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P T. 2018;43(10): 599-600, 628

Pharmaceutical Approval Update October 2018

Mary Choy PharmD, BCGP, FASHP

Ivosidenib (Tibsovo)

Manufacturer: Agios Pharmaceuticals, Inc., Cambridge, MA

Date of Approval: July 20, 2018

Indication: Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor used for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. It is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.

Drug Class: IDH1 inhibitors

Uniqueness of Drug: Ivosidenib is the first drug approved to treat AML patients with a specific mutation in the IDH1 gene and is also the first drug in its class.

Warnings and Precautions

Boxed warning. Patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated. The symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

QTc Interval Prolongation. Monitor electrocardiograms and electrolytes. If QTc interval prolongation occurs, reduce dose or withhold, then resume dose or permanently discontinue ivosidenib.

Guillain-Barré Syndrome. Monitor patients for signs and symptoms of new motor and/or sensory findings. Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barré syndrome.

Dosage and Administration

Patient Selection. Select patients for the treatment of AML with ivosidenib based on the presence of IDH1 mutations in the blood or bone marrow. Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse. Information on FDA-approved tests for the detection of IDH1 mutations in AML is available at

Recommended Dose

  • The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity.
  • For patients without disease progression or unacceptable toxicity, treat for a minimum of six months to allow time for clinical response.
  • Administer ivosidenib with or without food. Do not administer ivosidenib with a high-fat meal because of an increase in ivosidenib concentration.
  • Do not split or crush ivosidenib tablets.
  • If a dose of ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer two doses within 12 hours.

Mary Choy, PharmD, BCGP, FASHP

Commentary: The FDA based its approval of ivosidenib on a clinical trial of 174 people with AML with an IDH1 mutation, and whose cancer had come back after treatment or who had never responded to previous treatment. After an average follow-up time of 8.3 months, 32.8% of patients who were given ivosidenib had either no evidence of cancer and full recovery of blood counts, or no evidence of cancer and a partial recovery of blood counts. The improvement lasted for an average 8.2 months. The most common adverse reactions (≤ 20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolongation, rash, pyrexia, cough, and constipation.

Sources: Agios Pharmaceuticals, Inc., Tibsovo prescribing information.

Elagolix (Orilissa)

Manufacturer: AbbVie Inc, North Chicago, IL

Date of Approval: July 24, 2018

Indication: Elagolix is indicated for the management of moderate to severe pain associated with endometriosis.

Drug Class: Gonadotropin-releasing hormone antagonists

Uniqueness of Drug: Elagolix is the first FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over a decade. The FDA approved elagolix under priority review.

Warnings and Precautions

Bone Loss. There are dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Assess BMD in women with additional risk factors for bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy

Women who take elagolix may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue drug if pregnancy is confirmed.

Suicidal Ideation and Mood Disorders. Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new-onset or worsening depression, anxiety, or other mood changes.

Hepatic Transaminase Elevations. Use the lowest effective dose of elagolix and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver enzymes to determine whether the benefits of continued therapy outweigh the risks.

Reduced Efficacy with Estrogen-Containing Contraceptives. Based on the mechanism of action of elagolix, estrogen-containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use non-hormonal contraceptives during treatment with elagolix and for one week after discontinuing the drug.

Dosage and Administration

  • Normal liver function or mild hepatic impairment: 150 mg once daily for up to 24 months or 200 mg twice daily for up to six months.
  • Moderate hepatic impairment: 150 mg once daily for up to six months.
  • Exclude pregnancy before starting elagolix or start drug within seven days from the onset of menses.
  • Take elagolix at approximately the same time each day, with or without food.
  • Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives.
  • Limit the duration of use because of bone loss.

Commentary: The FDA approval is supported by data from two studies in the endometriosis phase 3 study program, which evaluated nearly 1,700 women with moderate to severe endometriosis pain. Clinical trial data demonstrated elagolix significantly reduced the three most common types of endometriosis pain: daily menstrual pelvic pain, non-menstrual pelvic pain and pain with sex. A higher proportion of women treated with elagolix 150 mg once daily and 200 mg twice daily were responders for daily menstrual pain and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at month 3. Both elagolix treatment groups showed statistically significant greater mean decreases from baseline compared to placebo in daily menstrual pain and non-menstrual pelvic pain at month 6. The most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes.

