrate in 0.1N HCl (pH 1.2) at 37°C is 0.61 mg/mL (reported as ixazomib). The solubility increases as the pH increases.

Ninlaro (ixazomib) capsules for oral use contain 4, 3 or 2.3 mg of ixazomib equivalent to 5.7, 4.3 or 3.3 mg of ixazomib citrate, respectively. Inactive ingredients include microcrystalline cellulose, magnesium stearate, and talc. Capsule shells contain gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide, the 3 mg capsule shell contains black iron oxide and the 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.

1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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 (2.1)]

Thrombocytopenia

Advise patients that they may experience low platelet counts (thrombocytopenia). Signs of thrombocytopenia may include bleeding and easy bruising. [see Warnings and Precautions (5.1)].

Gastrointestinal Toxicities

Advise patients they may experience diarrhea, constipation, nausea and vomiting and to contact their physician if these adverse reactions persist. [see Warnings and Precautions (5.2)].

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. [see Warnings and Precautions (5.3)].

Peripheral Edema

Advise patients to contact their physicians if they experience unusual swelling of their extremities or weight gain due to swelling [see Warnings and Precautions (5.4)].

Cutaneous Reactions

Advise patients to contact their physicians if they experience new or worsening rash [see Warnings and Precautions (5.5)].

Hepatotoxicity

Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

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

Ninlaro® (nin-LAR-oh)
(ixazomib)
capsules

Ninlaro is used with two other prescription medicines called REVLIMID® (lenalidomide) and dexamethasone. Read the Medication Guide that comes with REVLIMID® (lenalidomide). You can ask your healthcare provider or pharmacist for information about dexamethasone.

What is Ninlaro?

Ninlaro is a prescription medicine used to treat multiple myeloma in combination with the medicines REVLIMID® (lenalidomide) and dexamethasone, in people who have received at least one prior treatment for their multiple myeloma.

It is not known if Ninlaro is safe and effective in children.

Before taking Ninlaro, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems
• have kidney problems or are on dialysis
• are pregnant or plan to become pregnant. Ninlaro can harm your unborn baby.
  • Avoid becoming pregnant during treatment with Ninlaro.
  • Females who are able to become pregnant must use effective birth control during treatment and for 90 days after your final dose of Ninlaro.
  • Males with a female partner who is able to become pregnant must use effective birth control during treatment and for 90 days after your final dose of Ninlaro.
  • Talk to your healthcare provider about birth control methods that may be right for you.
  • Tell your healthcare provider right away if you or your partner become pregnant while you are receiving Ninlaro.
• are breastfeeding or plan to breastfeed. It is not known if Ninlaro passes into breast milk. Do not breastfeed during treatment with Ninlaro.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before starting any new medicines during treatment with Ninlaro.

How should I take Ninlaro?

• Take Ninlaro exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking Ninlaro without talking to your healthcare provider first.
• Ninlaro is taken in "cycles." Each cycle lasts 4 weeks (28 days).
  • The usual dose of Ninlaro is 1 capsule taken 1 time each week, on the same day of the week for the first 3 weeks of each cycle.
  • Take each dose of Ninlaro at about the same time of day.
  • Take REVLIMID (lenalidomide) and dexamethasone exactly as your healthcare provider tells you to.
  • Your healthcare provider will do blood tests during treatment with Ninlaro to check for side effects.
  • Your healthcare provider may change your dose or stop Ninlaro, REVLIMID (lenalidomide), or dexamethasone if you have side effects.
• Take Ninlaro at least 1 hour before or at least 2 hours after food.
• On the days that you take both Ninlaro and dexamethasone, do not take Ninlaro and dexamethasone at the same time. Take dexamethasone with food.
• Swallow Ninlaro capsules whole with water. Do not crush, chew or open the capsule.
• Avoid direct contact with the capsule contents. If you accidentally get powder from the Ninlaro capsule on your skin, wash the area well with soap and water. If you accidentally get powder from the Ninlaro capsule in your eyes, flush your eyes well with water.
• If you miss a dose of Ninlaro, or if you are late taking a dose, take the dose as long as the next scheduled dose is more than 3 days (72 hours) away. Do not take a missed dose of Ninlaro if it is within 3 days (72 hours) of your next scheduled dose.
• If you vomit after taking a dose of Ninlaro, do not repeat the dose. Take your next dose of Ninlaro on the next scheduled day and time.
• If you take more Ninlaro than your healthcare provider tells you to take, call your healthcare provider right away or go to the nearest hospital emergency room.

What are the possible side effects of Ninlaro?

