Decitabine/Cedazuridine

Inaqovi is a fixed-dose combination of two active substances. Decitabine is a hypomethylating nucleoside analogue. Cedazuridine inhibits cytidine deaminase (CDA), an enzyme present at high levels in the gastrointestinal tract and liver that rapidly breaks down cytidine nucleosides such as decitabine and so limits their oral bioavailability. When cedazuridine is given together with decitabine, a 5-day oral course reaches decitabine exposure equivalent to the intravenous regimen.

Mechanism of Action

• Decitabine: believed to act after phosphorylation and direct incorporation into DNA, where it inhibits DNA methyltransferase. This causes DNA hypomethylation and cellular differentiation and/or apoptosis, and may restore normal function to genes that control differentiation and proliferation in neoplastic cells. In rapidly dividing cells, covalent adducts between the methyltransferase and decitabine incorporated into DNA may add to the cytotoxicity.
• Cedazuridine: inhibits CDA, which blocks the first-pass breakdown of decitabine in the gut and liver and raises its systemic exposure after oral dosing.
• Evidence for oral dosing: a randomised, open-label, two-cycle crossover phase 3 study in 89 adults with de novo or secondary AML who were not candidates for standard induction chemotherapy compared Inaqovi with intravenous decitabine 20 mg/m², each given once daily on days 1 to 5 of a 28-day cycle.

Pharmacokinetics

• Exposure: the recommended dose for 5 consecutive days gives decitabine exposure equivalent to intravenous decitabine 20 mg/m². The ratio of the 5-day total decitabine AUC0–24h between Inaqovi and intravenous decitabine was 99% in patients with MDS or CMML and 100% in patients with AML. Steady state is reached with the second dose, when concentrations are about 1.8 times (decitabine) and 1.1 times (cedazuridine) those of day 1. In patients with MDS, steady-state AUC0–24h and Cmax were about 189 ng·h/mL and 145 ng/mL for decitabine and 3,290 ng·h/mL and 349 ng/mL for cedazuridine. Decitabine exposure with venetoclax was comparable to monotherapy.
• Absorption: at steady state the median time to peak is 1 hour for decitabine and 3 hours for cedazuridine. Cedazuridine bioavailability is about 20.7%. Food does not significantly affect cedazuridine, but a high-calorie, high-fat meal lowers decitabine AUC0–24h by 50% and Cmax by 70%, and a low-calorie, low-fat meal lowers them by 40% and 45%. Inaqovi is therefore taken fasted, with no food for 2 hours before and after the tablet.
• Distribution: decitabine is about 5% bound to plasma proteins, with an apparent volume of distribution at steady state of about 417 L. Cedazuridine is about 35% bound, with a volume of about 296 L.
• Metabolism: decitabine is broken down mainly by deamination through cytidine deaminases and by physicochemical degradation. The main route for cedazuridine is conversion to its epimer, by physicochemical conversion in the gastrointestinal tract before absorption.
• Elimination: after a single oral dose the terminal half-life is about 1.2 hours for decitabine and 6.3 hours for cedazuridine, and apparent oral clearance at steady state is about 197 L/h and 25.6 L/h respectively. Decitabine is eliminated mainly by metabolism and degradation, and the products are excreted mostly by the kidneys. Cedazuridine is cleared by renal elimination of the parent drug and by conversion to its epimer, which is then excreted by the kidneys; after a radiolabelled 100 mg dose, 46% (17.1% unchanged) was recovered in urine and 51% in faeces.
• Linearity: exposure rises in proportion to dose for decitabine (20 to 40 mg with 100 mg cedazuridine) and for cedazuridine (40 to 100 mg).
• Special populations: age, sex, body weight and body surface area have no clinically relevant effect. Pharmacokinetics have not been formally studied in renal or hepatic impairment. Renal impairment increases cedazuridine exposure and potentially decitabine exposure. Large effects of hepatic impairment are not expected, because cedazuridine is not metabolised by the liver and decitabine is broken down by cytidine deaminase present in several tissues.

• Acute myeloid leukaemia, monotherapy: Inaqovi is indicated as monotherapy for adults with newly diagnosed AML who are ineligible for standard induction chemotherapy.
• Acute myeloid leukaemia, with venetoclax: Inaqovi in combination with venetoclax is indicated for adults with newly diagnosed AML who are ineligible for standard induction chemotherapy.

• Hypersensitivity to the active substances or to any of the excipients.
• Breast-feeding.

The safety population was 80 patients with AML given Inaqovi alone (phase 3 study) and 189 patients given Inaqovi with venetoclax (phase 1/2 study); the profile also reflects that of intravenous decitabine. The most common reactions (≥20%), including grade 3 or higher, were thrombocytopenia (monotherapy study) and febrile neutropenia (venetoclax combination study).

