INQOVI Film-coated tablet Ref.[51655] Active ingredients: Cedazuridine Decitabine Decitabine and Cedazuridine

5.1 Myelosuppression

Fatal and serious myelosuppression can occur with INQOVI. 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 progression of underlying MDS.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1% [see Adverse Reactions (6.1)].

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended [see Dosage and Administration (2.3)].

5.2 Embryo-Fetal Toxicity

Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to a pregnant woman. In nonclinical studies with decitabine in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic at doses less than the recommended human dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia

The safety of INQOVI was evaluated in a pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02 [see Clinical Studies (14)].

Patients were randomized to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 in Cycle 1 and decitabine 20 mg/m² intravenously on Days 1 through 5 in Cycle 2, or the reverse sequence, and then INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 of each 28-day cycle in Cycles 3 and beyond. Patients were allowed to have one prior cycle of decitabine or azacitidine and there was no limit for body weight or surface area. Among the patients who received INQOVI, 61% of patients were exposed for 6 months or longer and 24% were exposed to INQOVI for greater than 1 year.

Serious adverse reactions occurred in 68% of patients who received INQOVI. Serious adverse reactions in >5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions occurred in 6% of patients. These included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received INQOVI. The most frequent adverse reactions resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%).

Dose interruptions due to an adverse reaction occurred in 41% of patients who received INQOVI. Adverse reactions requiring dosage interruptions in >5% of patients who received INQOVI included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anemia (5%).

Dose reductions due to an adverse reaction occurred in 19% of patients who received INQOVI. Adverse reactions requiring dosage reductions in > 2% of patients who received INQOVI included neutropenia (12%), anemia (3%), and thrombocytopenia (3%).

The most common adverse reactions (≥20%) were 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.

Table 2 summarizes the adverse reactions in the pooled safety population.

Table 2. Adverse Reactions (≥10%) in Patients Who Received INQOVI in Pooled Safety Population:

^* Includes adverse reactions that occurred during all cycles, including during treatment with 1 cycle of intravenous decitabine.
^† Includes fatigue, asthenia, and lethargy
^‡ Includes contusion, epistaxis, petechiae, hematuria, conjunctival hemorrhage, mouth hemorrhage, purpura, angina bullosa hemorrhagica, gingival bleeding, hematoma, hemoptysis, eye contusion, hemorrhagic diathesis, increased tendency to bruise, vaginal hemorrhage, abdominal wall hematoma, blood blister, bone contusion, catheter site bruise, ecchymosis, genital hemorrhage, intra-abdominal hematoma, oral mucosa hematoma, periorbital hemorrhage, procedural hemorrhage, pulmonary alveolar hemorrhage, retinal hemorrhage, scleral hemorrhage, thrombotic thrombocytopenic purpura, tongue hemorrhage, and vessel puncture site hemorrhage
^§ Includes edema peripheral, peripheral swelling, swelling face, fluid overload, localized edema, face edema, edema, eye swelling, eyelid edema, fluid retention, periorbital swelling, scrotal edema, scrotal swelling, and swelling
^¶ Includes constipation and feces hard
^# Includes oropharyngeal pain, stomatitis, mouth ulceration, proctalgia, oral pain, gingivitis, oral disorder, gingival pain, colitis, glossodynia, mouth swelling, pharyngitis, proctitis, duodenitis, enteritis, gingival discomfort, gingival swelling, lip disorder, lip ulceration, mucosal ulceration, nasal ulcer, noninfective gingivitis, oral mucosal blistering, oral mucosal erythema, pharyngeal erythema, pharyngeal ulceration, tongue ulceration, and vulvitis
^Þ Includes diarrhea and feces soft
^ß Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, liver function test increased, and transaminases increased
^à Includes abdominal pain, abdominal pain upper, abdominal pain lower, epigastric discomfort, and abdominal discomfort
^è Includes myalgia, pain in extremity, muscle spasms, pain, musculoskeletal pain, non-cardiac chest pain, muscular weakness, musculoskeletal chest pain, flank pain, musculoskeletal stiffness, muscle strain, and musculoskeletal discomfort
^ð Includes arthralgia, back pain, neck pain, joint stiffness, pain in jaw, joint swelling, bursitis, joint range of motion decreased, and joint injury
^ø Includes dyspnea, dyspnea exertional, hypoxia, wheezing, chronic obstructive pulmonary disease, and tachypnoea
^ý Includes cough and productive cough
^£ Includes maculo-papular rash, rash, erythema, skin lesion, folliculitis, dermatitis, dermatitis acneiform, eczema, erythema multiforme, rash erythematous, seborrheic keratosis, skin ulcer, dermatitis allergic, dermatitis contact, eczema nummular, genital erythema, rash papular, rash pruritic, rash pustular, seborrheic dermatitis, skin exfoliation, skin irritation, stasis dermatitis, and ulcerative keratitis
^¥ Includes dizziness, vertigo, postural dizziness, and positional vertigo
^ΠIncludes headache, sinus pain, and sinus headache
^œ Includes hypoesthesia, paresthesia, neuropathy peripheral, gait disturbance, peripheral sensory neuropathy, ataxia, balance disorder, brachial plexopathy, carpal tunnel syndrome, and radicular pain
^Ɖ Includes upper respiratory tract infection, nasopharyngitis, sinusitis, and viral upper respiratory tract infection
^A Includes pneumonia, pneumonitis, atypical pneumonia, and lung infection
^B Includes sepsis, bacteremia, septic shock, endocarditis, pseudomonal bacteremia, and staphylococcal bacteremia
^C Includes cellulitis, catheter site cellulitis, and infected bite
^D Includes blood creatinine increased, acute kidney injury, blood urea increased, blood creatine increased, and renal failure
^E Includes hypotension, blood pressure decreased, and cardiogenic shock
^F Includes sinus tachycardia, atrial fibrillation, bradycardia, tachycardia, atrial flutter, sinus bradycardia, and conduction disorder

