Consumer medicine information

Inqovi 35/100

Decitabine; Cedazuridine

BRAND INFORMATION

Brand name

Inqovi 35/100

Active ingredient

Decitabine; Cedazuridine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Inqovi 35/100.

SUMMARY CMI

INQOVI® 35/100

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using INQOVI 35/100?

INQOVI 35/100 contains the active ingredients decitabine and cedazuridine. INQOVI 35/100 is used to treat myelodysplastic syndrome (MDS) or chronic myelomonocytic leukaemia (CMML). For more information, see Section 1. Why am I using INQOVI 35/100? in the full CMI.

2. What should I know before I use INQOVI 35/100?

Do not use if you have ever had an allergic reaction to INQOVI 35/100 or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use INQOVI 35/100? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with INQOVI 35/100 and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use INQOVI 35/100?

  • Always take this medicine exactly as your doctor or pharmacist has told you
  • Take one tablet daily on the first five days of each 28 day treatment cycle or as directed by your doctor.
  • Swallow the tablets whole on an empty stomach with a full glass of water, and avoid eating at least 2 hours before and 2 hours afterwards. Do not chew or break the tablets.

More instructions can be found in Section 4. How do I use INQOVI 35/100? in the full CMI.

5. What should I know while using INQOVI 35/100?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using INQOVI 35/100.
  • Call your doctor straight away if you feel very unwell, have a fever and chills, bleed or bruise easily
  • Keep all your doctor's appointments so that your progress can be checked
  • Use contraception while undergoing treatment.
Things you should not do
  • Do not stop using this medicine without talking to your doctor
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how INQOVI 35/100 affects you.
Looking after your medicine
  • Store below 25°C.

For more information, see Section 5. What should I know while using INQOVI 35/100? in the full CMI.

6. Are there any side effects?

The most common side effects are tiredness, nausea, diarrhoea, constipation, or sudden shortness of breath. Serious side-effects include fever, chills, sudden shortness of breath, dry cough and tiredness which may be signs of infection; bleeding, or bruising more than normal.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

INQOVI® 35/100

Active ingredient(s): decitabine and cedazuridine

Consumer Medicine Information (CMI)

This leaflet provides important information about using INQOVI 35/100. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using INQOVI 35/100.

Where to find information in this leaflet:

1. Why am I using INQOVI 35/100?
2. What should I know before I use INQOVI 35/100?
3. What if I am taking other medicines?
4. How do I use INQOVI 35/100?
5. What should I know while using INQOVI 35/100?
6. Are there any side effects?
7. Product details

1. Why am I using INQOVI 35/100?

INQOVI 35/100 contains the active ingredients decitabine and cedazuridine. INQOVI 35/100 is an anti-cancer medicine and it works by preventing the growth of cancer cells.

INQOVI 35/100 is used to treat myelodysplastic syndrome (MDS) or chronic myelomonocytic leukaemia (CMML). These are types of blood cancers in which the bone marrow does not work properly to produce mature blood cells. This causes a lack of healthy blood cells in the body.

2. What should I know before I use INQOVI 35/100?

Warnings

Do not use INQOVI 35/100 if:

  • you are allergic to decitabine or cedazuridine, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you are pregnant

Check with your doctor if you:

  • have any other medical conditions such as severe heart, lung, liver or kidney problems
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Women and men of childbearing potential

Women must avoid becoming pregnant while taking INQOVI 35/100 but if you do become pregnant, tell your doctor immediately. Use an effective method of contraception during treatment with this medicine and for up to 6 months after taking your last dose.

Men must avoid fathering a child while taking INQOVI 35/100. Use barrier methods of contraception (e.g. condoms) during treatment with this medicine and for up to 3 months after taking your last dose if your partner is of childbearing potential. Talk to your doctor if you wish to conserve your sperm before having this treatment.

Children

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children has not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect INQOVI 35/100

4. How do I use INQOVI 35/100?

How much to take

  • The usual dose for this medicine is 1 tablet daily at the same time each day on the first 5 days of each 28 day treatment cycle.
  • Your doctor may prescribe a different course or length of treatment depending on your blood counts.
  • Follow the instructions provided and use INQOVI 35/100 until your doctor tells you to stop. The medicine is usually taken for at least 4 cycles or longer depending on your response.