Ninlaro may cause serious side effects, including:

• Low platelet counts (thrombocytopenia). Low platelet counts are common with Ninlaro, and can sometimes be serious. You may need platelet transfusions if your counts are too low. Tell your healthcare provider if you have any signs of low platelet counts, including bleeding and easy bruising.
• Stomach and intestinal (gastrointestinal) problems. Diarrhea, constipation, nausea, and vomiting are common with Ninlaro, and can sometimes be severe. Call your healthcare provider if you get any of these symptoms and they do not go away during treatment with Ninlaro. Your healthcare provider may prescribe medicine to help treat your symptoms.
• Nerve problems. Nerve problems are common with Ninlaro and may also be severe. Tell your healthcare provider if you get any new or worsening symptoms, including:

• Swelling. Swelling is common with Ninlaro and can sometimes be severe. Tell your healthcare provider if you develop swelling in your arms, hands, legs, ankles, or feet, or if you gain weight from swelling.
• Skin reactions. Tell your healthcare provider if you get a new or worsening rash.
• Liver problems. Tell your healthcare provider if you get these signs of a liver problem:
  • yellowing of your skin or the whites of your eyes
  • pain in your right upper stomach-area

Back pain is also common with Ninlaro.

These are not all the possible side effects of Ninlaro. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Ninlaro?

• Store Ninlaro at room temperature. Do not store above 86°F (30°C).
• Do not freeze Ninlaro.
• Store Ninlaro capsules in the original packaging until just before each use.
• Ask your pharmacist or healthcare provider about how to dispose of (throw away) unused Ninlaro.

Keep Ninlaro and all medicines out of the reach of children.

General information about the safe and effective use of Ninlaro.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Ninlaro for a condition for which it was not prescribed. Do not give Ninlaro to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Ninlaro that is written for healthcare professionals.

What are the ingredients in Ninlaro?

Active ingredient: ixazomib

Inactive ingredients: microcrystalline cellulose, magnesium stearate, and talc

Capsule shells: gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide. The 3 mg capsule shell contains black iron oxide. The 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.

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.
All other trademarks are the property of their respective owners.
©2015 Millennium Pharmaceuticals, Inc.
For more information, you may also go to www.Ninlaro.com or call 1-844-617-6468.

This Patient Information has been approved by the U.S. Food and Drug Administration.
Issued: November 2015

RX only

Contains 1 Capsule
Please read Package Insert before use.

NDC 63020-079-01

Ninlaro®
(ixazomib) capsules

3 mg

Takeda

Get emergency medical help if you have signs of an allergic reaction to Ninlaro: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Rare but serious side effects of Ninlaro may occur. Seek medical attention if you have:

• muscle weakness, numbness or loss of movement in your legs or feet;

• headache, confusion, changes in your vision or thinking;

• a seizure (convulsions);

• little or no urination;

• nosebleed, bruising, unusual tiredness; or

• fast or slow heart rate, feeling light-headed or short of breath.

Call your doctor at once if you have:

• severe ongoing nausea, vomiting, diarrhea, or constipation;

• back pain;

• new or worsening skin rash;

• blurred vision, dry or red eyes;

• easy bruising or bleeding;

• fluid retention - swelling in your hands or feet, rapid weight gain;

• nerve problems - numbness, tingling, pain, burning feeling in your hands or feet, weakness in your arms or legs;

• signs of shingles - flu-like symptoms, tingly or painful blistering rash on one side of your body;

• low white blood cell counts - fever, cold or flu symptoms, cough, sore throat, swollen gums, mouth sores, skin sores;

• liver problems - upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes); or

• severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Ninlaro side effects may include:

• fluid retention;

• numbness or tingling, bruising or bleeding;

• diarrhea, constipation;

• nausea, vomiting; or

• back pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to ixazomib: oral capsule

Cardiovascular

Very common (10% or more): Peripheral edema (18%)[Ref]

Dermatologic

Very common (10% or more): Rash (11%)
Postmarketing reports: Acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (36%), constipation (25%), nausea (21%)[Ref]

Hematologic

Very common (10% or more): Thrombocytopenia (78%), neutropenia (67%), thrombotic thrombocytopenic purpura[Ref]

Hepatic

Frequency not reported: Hepatotoxicity[Ref]

Immunologic

Postmarketing reports: Transverse myelitis[Ref]

Metabolic

Postmarketing reports: Tumor lysis syndrome[Ref]

Musculoskeletal

Very common (10% or more): Back pain (16%)[Ref]

Nervous system

Frequency not reported: Peripheral neuropathy (21%)
Postmarketing reports: Posterior reversible encephalopathy syndrome[Ref]

Ocular

Common (1% to 10%): Blurred vision, dry eye, conjunctivitis[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (14%)[Ref]

Some side effects of Ninlaro may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.