Clinically relevant adverse reactions in <10% of patients who received INQOVI included:

• Acute febrile neutrophilic dermatosis (Sweet’s syndrome) (1%)
• Tumor lysis syndrome (0.5%)

Table 3. Select Laboratory Abnormalities (>20%) Worsening from Baseline in Patients Who Received INQOVI in Pooled Safety Population:

^* Includes any lab abnormalities that worsened by one or more grades. Grade 3-4 includes any lab abnormalities that worsened to Grade 3 or Grade 4.
^† The denominator used to calculate the rate varied from 103 to 107 for INQOVI Cycle 1, from 102 to 106 for Intravenous Decitabine Cycle and from 203 to 208 for INQOVI All Cycles based on the number of patients with a baseline value and at least one post-treatment value.

The following adverse reactions have been identified during postapproval use of intravenous decitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Differentiation syndrome

Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease

Cardiac Disorders: Cardiomyopathy

7.1 Effects of INQOVI on Other Drugs

Drugs Metabolized by Cytidine Deaminase

Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme. Coadministration of INQOVI with drugs that are metabolized by CDA may result in increased systemic exposure with potential for increased toxicity of these drugs [see Clinical Pharmacology (12.3)]. Avoid coadministration of INQOVI with drugs that are metabolized by CDA.

Risk Summary

Based on findings from human data, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], INQOVI can cause fetal harm when administered to a pregnant woman. A single published case report of intravenous decitabine use throughout the first trimester during pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities). In animal reproduction studies, intravenous administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose on a body surface area (mg/m²) basis caused adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

There are no available data on INQOVI use in pregnant women.

A single published case report of intravenous decitabine pregnancy exposure in a 39-year-old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly, and rocker-bottom feet. The pregnancy was terminated.

Animal Data

No reproductive or developmental toxicity studies have been conducted with INQOVI or cedazuridine.

In utero exposure to decitabine causes temporal-related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, and micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal central nervous system (CNS) and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (Day 10 of gestation) induces bone loss in offspring.

In mice exposed to single intraperitoneal decitabine injections (0, 0.9 and 3.0 mg/m², approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation Days 8, 9, 10 or 11, no maternal toxicity was observed, but reduced fetal survival was observed after treatment at 3 mg/m² and decreased fetal weight was observed at both dose levels. The 3 mg/m² dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects, and digital defects of fore- and hind-limbs.

In rats given a single intraperitoneal injection of 2.4, 3.6 or 6 mg/m² decitabine (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation Days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation Day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m² was seen when decitabine was given on gestation Day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m². Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m². Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6 mg/m².

The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m² intraperitoneal injection (approximately 7% the recommended daily clinical dose) on Day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation Day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

Risk Summary

There are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk or on their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.

INQOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating INQOVI.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings of decitabine and cedazuridine in animals, INQOVI may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.

The safety and effectiveness of INQOVI have not been established in pediatric patients.

Of the 208 patients in clinical studies who received INQOVI, 75% were age 65 years and older, while 36% were age 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 years and older, 75 years and older, and younger patients.

No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min) [see Clinical Pharmacology (12.3)].