When to take INQOVI 35/100

  • INQOVI 35/100 should be taken on an empty stomach, for example in the morning before eating. Do not consume food for at least 2 hours before and 2 hours after taking INQOVI 35/100.
  • Food can interfere with the absorption of this medicine.
  • If you miss a dose of INQOVI, take your dose as soon as possible if it is within 12 hours of your usual time. Then, continue taking INQOVI at your scheduled time. If you missed a dose by more than 12 hours, do not take additional doses to make up for the missed dose. Take your next scheduled dose on the following day at your usual time.

If you vomit after taking INQOVI 35/100

If you vomit after taking the dose, do not take an additional dose. Take the next dose the next day as scheduled.

Talk to your doctor as he or she may give you a medicine to stop you from feeling sick.

If you forget to take INQOVI 35/100

INQOVI 35/100 should be used regularly at the same time each day.

If you miss your dose and it is within 8 hours of your usual time, take your dose as soon as you remember, and continue to take it as you would normally.

If it is over 8 hours of your usual time or almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much INQOVI 35/100

If you think that you have used too much INQOVI 35/100, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using INQOVI 35/100?

Things you should do

Call your doctor straight away if you:

  • feel very unwell and have fever, severe chills, sore throat or mouth ulcers
  • have signs of bleeding (e.g. nose bleeds) or bruising more easily than normal or if you are feeling more tired than usual
  • if you become pregnant while taking this medicine.

Keep all your doctor's appointments so that your progress can be checked. Your doctor will do some tests e.g. blood tests, at regular intervals to make sure the medicine is working and to prevent any unwanted side effects.

Remind any doctor, dentist or pharmacist you visit that you are using INQOVI 35/100.

Things you should not do

  • Do not stop using this medicine without talking to your doctor
  • Do not give your medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how INQOVI 35/100 affects you.

INQOVI 35/100 may cause fatigue and dizziness in some people.

Looking after your medicine

Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal related:
  • constipation or diarrhoea
  • nausea and vomiting
Pain related:
  • muscle aches
  • headaches
  • back pain
  • painful, swollen joints
  • swelling of the ankles, feet or legs
General well-being related:
  • tiredness or weakness
  • being short of breath when exercising, dizziness and looking pale
  • trouble sleeping
  • weight loss or decreased appetite
  • feeling unsteady on feet or falling over.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy related:
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
Infection related:
  • fever and severe chills
  • sore throat or mouth ulcers
  • sudden shortness of breath, dry cough, phlegm and occasionally blood
  • tiredness
  • swelling of the arms, legs, and neck
  • hot, tender and red skin
Bleeding related:
  • bleeding or bruising more easily than normal
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Some of side effects such as changes in liver enzymes, blood levels of electrolytes and creatinine can only be found when your doctor does tests to check your progress.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What INQOVI 35/100 contains

Active ingredient
(main ingredient)		Each tablet contains 35 mg of decitabine and 100 mg of cedazuridine.
Other ingredients
(inactive ingredients)
  • Lactose monohydrate
  • Hypromellose
  • Croscarmellose sodium
  • Colloidal anhydrous silica
  • Magnesium stearate.
  • The tablet film-coating contains OPADRY II complete film coating system 85F15458 RED (PI 110931)

Do not take this medicine if you are allergic to any of these ingredients.

What INQOVI 35/100 looks like

INQOVI 35/100 are biconvex, oval shaped, red film-coated tablets which are plain on one side and are marked with “H35” on the other side.

(AUST R 328904, 375556)

Who distributes INQOVI 35/100

Otsuka Australia Pharmaceutical Pty Ltd
Suite 2.03, Level 2
9 Help Street
Chatswood NSW 2067

This leaflet was prepared in December 2021.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Inqovi 35/100

Active ingredient

Decitabine; Cedazuridine

Schedule

S4

 

1 Name of Medicine

Decitabine and cedazuridine.

2 Qualitative and Quantitative Composition

Each Inqovi 35/100 tablet contains 35 mg of decitabine and 100 mg of cedazuridine.

Excipients with known effect.

Contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Inqovi 35/100 is a biconvex, oval shaped, red film-coated tablet, plain-faced on one side and debossed with "H35" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Inqovi 35/100 is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups, and patients with chronic myelomonocytic leukaemia (CMML).

4.2 Dose and Method of Administration

Dosage.

The recommended dose of Inqovi 35/100 is 1 tablet containing 35 mg of decitabine and 100 mg of cedazuridine taken orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles. Best response may take longer than 4 cycles. Continue treatment as long as the patient continues to benefit. Repeat cycles every 28 days in the absence of haematologic toxicities not attributed to active disease and blood counts show absolute neutrophil count at least 1,000/microL and platelets at least 50,000/microL, or at least return to pretreatment levels. Delay or reduce the dose per cycle for haematologic toxicity (see Dosage adjustment, Haematologic toxicity).
Prior to initiation of Inqovi 35/100, conduct baseline laboratory testing including complete blood cell counts with platelets, serum hepatic panel, and serum creatinine. Obtain complete blood cell counts prior to initiation of Inqovi 35/100 and prior to each cycle (see Dosage adjustment, Haematologic toxicity).

Method of administration.

Inqovi 35/100 tablets should be taken with water on an empty stomach, at approximately the same time each day. Do not consume food two hours before and two hours after taking Inqovi 35/100.
Agents that increase gastric pH should not be taken within 4 hours of Inqovi 35/100 administration (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Inqovi 35/100 is a cytotoxic drug. Inqovi 35/100 tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.

Missed or vomited dose.

If the patient misses a dose of Inqovi 35/100 within 12 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose by more than 12 hours, the patient should not take the missed dose and should resume the usual dosing schedule the next day to complete 5 days of treatment per cycle.
If the patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Consider pre-medicating with antiemetics for next dose.

Dosage adjustment.

Monitor blood counts frequently through resolution of cytopenias. Management of some adverse reactions may require dose delay or dose reduction of Inqovi 35/100 (also see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Haematologic toxicity.

Obtain complete blood cell counts prior to initiating Inqovi 35/100 and before each cycle. Dose reduction is not recommended for the first 2 cycles. In case of persistent cytopenias at 4 weeks after start of treatment cycle, delay the next cycle if absolute neutrophil count (ANC) is less than 1,000/microL and platelets are less than 50,000/microL in the absence of active disease. Monitor complete blood cell counts until ANC is 1,000/microL or greater and platelets are 50,000/microL or greater.
If haematologic recovery occurs (ANC at least 1,000/microL and platelets at least 50,000/microL) within 2 weeks from the delayed cycle, continue Inqovi 35/100 at the same dose.
If haematologic recovery does not occur (ANC at least 1,000/microL and platelets at least 50,000/microL) within 2 weeks from the delayed cycle,
Delay Inqovi 35/100 for up to 2 additional weeks; and
Resume at a reduced dose by administering Inqovi 35/100 on Days 1 through 4. Consider further dose reductions in the order listed in Table 1 if myelosuppression persists after a dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated.
Manage persistent severe neutropenia and febrile neutropenia with supportive treatment such as growth factors and anti-infective therapy, including anti-fungals (see Section 4.4 Special Warnings and Precautions for Use).

Non-haematologic toxicity.

Delay subsequent Inqovi 35/100 cycles for any of the following non-haematologic toxicities, if not present prior to treatment, until toxicities resolve or an alternative cause for the toxicity is clearly established:
Serum creatinine equal to or greater than 176.80 micromol/L;
Serum bilirubin equal to or greater than 2 times upper limit of normal (ULN);
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) equal to or greater than 2 times ULN;
Active or uncontrolled infection.

4.3 Contraindications

Pregnancy.
Hypersensitivity to the active substances, decitabine or cedazuridine, or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Myelosuppression.

Fatal and serious myelosuppression may occur with Inqovi 35/100. 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%. Anaemia 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, anaemia, and febrile neutropenia) is the most frequent cause of Inqovi 35/100 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 may occur with Inqovi 35/100. 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 Section 4.8 Adverse Effects (Undesirable Effects)).
Obtain complete blood cell counts prior to initiation of Inqovi 35/100, and 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 Section 4.2 Dose and Method of Administration, Haematologic toxicity).