Very common (≥1/10): other viral, bacterial and fungal infections, pneumonia, sepsis, urinary tract infection, leukopenia, thrombocytopenia, anaemia, neutropenia, febrile neutropenia, hyperglycaemia, stomatitis, nausea, diarrhoea, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase, increased blood bilirubin, pyrexia.

Common (≥1/100 to <1/10): sinusitis, headache, epistaxis, neutropenic colitis.

Uncommon (≥1/1,000 to <1/100): pancytopenia, cardiomyopathy, acute febrile neutrophilic dermatosis (Sweet’s syndrome).

Not known: differentiation syndrome, interstitial lung disease.

Sinusitis, pancytopenia, cardiomyopathy and Sweet’s syndrome were not seen in the Inaqovi studies but are listed from trials of intravenous decitabine; differentiation syndrome, interstitial lung disease and caecitis (part of neutropenic colitis) come from post-marketing use of intravenous decitabine. Deaths on treatment occurred in 24% of patients; the most frequent fatal reactions were pneumonia (8%), sepsis (3%) and central nervous system haemorrhage with thrombocytopenia (3%). The most common serious reactions (≥20%) were febrile neutropenia, sepsis and pneumonia. Thrombocytopenia can cause bleeding that may be fatal.

• Cytochrome P450: decitabine and cedazuridine are neither substrates nor inhibitors of CYP450 enzymes, so interactions with CYP inhibitors or inducers are not expected.
• Other cytidine deaminase inhibitors: avoid them, because they may raise decitabine exposure.
• Medicines broken down mainly by cytidine deaminase (cytarabine, gemcitabine, azacitidine): cedazuridine may increase their systemic exposure and toxicity. Co-administration should be avoided.
• Venetoclax: Inaqovi must not be taken at the same time as venetoclax; the two are separated by at least 2 hours, because venetoclax is taken with food.
• Food: a meal lowers decitabine exposure (see Pharmacokinetics), so no food is taken for 2 hours before and after each dose.
• Hormonal contraceptives: use together with decitabine and cedazuridine has not been studied.

Treatment must be started and supervised by a physician experienced in the use of anticancer therapies. Inaqovi is taken by mouth: the tablets are swallowed whole with water at about the same time each day. No food is eaten for 2 hours before and 2 hours after the dose. The tablets must not be chewed, crushed or broken, to avoid skin contact with the active substances or their release into the air. Inaqovi is a cytotoxic medicinal product, and handling and disposal follow section 6.6 of the SmPC.

Recommended Dose

• One tablet (decitabine 35 mg and cedazuridine 100 mg) once daily on days 1 to 5 of each 28-day cycle, repeated every 28 days.
• Treatment continues for a minimum of 4 cycles until disease progression or unacceptable toxicity; a complete or partial response may take longer than 4 cycles.
• Intravenous decitabine must not be substituted for Inaqovi within a cycle.
• Standard antiemetic premedication before each dose should be considered.
• With venetoclax: the Inaqovi dose and 28-day cycle are the same, and day 1 of each Inaqovi cycle is matched with the venetoclax schedule. Venetoclax dosing, and its risk of tumour lysis syndrome, are described in the venetoclax SmPC.

Dose Adjustments: Monotherapy

• Blood counts: in the absence of active disease, the next cycle is delayed if the absolute neutrophil count is below 1.0 × 10⁹/L and platelets are below 50 × 10⁹/L, and counts are monitored until the neutrophil count is at least 1.0 × 10⁹/L and platelets at least 50 × 10⁹/L.
• Recovery within 2 weeks of the last cycle: continue at the same dose.
• No recovery within 2 weeks: delay for up to 2 more weeks and restart at a reduced dose on days 1 to 4. If myelosuppression persists, further reductions follow in order: 1 tablet on days 1 to 4, then days 1 to 3, then days 1, 3 and 5. The dose is maintained or increased in later cycles as clinically indicated.
• Non-haematological reactions: later cycles are delayed, and resumed at the same or a reduced dose once resolved, for serum creatinine of 2 mg/dL or more, serum bilirubin of at least 2 times the upper limit of normal, ALT or AST of at least 2 times the upper limit of normal, or an active or uncontrolled infection. Other grade 3 or higher reactions are managed according to institutional guidelines.
• Persistent severe neutropenia and febrile neutropenia are managed with supportive treatment.

Dose Adjustments: With Venetoclax

• Blood counts are monitored frequently until cytopenias resolve. Dose changes and interruptions depend on remission status; in the absence of remission the Inaqovi schedule is not delayed (see the SmPC for the bone marrow blast criterion). In cycle 1, bone marrow assessment can be done as early as day 22.
• If neutrophils and platelets recover (at least 1.0 × 10⁹/L and 50 × 10⁹/L) within 2 weeks of the last cycle, the dose stays the same. If they do not recover within 2 weeks of achieving remission, the cycle is delayed for up to 2 more weeks and fewer Inaqovi days per cycle should be considered: first reduction days 1 to 3, second days 1, 3 and 5, third days 1 and 3.
• From cycle 3 onwards, the same reductions apply to non-haematological reactions. Dose changes for reactions linked to venetoclax follow the venetoclax SmPC.

