Inqovi® Now Approved for the Treatment of Myelodysplastic Syndromes
by Dr. David Schoenbaechler, PharmD, BCOP, CSP
Dr. Joseph Barone, PharmD, BCOP
Inqovi is a combination of decitabine and cedazuridine indicated for the treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
Decitabine is a nucleoside metabolic inhibitor that is believed to exert its effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Cedazuridine is a cytidine deaminase (CDA) inhibitor. CDA is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver degrade decitabine and limit its oral bioavailability. Administration of cedazuridine with decitabine increases systemic absorption of decitabine.
The FDA approval of Inqovi was based on clinical trial results which showed similar drug concentrations between intravenous decitabine and Inqovi. Additionally, about half of the patients who were formerly dependent on transfusions no longer required transfusions during an eight-week period.
The recommended dosage of Inqovi is one tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle. Patients should be instructed to take Inqovi tablets at the same time each day. Inqovi tablets should be swallowed whole and taken on an empty stomach at least two hours before and two hours after food intake. If the patient misses a dose within 12 hours of the time it is usually taken, patients should take the missed dose as soon as possible and then resume the normal daily dosing schedule. The dosing period should be extended by one day for every missed dose to complete five daily doses for each cycle. If vomiting occurs after Inqovi administration, an additional dose should not be taken but rather continue with the next scheduled dose.
Inqovi has warnings and precautions for myelosuppression and embryo-fetal toxicity. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate the progression of underlying MDS.
Based on findings from human data, animal studies, and its mechanism of action, Inqovi can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should use effective contraception during treatment with Inqovi and for six months after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment with Inqovi and for three months after the last dose.
The most common adverse reactions (incidence ≥ 20%) of Inqovi are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.
Coadministration of Inqovi with drugs that are metabolized by CDA (i.e., Azacitidine, Capecitabine, Cytarabine, Gemcitabine) may result in increased systemic exposure with the potential for increased toxicity of these drugs. Coadministration of Inqovi with drugs that are metabolized by CDA should be avoided.
Inqovi tablets are packaged with five tablets in one blister card in a child-resistant carton. The tablets should be stored at room temperature (68°F to 77°F with excursions permitted from 59 degrees F to 86 degrees F). Inqovi is a hazardous drug so applicable special handling and disposal procedures should be followed.
References:
- Inqovi [package insert]. Princeton, NJ: Taiho Oncology, 2020.
- S. Food & Drug Administration News Release: “FDA Approves New Therapy for Myelodysplastic Syndromes (MDS) That Can Be Taken at Home”. July 7, 2020.