Sources: AbbVie Inc, Orilissa prescribing information

Mogamulizumab-kpkc (Poteligeo)

Manufacturer: Kyowa Kirin, Inc., Bedminster, NJ

Date of Approval: August 8, 2018

Indication: Mogamulizumab-kpkc is a CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody. It is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.

Drug Class: CCR4-directed monoclonal antibody

Uniqueness of Drug: Mogamulizumab-kpkc is a monoclonal antibody that binds to CCR4 proteins occurring on some cancer cells. This FDA approval provides a new treatment option for patients with MF and is the first drug indicated specifically for the treatment of SS. This application was granted Priority Review and Breakthrough Therapy designations. Mogamulizumab-kpkc also received Orphan Drug designation.

Warnings and Precautions

Dermatologic Toxicity. Fatal and life-threatening skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in recipients of mogamulizumab-kpkc. Monitor patients for rash throughout the treatment course. Management of dermatologic toxicity includes topical corticosteroids and interruption or permanent cessation of mogamulizumab-kpkc. Consider skin biopsy to help distinguish drug eruption from disease progression. Discontinue mogamulizumab-kpkc permanently for SJS or TEN or for any life-threatening (grade 4) reaction. For possible SJS or TEN, interrupt mogamulizumab-kpkc and do not restart unless SJS or TEN is ruled out and the cutaneous reaction has resolved to grade 1 or less.

Infusion Reactions. Temporarily interrupt mogamulizumab-kpkc for any infusion reaction. The most commonly reported signs include chills, nausea, fever, tachycardia, rigors, headache, and vomiting. Consider premedication (such as diphenhydramine and acetaminophen) for the first infusion of mogamulizumab-kpkc in all patients. Monitor patients closely for signs and symptoms of infusion reactions and interrupt the infusion for any grade reaction and treat promptly.

Infections. Fatal and life-threatening infections have occurred in patients treated with mogamulizumab-kpkc, including sepsis, pneumonia, and skin infection. Monitor patients for signs and symptoms of infection and treat promptly.

Autoimmune Complications. Fatal and life-threatening immune-mediated complications have been reported in recipients of mogamulizumab-kpkc. Grade 3 or higher immune-mediated or possibly immune-mediated reactions have included myositis, myocarditis, polymyositis, hepatitis, pneumonitis, and a variant of Guillain-Barré syndrome. Interrupt or permanently discontinue mogamulizumab-kpkc as appropriate for suspected immune-mediated adverse reactions. Consider the benefit/risk of mogamulizumab-kpkc in patients with a history of autoimmune disease.

Complications of allogeneic HSCT after mogamulizumab-kpkc. Increased risks of transplant complications have been reported in patients who receive allogeneic HSCT after mogamulizumab-kpkc including severe (grade 3 or 4) acute graft-versus-host disease (GVHD), steroid-refractory GVHD, and transplant-related death. Among recipients of pre-transplantation mogamulizumab-kpkc, a higher risk of transplant complications has been reported if mogamulizumab-kpkc is given within a shorter time frame (approximately 50 days) before HSCT. Follow patients closely for early evidence of transplant-related complications.

Dosage and Administration

  • The recommended dose of mogamulizumab-kpkc is 1 mg/kg administered as an intravenous infusion over at least 60 minutes.
  • Administer on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity.
  • Administer mogamulizumab-kpkc within two days of the scheduled dose. If a dose is missed, administer the next dose as soon as possible and resume dosing schedule.
  • Do not administer mogamulizumab-kpkc subcutaneously or by rapid intravenous administration.
  • Administer premedication with diphenhydramine and acetaminophen for the first mogamulizumab-kpkc infusion.
  • Administer infusion solution over at least 60 minutes through an intravenous line containing a sterile, low protein binding, 0.22 micron (or equivalent) in-line filter.
  • Do not mix mogamulizumab-kpkc with other drugs.
  • Do not co-administer other drugs through the same intravenous line.

Commentary: The FDA approval was based on a clinical trial of 372 patients with relapsed MF or SS who received either mogamulizumab-kpkc or a type of chemotherapy called vorinostat. Progression-free survival was longer for patients taking mogamulizumab-kpkc (median 7.6 months) compared to patients taking vorinostat (median 3.1 months). The most common adverse reactions (reported in ≥ 20% of patients) were rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infections.

Sources: Kyowa Kirin, Inc., Poteligeo prescribing information.

Author bio: 
Dr. Choy is a freelance medical writer living in New York City.