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Ixazomib Citrate – Uses, Dosage, Side Effects, Interaction – Rxharun

Ixazomib Citrate – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Ixazomib is an N-capped dipeptidyl leucine boronic acid that reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. At higher concentrations, ixazomib also seems to inhibit the proteolytic β1 and β2 subunits and induce the accumulation of ubiquitinated proteins. In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition.

At therapeutic concentrations, ixazomib selectively and reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5)[rx] with a dissociation half-life of 18 minutes. This mechanism is the same as that of bortezomib, which has a much longer dissociation half-life of 110 minutes; the related drug carfilzomib, by contrast, blocks PSMB5 irreversibly. Proteasome subunits beta type-1 and type-2 are only inhibited at high concentrations reached in cell culture models.[rx]

PSMB5 is part of the 20S proteasome complex and has an enzymatic activity similar to chymotrypsin. It induces apoptosis, a type of programmed cell death, in various cancer cell lines. A synergistic effect of ixazomib and lenalidomide has been found in a large number of myeloma cell lines. Ixazomib a second-generation proteasome inhibitor (PI) and the first oral PI approved by the FDA in November 2015 for multiple myeloma treatment in combination with 2 other therapies (lenalidomide and dexamethasone) for patients who have received at least 1 prior therapy.

Indications

  • Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. It is used in combination with dexamethasone and lenalidomide in patients who have had one prior treatment, allowing patients to be on a fully oral regimen, which has been proven to have a progression-free survival benefit.
  • Treatment of lymphoid malignancies (excluding multiple myeloma)
  • Ixazomib is a small-molecule proteasome inhibitor that is used in combination with other antineoplastic agents to treat refractory multiple myeloma
  • Treatment of systemic light chain amyloidosis.
  • Ixazomib is a monoclonal antibody used with other medications to treat multiple myeloma in patients who have received one other therapy already.

Use in Cancer

Ixazomib citrate is approved to be used with lenalidomide and dexamethasone to treat:

  • Multiple myeloma in patients who have already received at least one other type of treatment.

Ixazomib citrate is also being studied in the treatment of other types of cancer.

Contraindications

  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
  • liver problems
  • fluid retention in the legs, feet, arms or hands
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)
  • kidney disease with likely reduction in kidney function
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 2.3 mg; 3 mg; 4 mg

Multiple Myeloma

  • 4 mg orally once a week on Days 1, 8, and 15 of a 28-day cycle
  • This drug is only given in combination with lenalidomide and dexamethasone.
  • For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.
  • Antiviral prophylaxis should be considered to decrease the risk of herpes zoster reactivation.
  • Prior to initiating a new cycle of therapy:
  • The absolute neutrophil count should be at least 1,000/mm3, the Platelet count should be at least 75,000/mm3, and Nonhematologic toxicities should, at physician discretion, generally be recovered to patient baseline condition or Grade 1 or lower
  • Treatment should be continued until the disease progresses or has unacceptable toxicity.
  • In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy

Dose Adjustments

DOSE REDUCTIONS DUE TO ADVERSE REACTIONS:

  • Recommended starting dose: 4 mg
  • First reduction recommendation: 3 mg
  • Second reduction recommendation: 2.3 mg
  • Discontinue therapy

DOSE MODIFICATION GUIDELINES FOR THIS DRUG IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE:
THROMBOCYTOPENIA:
Platelet count less than 30,000/mm3:

  • Withhold this drug and lenalidomide until the platelet count is at least 30,000/mm3.
  • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume this drug at its most recent dose.
  • If the platelet count falls to less than 30,000/mm3 again, withhold this drug and lenalidomide until the platelet count is at least 30,000/mm3.
  • Following recovery, resume this drug at the next lower dose and resume lenalidomide at its most recent dose.

NEUTROPENIA:
Absolute neutrophil count less than 500/mm3:

  • Withhold this drug and lenalidomide until the absolute neutrophil count is at least 500/mm3. Consider adding granulocyte colony-stimulating factor (G-CSF) as per clinical guidelines.
  • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume this drug at its most recent dose.
  • If the absolute neutrophil count falls to less than 500/mm3 again, withhold this drug and lenalidomide until the absolute neutrophil count is at least 500/mm3.
  • Following recovery, resume this drug at the next lower dose and resume lenalidomide at its most recent dose.