Haemorrhage.

Serious bleeding-related treatment-emergent adverse events (TEAEs) have been reported with Inqovi 35/100 due to severe thrombocytopenia. Gastrointestinal haemorrhage was reported in 6.7% including Grade ≥ 3 in 2.4%. Intracranial haemorrhage was reported in 1.9% including Grade ≥ 3 in 1.4%. Monitor patients receiving Inqovi 35/100 closely for signs and symptoms of serious bleeding-related adverse reactions.

Embryofetal toxicity.

Based on its mechanism of action and findings in animals, Inqovi 35/100 can cause fetal harm when administered to a pregnant woman. Decitabine alters DNA synthesis and is expected to result in adverse reproductive effects (see Section 4.6 Fertility, Pregnancy and Lactation). In studies with decitabine in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic at doses less than the recommended human dose.
If Inqovi 35/100 is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Advise women of childbearing potential to avoid becoming pregnant while taking Inqovi 35/100 and for 6 months following the last dose. Advise men with female partners of childbearing potential to avoid fathering a child while receiving treatment with Inqovi 35/100, and for 3 months following the last dose. Counsel patients of childbearing potential to use effective contraception during this time (see Section 4.6 Fertility, Pregnancy and Lactation).

Cardiovascular.

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore the safety and efficacy of Inqovi 35/100 in these patients has not been established. Patients with history of severe congestive heart failure or clinically unstable cardiac disease should be closely monitored.

Interstitial lung disease.

Interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology were reported in patients receiving intravenous decitabine. Assess patients with acute onset or unexplained worsening of pulmonary symptoms to exclude ILD. If ILD is confirmed, initiate appropriate treatment.

Use in hepatic impairment.

A population PK analysis indicated that mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 x ULN) does not have a clinically meaningful effect on the pharmacokinetics of decitabine or cedazuridine after dosing with Inqovi 35/100. The effects of moderate and severe hepatic impairment (1.5 x ULN) on the pharmacokinetics of decitabine and cedazuridine are unknown. (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No modification to the starting dose is recommended in patients with mild or moderate renal impairment (creatinine clearance [CrCL] of 20 to 59 mL/min/1.73 m2). Inqovi 35/100 has not been studied in patients with severe renal impairment (CrCL < 20 mL/min/1.73 m2) or end stage renal disease (see Section 5.2 Pharmacokinetic Properties).
Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CrCL 20 to 39 mL/min/1.73 m2).

Use in the elderly.

Of the 208 patients treated with Inqovi 35/100, 75% were age 65 years and over, while 36% were age 75 years and over. No overall difference in safety was noted between patients age 65 years or older and younger patients.

Paediatric use.

The safety and effectiveness of Inqovi 35/100 in paediatric patients have not been established.

Effects on laboratory tests.

There was no clinically notable central tendency shifts in liver or renal laboratory values over multiple treatment cycles. In haematology, neutrophils decreased in the first 2 cycles then stabilised or increased, while haemoglobin and platelets tended to increase over multiple cycles as patients responded to treatment.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme. Same day concomitant administration of Inqovi 35/100 with drugs metabolised by CDA may result in their increased systemic exposure with potential for increased toxicity of these drugs. Avoid coadministration of Inqovi 35/100 on the same day as other drugs known to be metabolised by CDA.
Drug interaction studies have not been conducted with Inqovi 35/100 in vivo. In vitro studies show that cedazuridine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4/5 at clinically relevant concentrations and does not induce CYP1A, 2B6, 2C9 or 3A4. Cedazuridine is not a substrate of P-glycoprotein, MATE1, MATE2-k, OAT1, OAT3, OATP1B1, OAPT1B3, OATP2B1, OCT1 or OCT2 and does not inhibit P-glycoprotein, BCRP, BSEP, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OAPT1B3 or OCT2.
In vitro data show that decitabine is not a substrate or inhibitor of P-glycoprotein, does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6 or 3A4/5 at clinically relevant concentrations, and is not an inducer of CYP1A2, 2B6, 2C9 or 3A4/5.
Cedazuridine is converted to its epimer prior absorption and its bioavailability may be affected by gastric pH. However, no effect on cedazuridine or decitabine PK was shown when co-administered with gastric pH modifying drugs as long as they are not administered within 4 hours of Inqovi 35/100 administration.