Special Populations

• Hepatic impairment: not studied, and the need for dose adjustment has not been evaluated. Patients should be monitored carefully if hepatic function worsens.
• Renal impairment: no change to the starting dose in mild or moderate impairment (creatinine clearance of 30 mL/min/1.73 m² or more), but patients with moderate impairment (30 to 59) must be monitored because of possible increased reactions. Inaqovi has not been studied in severe impairment (15 to 29) or end-stage renal disease (below 15).
• Children and adolescents: safety and efficacy below 18 years have not been established, and no data are available.

Missed or Vomited Dose

• Missed by less than 12 hours: take it as soon as possible and resume the normal schedule.
• Missed by 12 hours or more: wait and take the missed dose the next day at the usual time, then extend the dosing period by one day for each missed dose so that 5 daily doses are completed in the cycle.
• If the patient vomits after a dose, no extra dose is taken that day; the next dose is taken at the usual time and the dosing period is not extended.

Myelosuppression and Neutropenia

Fatal and serious myelosuppression can occur. Complete blood counts are taken before treatment starts, before each cycle and as clinically indicated. Growth factors and anti-infective therapy are given for treatment or prophylaxis as appropriate, including prophylactic antibiotics and/or G-CSF for neutropenia according to institutional guidelines. The next cycle is delayed and resumed at the same or a reduced dose as described above. Patients are monitored for signs and symptoms of infection and treated promptly.

Tumour Lysis Syndrome

For patients taking venetoclax, the risk of tumour lysis syndrome is described in sections 4.2, 4.4 and 4.8 of the venetoclax SmPC.

Interstitial Lung Disease

Interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infection has been reported with intravenous decitabine. Patients with an acute onset or unexplained worsening of lung symptoms must be assessed carefully to exclude it, and appropriate treatment started if it is confirmed.

Hepatic and Renal Impairment

Use in hepatic impairment has not been established; caution is needed, and liver function tests are done before treatment, before each cycle and as clinically indicated. Severe renal impairment (creatinine clearance below 30 mL/min) has not been studied; caution is needed, and renal function tests are done before treatment, before each cycle and as clinically indicated.

Cardiac Disease

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from the clinical studies. Cardiomyopathy with cardiac decompensation, in some cases reversible, has been reported after marketing of intravenous decitabine. Patients, especially those with a cardiac history, must be monitored for signs and symptoms of heart failure.

Differentiation Syndrome

Differentiation syndrome (retinoic acid syndrome) has been reported after marketing of intravenous decitabine and may be fatal. At the first signs or symptoms suggestive of it, high-dose intravenous corticosteroids and haemodynamic monitoring must be considered. Treatment must be stopped temporarily until symptoms resolve, and caution is advised if it is resumed.

Nausea and Vomiting

Nausea and vomiting may occur. Standard antiemetic therapy before each dose should be considered.

Pregnancy, Breastfeeding and Fertility

• Contraception: because decitabine is genotoxic, women of childbearing potential must use effective contraception and avoid pregnancy during treatment and for 6 months after the last dose. Men should use effective contraception and not father a child during treatment and for 3 months after. Use together with hormonal contraceptives has not been studied.
• Pregnancy: human data are absent or limited, and animal studies show reproductive toxicity. Inaqovi may harm the foetus and is not recommended during pregnancy or in women of childbearing potential not using effective contraception. A pregnancy test is done in all women of childbearing potential before treatment. A patient treated during pregnancy, or who becomes pregnant, is told of the potential hazard to the foetus.
• Breastfeeding: it is unknown whether decitabine, cedazuridine or their metabolites pass into breast milk, and a risk to the infant cannot be excluded. Inaqovi is contraindicated during breast-feeding.
• Fertility: there are no human data. Ovarian and testicular toxicity, including mutagenicity, was seen in repeat-dose studies in mice.

Lactose and Sodium

Each tablet contains 306 mg lactose (as lactose monohydrate). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Inaqovi. Each tablet contains less than 1 mmol sodium (23 mg), that is, it is essentially ‘sodium-free’.

Effect on Driving

Inaqovi has a moderate influence on the ability to drive and use machines. Patients may experience undesirable effects such as anaemia during treatment, so caution is advised when driving or operating machinery.

Store in the original package to protect from moisture. Inaqovi needs no special temperature storage conditions, and no refrigeration is required. It is supplied as 5 film-coated tablets in PVC/aluminium blisters. As a cytotoxic medicinal product, it is handled and disposed of according to section 6.6 of the SmPC.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Inaqovi is subject to restricted medical prescription, and treatment must be started and supervised by a physician experienced in the use of anticancer therapies. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.