Ixabepilone Contraindications, Pregnancy Category

Ixabepilone Contraindications
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Ixabepilone Contraindications is an orally bioavailable semisynthetic analog of epothilone B with antineoplastic activity. Ixabepilone binds to tubulin and promotes tubulin polymerization and microtubule stabilization, thereby arresting cells in the G2-M phase of the cell cycle and inducing tumor cell apoptosis. This agent demonstrates antineoplastic activity against taxane-resistant cell lines.
Ixabepilone is a semisynthetic epothilone analog that acts to stabilize microtubules thereby preventing mitosis and causing growth arrest in cancer cells. Ixabepilone is approved for use in refractory cases of advanced breast cancer. Its use is associated with a low rate of serum enzyme elevation, but ixabepilone has not been linked to cases of clinically apparent liver injury with jaundice.

Mechanism of Action of Ixabepilone

Binding of Ixabepilone to beta-tubulins (e.g. beta-III tubulin) stabilizes microtubules. Microtubules are essential to cell division, and epothilones, therefore, stop cells from properly dividing. Like taxol, Ixabepilone binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules.
Ixabepilone is a microtubule inhibitor belonging to the epothilone class of antineoplastic agents. Epothilones are naturally occurring products of fermentation from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic derivative of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone. Ixabepilone binds to beta-tubulin subunits on microtubules and stabilizes and suppresses microtubule activity resulting in mitotic arrest and apoptosis. Although ixabepilone appears to share a similar antimicrotubule mechanism of action with taxanes, the drug differs structurally from taxanes and does not appear to be affected by common mechanisms of taxane resistance.

Indications of Ixabepilone

  • Investigated for use/treatment in breast cancer, head and neck cancer, melanoma, lung cancer, lymphoma (non-Hodgkin’s), prostate cancer, renal cell carcinoma, and cancer/tumors (unspecified).
  • Ixabepilone is a semisynthetic epothilone analog that acts to stabilize microtubules thereby preventing mitosis and causing growth arrest in cancer cells. Ixabepilone is approved for use in refractory cases of advanced breast cancer. Its use is associated with a low rate of serum enzyme elevation, but ixabepilone has not been linked to cases of clinically apparent liver injury with jaundice.
  • Breast Cancer
  • Breast Cancer, Metastatic
  • Locally Advanced Breast Cancer
  • Metastatic Breast Cancer
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Therapeutic Uses

  • Ixabepilone is used in combination with oral capecitabine for the treatment of metastatic or locally advanced breast cancer in patients whose disease is resistant to treatment with an anthracycline and a taxane or in patients whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
  • Anthracycline resistance is defined as progression during therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression during therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.
  • Ixabepilone is used as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.
  • Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane-resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analog approved by the U.S. Food and Drug Administration.
  • Ixabepilone has been shown to have preclinical activity in chemotherapy-sensitive and chemotherapy-resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single-agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers.

Contraindications of Ixabepilone

  • Severe infection
  • Diabetes
  • Anemia
  • Decreased Blood Platelets
  • Severely Decreased Platelets
  • Decreased Neutrophils a Type of White Blood Cell
  • Peripheral neuropathy
  • Disease of Inadequate Blood Flow to the Heart Muscle
  • Abnormal heart rhythm
  • Heart Disease
  • Liver problems
  • Severe liver disease
  • High Amount of Bilirubin in the Blood
  • Abnormal liver function tests
  • Pregnancy
  • A mother who is producing milk and breastfeeding
  • Severely Decreased Levels of Neutrophils in the Blood

Dosage of Ixabepilone

Strengths: 15 mg; 45 mg

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Breast Cancer

  • 40 mg/m2 infused intravenously over 3 hours every 3 weeks. The dosage for patients with a BSA exceeding 2.2 m2 should be calculated based on a 2.2 m2 body surface area.

Premedication-  all patients must be premedicated approximately 1 hour prior to ixabepilone administration (to minimize the chance of a hypersensitivity reaction) as follows

  • with an H1 antagonist (e.g., diphenhydramine 50 mg orally or an equivalent agent) plus
  • an H2 antagonist (e.g., ranitidine 150 mg to 300 mg orally or an equivalent agent)

Side Effects of Ixabepilone

The Most Common

  • abdominal pain
  • bone fractures
  • increased blood pressure
  • increased cholesterol levels
  • signs of infection (e.g., severe fever, chills, mouth ulcers, shortness of breath, sudden lack of energy)
  • signs of depression (such as feeling sad, losing interest in things you used to enjoy, weight changes, changes in sleep habits, feelings of guilt or worthlessness, thoughts of suicide)
  • signs of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
  • signs of liver problems (e.g., yellow skin and eyes, nausea, loss of appetite, dark-colored urine)

More Common

  • Black, tarry stools
  • body aches or pain
  • burning, numbness, tingling, or painful sensations
  • burning pain on urination
  • chest pain
  • chills
  • cough
  • difficult or labored breathing
  • ear congestion
  • fever
  • headache
  • loss of voice
  • lower back or side pain
  • nasal congestion
  • painful or difficult urination
  • pale skin
  • red, swelling, or painful skin

Rare

  • Bad, unusual, or unpleasant (after) taste
  • change in taste
  • cracked lips
  • diarrhea
  • difficulty having a bowel movement (stool)
  • discoloration of the fingernails or toenails
  • feeling of warmth
  • hair loss or thinning of the hair
  • heartburn
  • lack or loss of strength
  • loss of appetite
  • nausea
  • redness of the face, neck, arms, and occasionally, upper chest
  • stomach pain
  • sudden sweating
  • swelling or inflammation of the mouth

Drug Interactions of Ixabepilone

Ixabepilone may interact with following drugs, supplements & may change the efficacy of drugs

  • “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
  • BCG vaccine
  • calcium channel blockers (e.g., diltiazem, nicardipine, verapamil)
  • carbamazepine
  • carvedilol
  • cimetidine
  • clozapine
  • cyclosporine
  • desipramine
  • dexamethasone
  • diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin, rosiglitazone)
  • hepatitis protease inhibitors (e.g., boceprevir, simeprevir)
  • fosphenytoin
  • grapefruit juice
  • haloperidol
  • HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delavirdine, efavirenz, etravirine, nevirapine)
  • HIV protease inhibitors (atazanavir, darunavir, lopinavir, ritonavir)
  • macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
  • metronidazole
  • mifepristone
  • mirabegron
  • modafinil
  • norfloxacin
  • oxcarbazepine
  • pentobarbital
  • phenobarbital
  • phenytoin
  • prazosin
  • progesterone
  • propranolol
  • protein kinase inhibitors (e.g., crizotinib, dabrafenib, imatinib, lapatinib, nilotinib)
  • St. John’s Wort
  • tacrolimus
  • tamoxifen
  • tocilizumab
  • trastuzumab
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Pregnancy Category

FDA Pregnancy Category – D

Pregnancy

It is suspected that the use of ixabepilone during pregnancy could cause miscarriages and other serious problems. It is not intended to be taken by women who have not reached menopause. This medication should not be taken during pregnancy unless the benefits outweigh the risks. Any woman taking this medication who may become pregnant should practice effective birth control and contact her doctor immediately if pregnancy is suspected while taking this medication.

Lactation

It is not known if  Ixabepilone passes into breast milk. If you breastfeeding feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. The safety and effectiveness of this medication have not been established for children. Children under 18 years of age should not use this medication.

References

Ixabepilone Contraindications

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