Food.

Inqovi 35/100 tablets should be taken with water on an empty stomach. The oral bioavailability of decitabine is decreased in the presence of food (see Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on findings with decitabine in animals, male fertility may be compromised by treatment with Inqovi 35/100.
Decitabine impaired fertility in male mice given IP doses ≥ 0.3 mg/m2 (well below the clinical dose). This was accompanied by reduced testes weights, abnormal histology and marked decreases in sperm count. Pre-implantation loss was significantly increased in females mated with treated males.
No fertility studies have been conducted with cedazuridine.

Females and males of reproductive potential.

Conduct pregnancy testing of females of reproductive potential prior to initiating Inqovi 35/100 (see Use in pregnancy).
Inqovi 35/100 may cause severe fetal harm when administered to a pregnant woman (see Use in pregnancy; see Section 4.4 Special Warnings and Precautions for Use, Embryofetal toxicity).
Advise females of reproductive potential to avoid pregnancy and use effective contraception while receiving Inqovi 35/100 and for 6 months following the last dose.
Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Inqovi 35/100 and for 3 months following the last dose.
(Category X)
Inqovi 35/100 is contraindicated in pregnancy. Based on findings from human data, animal studies, and the mechanism of action for decitabine, Inqovi 35/100 may cause severe fetal harm when administered to a pregnant woman (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).
There are no available data on Inqovi 35/100 use in pregnant women. No reproductive or developmental toxicity studies have been conducted with Inqovi 35/100 or cedazuridine.
When administered intravenously decitabine is known to be teratogenic, fetotoxic, and embryotoxic.
Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal central nervous system (CNS) in the developing murine fetus.
Decitabine was shown to cause malformations and embryofetal lethality in pregnant mice and rats following single IP administration at dose levels well below the clinical dose. Fetal abnormalities observed in animals included fused vertebrae and ribs, cleft palate, exophthalmia, exencephaly, and limb and digital defects.
Animal embryofetal development studies have not been performed with cedazuridine.
In rats given a single IP 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.
A single published case report of intravenous (IV) decitabine pregnancy exposure in a 39 year old woman with a haematological 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.
 There are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk, the effects on the breastfed child, or on milk production. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from Inqovi 35/100 in a nursing child, advise lactating women to avoid breastfeeding during treatment with Inqovi 35/100 and for at least 2 weeks after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects on the ability to drive or use machines have been performed. Patients should be advised that they may experience undesirable effects, such as fatigue and dizziness due to anaemia, during treatment. Therefore, caution should be recommended when driving a car or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The safety of Inqovi 35/100 was evaluated in a pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients were randomized to receive Inqovi 35/100 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 35/100 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 35/100, 61% of patients were exposed for 6 months or longer and 24% were exposed to Inqovi 35/100 for greater than 1 year.
Serious adverse reactions occurred in 68% of patients who received Inqovi 35/100. 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 haemorrhage and sudden death.
Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received Inqovi 35/100. 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 35/100. Adverse reactions requiring dosage interruptions in > 5% of patients who received Inqovi 35/100 included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anaemia (5%).
Dose reductions due to an adverse reaction occurred in 19% of patients who received Inqovi 35/100. Adverse reactions requiring dosage reductions in > 2% of patients who received Inqovi 35/100 included neutropenia (12%), anaemia (3%), and thrombocytopenia (3%).
The most common adverse reactions (≥ 20%) were fatigue, constipation, haemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnoea, diarrhoea, rash, dizziness, febrile neutropenia, oedema, 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 haemoglobin decreased. (See Table 3).
Table 2 summarizes the adverse reactions in the pooled safety population.
Clinically relevant adverse reactions in < 10% of patients who received Inqovi 35/100 included:
Acute febrile neutrophilic dermatosis (Sweet's syndrome) (1%).
Tumour lysis syndrome (0.5%).

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of decitabine administered intravenously. 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 disorders.

Interstitial lung disease.

Cardiac disorders.