NONHEMATOLOGIC TOXICITIES RECOMMENDED DOSE MODIFICATIONS:
Grade 2 or 3 rash:

  • Withhold lenalidomide until the rash recovers to Grade 1 or lower.
  • Following recovery, resume lenalidomide at the next lower dose according to its prescribing information.
  • If a Grade 2 or 3 rash occurs again, withhold this drug and lenalidomide until the rash recovers to Grade 1 or lower.
  • Following recovery, resume this drug at the next lower dose and resume lenalidomide at its most recent dose.

Grade 4 rash:

  • Discontinue therapy.

PERIPHERAL NEUROPATHY RECOMMENDED DOSE MODIFICATIONS:
Grade 1 peripheral neuropathy with pain or Grade 2 peripheral neuropathy:

  • Withhold this drug until peripheral neuropathy recovers to Grade 1 or lower without pain or the patient’s baseline.
  • Following recovery, resume this drug at its most recent dose.

Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy:

  • Withhold this drug. Toxicities should, at the physician’s discretion, generally recover to the patient’s baseline condition or Grade 1 or lower prior to resuming this drug.
  • Following recovery, resume this drug at the next lower dose.

Grade 4 peripheral neuropathy:

  • Discontinue therapy.

OTHER NONHEMATOLOGIC TOXICITIES RECOMMENDED DOSE MODIFICATIONS:
Other Grade 3 or 4 nonhematological toxicities:

  • Withhold this drug. Toxicities should, at the physician’s discretion, generally recover to the patient’s baseline condition or Grade 1 or lower prior to resuming this drug.
  • If attributable to this drug, resume this drug at the next lower dose following recovery.

Patients take ixazomib by mouth; based on the drug approval study, it should be taken weekly on days 1, 8, and 15 of a 28-day cycle. The recommended dose is 4 mg, and for patients with moderate or severe hepatic impairment, renal impairment, or need dialysis, this dose is reduced to 3 mg. Ixazomib comes in three different capsule doses, which are 4 mg, 3 mg, and 2.3 mg.

It is also important to keep in mind that ixazomib should be given with dexamethasone and lenalidomide, which have their specific dosing schedules within a cycle. Both ixazomib and dexamethasone are given on days 1, 8, and 15; hence it is important to separate them since ixazomib should not be taken with food, whereas dexamethasone should be.

Administration advice:

  • Capsules should not be opened or crushed.
  • This drug is cytotoxic and direct contact with the capsule contents should be avoided.
  • 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 of in accordance with local requirements.
  • The patient should be advised to read the approved patient labeling.
  • If a dose is delayed or missed, the dose should be taken only if the next scheduled dose is 72 hours away or more.
  • 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.
  • Patients should be advised to take this drug exactly as prescribed.
  • Patients should be advised to take this drug at least 1 hour before or at least 2 hours after food.
  • Patients should be advised that this drug and dexamethasone should not be taken at the same time, because dexamethasone should be taken with food.
  • Patients should swallow the capsule whole with water. The capsule should not be crushed, chewed or opened.
  • Patients should be advised that direct contact with the capsule contents should be avoided.
  • Patients should be advised to wash thoroughly with soap and water If contact occurs with the skin and to flush thoroughly with water If contact occurs with the eyes.

Side Effects

The Most Common

  • diarrhea
  • constipation
  • nausea
  • new or worsening rash
  • back pain
  • unusual swelling of your arms or legs
  • weight gain due to swelling
  • blurred vision
  • dry eyes
  • pink eye
  • nausea
  • extreme tiredness
  • loss of appetite
  • flu-like symptoms
  • unusual bleeding or bruising
  • yellowing of your skin or eyes
  • pain in the upper right part of your stomach
  • burning, tingling, numbness, pain, or weakness in arms or legs
  • bloody or black, tarry stool

More common

  • Black, tarry stools
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • burning, numbness, tingling, or painful sensations
  • chills
  • cough
  • dark urine
  • diarrhea
  • dizziness
  • fever
  • headache
  • itching or rash
  • light-colored stools
  • loss of appetite
  • lower back or side pain
  • nausea
  • numbness, tingling, or pain in the hands or feet
  • painful or difficult urination
  • pale skin
  • rapid weight gain
  • rash with flat lesions or small raised lesions on the skin
  • redness or discoloration of the skin
  • sore throat
  • stomach pain
  • tingling of the hands or feet
  • ulcers, sores, or white spots in the mouth
  • unpleasant breath odor
  • unsteadiness or awkwardness
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting of blood
  • weakness in the arms, hands, legs, or feet
  • yellow eyes or skin

Rare

  • Bleeding gums
  • blood in the urine or stools
  • pinpoint red spots on the skin
  • Blistering, peeling, or loosening of the skin
  • bloody nose
  • heavier menstrual periods
  • joint or muscle pain
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • Back pain
  • blurred vision
  • body aches or pain
  • burning, dry, or itching eyes
  • difficulty having a bowel movement (stool)
  • discharge, excessive tearing
  • ear congestion
  • loss of voice
  • nasal congestion
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • sneezing

Drug Interaction

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Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned.

Pregnancy

This drug can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with this drug. Male and female patients of reproductive potential should use effective contraceptive measures during and for 90 days following therapy with this drug. Females using oral hormonal contraceptives should additionally use a barrier method of contraception. Based on animals and the drug mechanism of action, this drug can cause fetal harm.

Lactation

No information is available on the clinical use of ixazomib during breastfeeding. Because its half-life is about 9.5 days, it is likely to accumulate in the infant. It is also given in combination with leflunomide and dexamethasone, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during ixazomib therapy and for 90 days after the last dose.

Why is this medication prescribed?

Ixazomib is used in combination with lenalidomide (Revlimid) and dexamethasone to treat multiple myeloma (cancer of the plasma cells in the bone marrow) that has worsened after treatment with other chemotherapy medications. Ixazomib is in a class of medications called proteasome inhibitors. It works by helping to kill cancer cells.

How should this medicine be used?

Ixazomib comes as a capsule to take by mouth. It is usually taken with water on an empty stomach, at least 1 hour before or 2 hours after eating. It is taken on days 1,8, and 15 of a 28 day treatment cycle. Take ixazomib at around the same time on every day that you take it. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ixazomib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Do not take ixazomib and dexamethasone at the same time because you should take dexamethasone with food.

Swallow the capsules whole; do not split, chew, or crush them.

Be careful when handling ixazomib capsules. Do not allow your skin, eyes, mouth, or nose to come into contact with broken or crushed ixazomib capsules. If such contact occurs, wash your skin well with soap and water or rinse your eyes well with plain water.

If you vomit after taking ixazomib, do not repeat the dose. Take your next dose of ixazomib on the next scheduled day that you are supposed to take it.

Your doctor may need to temporarily or permanently stop your treatment or decrease your dose of ixazomib, or of the other medications that you are taking, depending on the side effects that you experience. Be sure to talk to your doctor about how you are feeling during your treatment. Do not stop taking ixazomib without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking ixazomib,

  • tell your doctor and pharmacist if you are allergic to ixazomib, any other medications, or any of the ingredients in ixazomib capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements you are taking or plan to take. Be sure to mention any of the following: carbamazepine (Epitol, Equetro, Carbatrol, Tegretol, Teril), efavirenz (Sustiva, in Atripla), nevirapine (Viramune), phenobarbital, pioglitazone (Actos, in Actoplus, Duetact, Oseni), phenytoin (Dilantin, Phenytek), rifabutin (Mycobutin), and rifampin (Rifadin, Rimactane, in Rifamate, Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have or have ever had liver or kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant, or plan to father a child. You should not become pregnant while you are taking ixazomib. Use effective birth control during your treatment with ixazomib and for 90 days after your final dose. If you are a male and your partner can become pregnant, you should use effective birth control during your treatment and for 90 days after your final dose. Talk to your doctor about birth control methods that will work for you. If you or your partner become pregnant while taking ixazomib, call your doctor immediately. Ixazomib can harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking ixazomib.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is within 72 hours (3 days) of your next scheduled dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

References

Consumer Information – TrustArc The Leader in Privacy Management SoftwareLooking online for info on your child's health? Here are some tipsJanja Kristan - Chief Administrative Officer - AACI | LinkedIn
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