Cardiomyopathy.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no known antidote for overdosage with Inqovi 35/100. Overdosage could cause increased myelosuppression, and neutropenia-related infections such as pneumonia and sepsis. For patients who experience overdose, closely monitor, and provide appropriate supportive treatment.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Decitabine.

Decitabine is a nucleoside metabolic inhibitor that is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation, proliferation, and the immune system. 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. Non-proliferating cells are relatively insensitive to decitabine.
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. At the recommended Inqovi 35/100 dose, maximal or near maximal pharmacodynamic effect of long interspersed nucleotide elements-1 (LINE-1) demethylation was observed over the range of decitabine systemic exposures based on modelling.

Cedazuridine.

Cedazuridine inhibits cytidine deaminase (CDA). CDA is an enzyme that is responsible for the degradation of nucleosides, including decitabine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability.
Oral administration of cedazuridine with decitabine enhances the oral bioavailability of decitabine via inhibition of first pass metabolism of decitabine in the gut and liver by CDA.

Clinical trials.

Study ASTX727-01-B (phase 2).

The efficacy of Inqovi 35/100 was evaluated in an open-label, randomised, 2-cycle, 2-sequence crossover study with IV decitabine followed by a single-arm Inqovi 35/100 treatment study. The study was conducted in 80 patients with MDS (International Prognostic Scoring System intermediate [IPSS] intermediate-1, intermediate-2, or high-risk) and CMML, who were candidates for treatment with a hypomethylating (HMA) agent. Patients were randomised to receive Inqovi 35/100 in Cycle 1 and IV decitabine (20 mg/m2) in Cycle 2 or the reverse sequence. Both Inqovi 35/100 and IV decitabine were dosed once daily for 5 days in 28 day cycles. All patients received Inqovi 35/100 after Cycle 2 and treatment continued until disease progression, death, or unacceptable toxicity.
The major efficacy outcome measure was response rate. Additional efficacy outcome measures included duration of response, rate of transfusion independence (no transfusions for at least 56-day consecutive period), time to acute myeloid leukaemia (AML), and overall survival (OS).
The efficacy results are shown in Table 4. The median duration of treatment was 7 cycles (range: 1 to 29) and the median follow-up time was 24 months (range: 12 to 29 months).

Study ASTX727-02 (phase 3).

Inqovi 35/100 was evaluated in an open-label, randomised, 2-cycle, 2-sequence crossover with IV decitabine study followed by a single-arm Inqovi 35/100 treatment study. The study was conducted in 133 patients with MDS (IPSS intermediate-1, intermediate-2, or high-risk), and CMML. Patients were randomised 1:1 to receive Inqovi 35/100 in Cycle 1 and IV decitabine (20 mg/m2) in Cycle 2 or the reverse sequence. Both Inqovi 35/100 and IV decitabine were dosed once daily for 5 days in each 28-day cycle. All patients received Inqovi 35/100 after Cycle 2 and treatment continued until disease progression, death, or unacceptable toxicity.
The primary outcome measure of this study was decitabine 5-day AUC between Inqovi 35/100 and IV decitabine. Inqovi 35/100 achieved decitabine AUC exposures equivalent to IV infusion of decitabine at 20 mg/m2 (Table 5).
The median duration of treatment for all treated subjects was 8.2 months (range 0.2 to 19.7) with a median follow-up time of 12.6 months (range: 9.3 to 20.5). Twenty-seven (20%) of the 133 treated patients went on to transplant. Clinical response data from all 133 treated patients are presented in Table 6.
Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 76 patients who were independent of both of both RBC and platelet transfusions at baseline, 48 (63%) remained transfusion-independent during any 56-day post-baseline period.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of Inqovi 35/100, the median Tmax was 3 hours (range: 0.52 to 7.9) for cedazuridine and 1 hour (range: 0.3 to 3) for decitabine. When co-administered with cedazuridine, decitabine oral relative bioavailability is enhanced to achieve systemic AUC exposures seen with IV decitabine. In a 14C ADME study, approximately 47.5% of oral cedazuridine dose was absorbed and bioavailability was 20.7%.
Administration of Inqovi 35/100 with a high-fat, high-calorie meal (comprised of approximately 800-1000 kilocalories (kcal), including approximately 500-600 kcal from fat) decreased the mean maximum decitabine concentration (Cmax) by 54% and AUC by approximately 40%. Administration with food delayed cedazuridine time to maximum concentration (Tmax) slightly but had little effect on systemic exposures.

Distribution.

Cedazuridine is approximately 35% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution for cedazuridine is 296 L (51%).
Decitabine is approximately 5% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution at steady state is 417 L (54%).

Metabolism.

The primary metabolic pathway for cedazuridine is conversion to its epimer. This occurs non-enzymatically. The epimer of cedazuridine is a major circulating metabolite but possesses much weaker pharmacological activity than its parent.
Decitabine is mainly metabolised via deamination by cytidine deaminase (CDA). Decitabine is also subject to chemical degradation, involving oxidation, ring opening and deformylation.

Excretion.

Following a single oral dose of Inqovi 35/100, the mean (CV%) terminal elimination half-life (T1/2) of cedazuridine was 6.3 (18%) hours. The apparent clearance was 30.6 L/hr at Day 1 and 30.3 L/hr at steady state. Following a single oral dose of 100 mg radiolabeled cedazuridine, 46% (17.1% unchanged) of the administered dose was recovered in urine and 51% (mostly unabsorbed drug) was recovered in the faeces. Predominant elimination pathway of cedazuridine is renal, as parent and epimer.
Following a single oral dose of Inqovi 35/100, the mean (CV%) terminal elimination half-life (T1/2) of decitabine was 1.2 (23%) hours. The apparent clearance was 342 L/hr at Day 1 and 197 L/hr at steady state. The primary elimination pathway for decitabine is metabolic, by cytidine deaminase and also physicochemical degradation at physiological conditions.

Special populations.

Age (32-90 years), sex, body weight (41-158 kg), or mild to moderate hepatic impairment (total bilirubin > ULN to ≤ 1.5 x ULN or > 1.5 to ≤ 3 x ULN) do not have a clinically meaningful effect on the pharmacokinetics of decitabine or cedazuridine after dosing with Inqovi 35/100.
Mild or moderate renal impairment (CrCL ≥ 20 up to 59 mL/min/1.73 m2) had an effect on cedazuridine exposures, but not considered to be clinically meaningful. The effects of severe hepatic impairment (total bilirubin > 3 x ULN) or severe renal impairment (CrCL < 20 mL/min/1.73 m2) on the pharmacokinetics of decitabine and cedazuridine is unknown.

5.3 Preclinical Safety Data

Genotoxicity.

Cedazuridine and decitabine are genotoxic.
Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine also caused chromosomal rearrangements in larvae of fruit flies.
Cedazuridine was genotoxic in a reverse bacterial mutation assay (Ames test) and in an in vitro chromosomal aberration assay in human lymphocytes. Negative results were obtained for cedazuridine in an in vivo mouse bone marrow micronucleus test.

Carcinogenicity.

Carcinogenicity studies with decitabine, cedazuridine or the two medicines in combination have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of Inqovi 35/100 contains the following inactive ingredients: lactose monohydrate, hypromellose, croscarmellose sodium, colloidal anhydrous silica, and magnesium stearate. The film coating material contains Opadry II complete film coating system 85F15458 Red (PI 110931).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Inqovi 35/100 is available in blisters and bottles.

Blisters.

PVC/aluminium foil blisters. Pack size: 5 film-coated tablets.

Bottles.

High-density polyethylene (HDPE) bottles with child resistant closure containing a silica gel desiccant. Pack size: 5 film-coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Decitabine.

Decitabine is a nucleoside metabolic inhibitor. Decitabine is white to off-white solid with the molecular formula of C8H12N4O4 and a molecular weight of 228.21 daltons. Its IUPAC chemical name is 4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2(1H)-one and it has the following structural formula:

Cedazuridine.

Cedazuridine is a cytidine deaminase inhibitor. Cedazuridine is white to off-white solid with molecular formula of C9H14F2N2O5 and a molecular weight of 268.21 daltons. Its international union of pure and applied chemistry (IUPAC) chemical name is (4R)-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one and has the following structural formula:

CAS number.

Decitabine.

2353-33-5.

Cedazuridine.

1141397-80-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes