4.1. Therapeutic indications

Inaqovi is indicated as monotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for standard induction chemotherapy.

4.2. Posology and method of administration

Treatment must be initiated and supervised by a physician experienced in the use of anticancer therapies.

Posology

The recommended dose of Inaqovi is 1 tablet once daily on Days 1 through 5 of each 28-day cycle.

Cycles are to be repeated every 28 days. Treatment is to be continued for a minimum of 4 cycles until disease progression or unacceptable toxicity. A complete or partial response may take longer than 4 cycles.

• Substitution with an intravenous decitabine product within a cycle is not recommended.

• Premedication with standard antiemetic therapy prior to each dose to minimise nausea and vomiting is to be considered (see section 4.4).

• A delay or reduction in the dose per cycle is to be considered for patients who experience haematologic and non-haematologic toxicities (see “Dose adjustments”).

Missed or vomited dose

• If the patient misses a dose within 12 hours of the time it is usually taken, the patient must take the missed dose as soon as possible and resume the normal daily dosing schedule.

• If the patient misses a dose by 12 or more hours, the patient must wait and take the missed dose the following day at the usual time and then extend the dosing period by one day for every missed dose to complete 5 daily doses for each cycle.

• If the patient vomits following dosing, no additional dose is to be taken that day. The next dose must be taken at the usual time and resume the normal daily dosing, with no extension of the dosing period.

Dose adjustments

Haematologic adverse reactions

The next cycle must be delayed if absolute neutrophil count (ANC) is less than 1.0 × 109/L and platelets are less than 50 × 109/L in the absence of active disease. Complete blood cell (CBC) counts must be monitored until ANC is 1.0 × 109/L or greater and platelets are 50 × 109/L or greater.

In the absence of active disease:

• If haematological recovery occurs (ANC at least 1.0 × 109/L and platelets at least 50 × 109/L) within 2 weeks of the last treatment cycle, treatment is to be continued at the same dose.

• If haematological recovery does not occur (ANC at least 1.0 × 109/L and platelets at least 50 × 109/L) within 2 weeks of the last treatment cycle:

o

Treatment must be delayed for up to 2 additional weeks AND

o

The patient must resume treatment at a reduced dose on Days 1 through 4. Further dose reductions have to be considered in the order listed in Table 1 if myelosuppression persists after a dose reduction.

o

Dose has to be maintained or increased in subsequent cycles as clinically indicated.

Patients are to be treated with a minimum of 4 cycles of treatments with active disease.

Table 1: Recommended dose reductions for myelosuppression

Dose reduction

Dose

First

1 tablet once daily on Days 1 through 4

Second

1 tablet once daily on Days 1 through 3

Third

1 tablet once daily on Days 1, 3 and 5

Persistent severe neutropaenia and febrile neutropaenia have to be managed with supportive treatment (see section 4.4).

Non-haematologic adverse reactions

Subsequent treatment cycles must be delayed for the following non-haematologic adverse reactions and resumed at the same or reduced dose upon resolution:

• Serum creatinine 2 mg/dL or greater

• Serum bilirubin 2 times the upper limit of normal (ULN) or greater

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 2 times the ULN or greater

• Active or uncontrolled infection

Dose adjustments for all other Grade 3 or higher adverse reactions should follow institutional guidelines.

Special populations

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. The need for dose adjustment in patients with hepatic impairment has not been evaluated. If worsening hepatic function occurs, patients should be carefully monitored (see sections 4.4 and 5.2).

Renal impairment

No adjustment of starting dose is recommended for patients with mild or moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min/1.73 m2). Due to the potential for increased adverse reactions, patients with moderate renal impairment (CrCl 30 to 59 mL/min/1.73 m2) must be monitored. Inaqovi has not been studied in patients with severe renal impairment (CrCl 15 to 29 mL/min/1.73 m2) or end stage renal disease (CrCl <15 mL/min/1.73 m2) (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Inaqovi in the paediatric population (aged less than 18 years) have not been established. No data are available.

Method of administration

Inaqovi is for oral use. The tablets must be swallowed whole with water at approximately the same time each day. Food is not to be consumed 2 hours before and 2 hours after taking treatment in order to avoid a risk for lack of efficacy (see section 4.5).

The tablets must not be chewed, crushed, or broken in order to avoid skin contact or release of active substance into the air.

Inaqovi is a cytotoxicmedicinal product. For proper handling and disposal procedures see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

Myelosuppression

Fatal and serious myelosuppression can occur with treatment (see section 4.8).

Complete blood cell counts must be obtained prior to the initiation of treatment, prior to each cycle, and as clinically indicated to monitor response and toxicity. Growth factors and anti-infective therapies must be administered for treatment or prophylaxis as appropriate. The next cycle must be delayed and resumed at the same or reduced dose as recommended (see sections 4.2 and 4.8). Patients must be monitored for signs and symptoms of infection and treated promptly.

Neutropaenia

Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia according to institutional guidelines. For situations where administration must be delayed, see section 4.2.

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving intravenous decitabine. Patients with an acute onset or unexplained worsening of pulmonary symptoms must be carefully assessed to exclude ILD. If ILD is confirmed, appropriate treatment must be initiated (see section 4.8).

Hepatic impairment

Use in patients with hepatic impairment has not been established. Caution must be exercised in the administration of medicinal product to patients with hepatic impairment and in patients who develop signs or symptoms of hepatic impairment. Liver function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).

Renal impairment

Use in patients with severe renal impairment has not been studied. Caution must be exercised in the administration of the medicinal product to patients with severe renal impairment (CrCl < 30 mL/min). Renal function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).

Cardiac disease

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 the medicinal product in these patients has not been established. Cases of cardiomyopathy with cardiac decompensation, in some cases reversible after treatment discontinuation, dose reduction or corrective treatment, have been reported in the postmarketing setting with intravenous decitabine (see section 4.8). Patients, especially those with a history of cardiac disease, must be monitored for signs and symptoms of heart failure.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported during the post-marketing period with intravenous decitabine (see section 4.8). Differentiation syndrome may be fatal (see section 4.8). Treatment with high-dose intravenous corticosteroids and haemodynamic monitoring must be considered at first onset of symptoms or signs suggestive of differentiation syndrome. Treatment must be temporarily discontinued until symptoms resolve, and if resumed, caution is advised.

Administration of antiemetics

Nausea and vomiting may occur during treatment. Administration of standard antiemetic therapy prior to each dose should be considered to minimise nausea and vomiting.

Excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on Inaqovi

Decitabine and cedazuridine are not substrates or inhibitors for cytochrome P450 (CYP450); thus interactions with CYP inhibitors or inducers are not expected.

Cytidine deaminase inhibitors

Because decitabine is a substrate for the cytidine deaminase (CDA) enzyme, which metabolises decitabine resulting in an inactive deaminated form, other medicinal products inhibiting CDA should be avoided, as co-administration may result in increased decitabine exposure.

Effect of Inaqovi on other medicinal products

Medicinal products metabolised by cytidine deaminase

Cedazuridine is an inhibitor of CDA and thereby increases the exposure of decitabine following oral administration. Concomitant administration of Inaqovi with medicinal products metabolised by CDA (i.e., cytarabine, gemcitabine, azacitidine) may result in increased systemic exposure with a potential for increased toxicity of these medicinal products. Co-administration of Inaqovi with medicinal products metabolised primarily by CDA should be avoided.

Food

Overall decitabine exposure has been shown to be reduced when decitabine is administered with a high-fat, high-calorie meal (see section 4.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in men and women

Due to the genotoxic potential of decitabine (see section 5.3), women of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with Inaqovi and for 6 months following completion of treatment. Men should use effective contraceptive measures and be advised to not father a child while receiving Inaqovi, and for 3 months following completion of treatment (see section 5.3).

The use of decitabine and cedazuridine with hormonal contraceptives has not been studied.

Pregnancy

There are no or a limited amount of human data from the use of decitabine and cedazuridine in pregnant women.

Based on the results of embryo-foetal toxicity studies conducted in animals (see section 5.3), Inaqovi may harm the foetus when administered to pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Inaqovi is not recommended during pregnancy and in women of childbearing potential not using effective contraception. A pregnancy test should be performed on all women of childbearing potential before treatment is started. If Inaqovi is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.

Breast-feeding

It is unknown whether decitabine, cedazuridine, or their metabolites are excreted in breast milk.

A risk to the newborns/infants cannot be excluded.

Inaqovi is contraindicated during breast-feeding (see section 4.3).

Fertility

No human data on the effect of decitabine and cedazuridine on fertility are available. Ovarian and testicular toxicity, including mutagenicity, has been observed in repeat-dose toxicity studies in mice. Because of the possibility of infertility as a consequence of therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiating treatment. Before starting treatment or planning pregnancy, consider the above guidance (see section 5.3).

4.7. Effects on ability to drive and use machines

Inaqovi has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects, such as anaemia during treatment. Therefore, caution should be observed when driving a car or operating machinery.

4.8. Undesirable effects

Summary of safety profile

The safety of Inaqovi was evaluated in one Phase 3 study (ASTX727-02-EU) where 80 AML patients received the medicinal product. The overall safety profile for Inaqovi is described below and also reflects the known safety profile of intravenous decitabine.

Among the 80 patients who received treatment, the most common adverse drug reaction (≥ 20%) including Grade ≥ 3 was thrombocytopaenia.

The most common serious adverse reactions (≥ 20%) were febrile neutropaenia and pneumonia.

Deaths while on treatment occurred in 24% of patients. The most frequent adverse reactions resulting in death included pneumonia (8%), sepsis (3%) and central nervous system haemorrhage in the setting of thrombocytopaenia (3%).

Permanent discontinuation occurred in 14% of patients while on treatment. The most frequent adverse reaction resulting in permanent discontinuation was pneumonia (5%).

Treatment interruption and dose reductions occurred in 48% of patients. The most frequent adverse reaction resulting in treatment interruption and dose reduction was myelosuppression occurring in 19% of patients (n=15) (neutropaenia [13%, n=10], febrile neutropaenia [5%, n=4], and thrombocytopaenia [3%, n=2]). The adverse reaction pneumonia led to treatment interruption and dose reduction in 5% of patients.

Tabulated list of adverse reactions

The safety evaluation of adverse reactions is largely based on experience with Dacogen in patients with AML. The safety of Inaqovi in adult patients was evaluated in a safety population that included AML patients from one Phase 3 study (ASTX727-02-EU, N=80).

Among the 80 patients who received Inaqovi, 38% were exposed for 6 months or longer and 6% were exposed for greater than 1 year.

Table 2 lists adverse drug reactions associated with Inaqovi (N=80), or that have been associated with intravenous decitabine, according to system organ class (SOC) in MedDRA. Within each SOC, the adverse drug reactions are ranked by frequency and then presented in order of decreasing seriousness. The corresponding frequency category for each adverse drug reaction is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data).

Table 2: Adverse drug reactions observed with Inaqovi or with intravenous decitabine therapy in AML patients

MedDRA SOC

MedDRA Term a

AML (N=80)

All CTCAE Grades

CTCAE Grade 3-4

%

Frequency

%

Frequency

Infections and infestations

All other infections (viral, bacterial, fungal) b

50.0

Very common

25.0

Very common

Pneumonia c

23.8

Very common

18.8

Very common

Sepsis d

10.0

Very common

6.3

Common

Urinary tract infection e

17.5

Very common

2.5

Common

Sinusitis (including fungal f and bacterial g)

2.5

Common

2.5

Common

Blood and lymphatic system disorders

Leukopenia h

81.3

Very common

67.5

Very common

Thrombocytopaenia h,i

73.8

Very common

67.5

Very common

Anaemia h

67.5

Very common

60.0

Very common

Neutropaenia h,j

41.8

Very common

41.8

Very common

Febrile neutropaenia

28.8

Very common

26.3

Very common

Pancytopaenia k

Not known

Uncommon k

Not known

Uncommon k

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Differentiation syndrome l

Not known

Not known

Not known

Not known

Metabolism and nutrition disorders

Hyperglycaemia h,m

61.1

Very common

4.2

Common

Nervous system disorders

Headache n

2.5

Common

Not known

Common n

Cardiac disorders

Cardiomyopathy o

Not known

Uncommon

Not known

Uncommon

Respiratory, thoracic and mediastinal disorders

Epistaxis n

6.3

Common

Not known

Common n

Interstitial lung disease l

Not known

Not known

Not known

Not known

Gastrointestinal disorders

Stomatitis p

10.0

Very common

1.3

Common

Nausea q

21.3

Very common

Not known

Uncommon q

Diarrhoea r

13.8

Very common

Not known

Common r

Vomiting r

12.5

Very common

Not known

Common r

Neutropaenic colitis s

1.3

Common

1.3

Common

Hepatobiliary disorders

Aspartate aminotransferase increased h,t

30.6

Very common

2.8

Common

Alanine aminotransferase increased h,u

28.8

Very common

2.7

Common

Alkaline phosphatase increased h,v

43.7

Very common

0

Not applicable

Bilirubin increased h,w,q

23.3

Very common

Not known

Uncommonf

Skin and subcutaneous tissue disorders

Acute febrile neutrophilic dermatosis (Sweet's syndrome) x

Not known

Uncommon x

Not applicable y

Not applicable y

General disorders and administration site conditions

Pyrexia z

23.8

Very common

1.3

Common

a The corresponding frequency category for each adverse drug reaction is based on the CIOMS III convention

b Grouped terms include anal abscess, anorectal infection, bacteraemia, cellulitis, cellulitis staphylococcal, corona virus infection, coronavirus test positive, enterococcal bacteraemia, enterocolitis viral, erythema, escherichia bacteraemia, folliculitis, furuncle, gingival swelling, herpes virus infection, infection, klebsiella bacteraemia, nasal congestion, nasopharyngitis, oral candidiasis, oral herpes, oropharyngeal candidiasis, otitis externa, periodontitis, pharyngitis, polyserositis, pseudomonal bacteraemia, staphylococcal bacteraemia, staphylococcal infection, streptococcal bacteraemia, respiratory tract infection, skin infection, tooth abscess, tooth infection, upper respiratory tract infection, varicella zoster virus infection

c Grouped terms include bronchitis, pneumonia

d Grouped terms include sepsis, septic shock, systemic candidiasis, urosepsis

e Grouped terms include bacteriuria, cystitis, dysuria, escherichia urinary tract infection, urinary tract infection, urinary tract infection enterococcal

f Grouped terms include sinusitis aspergillus, sinusitis fungal

g Sinusitis bacterial was not observed in the clinical trial with Inaqovi, however sinusitis (organism not specified) was observed in clinical trials with IV decitabine at a frequency of common (3%, 1%)

h Based on laboratory values

i Thrombocytopaenia may lead to bleeding and haemorrhagic reactions that may be fatal

j Neutrophils decreased (n=79)

k Pancytopaenia, including fatal events, was not observed in the clinical trial with Inaqovi, however it was observed in clinical trials with IV decitabine at a frequency of uncommon (< 1%)

l Differentiation syndrome and interstitial lung disease were not observed in the clinical trial with Inaqovi, however they were observed in post-market setting with the use of IV decitabine

m Hyperglycemia (n=72)

n Headache and epistaxis Grade 3-4, were not observed in the clinical trial with Inaqovi, however they were observed in clinical trials with IV decitabine at a frequency of common (1% and 2%)

o Cardiomyopathy was not observed in the clinical trial with Inaqovi, however it was observed in clinical trials with IV decitabine at a frequency of uncommon (< 1%)

p Grouped terms include aphthous ulcer, glossitis, oral discomfort, oropharyngeal discomfort, oropharyngeal pain, stomatitis, tongue ulceration, toothache

q Nausea and bilirubin increased, Grade 3-4, were not observed in the clinical trial with Inaqovi, however it was observed in clinical trials with IV decitabine at a frequency of uncommon (< 1%)

r Diarrhoea and vomiting, Grade 3-4, were not observed in the clinical trial with Inaqovi, however they were observed in clinical trials with IV decitabine at a frequency of common (2% and 1%)

s Caecitis (including fatal events) was not observed in the clinical trial with Inaqovi, however they were observed in post-market setting with the use of IV decitabine

t Aspartate aminotransferase increased (n=72)

u Alanine aminotransferase increased (n=73)

v Alkaline phosphatase increased (n=71)

w Bilirubin increased (n=73)

x Acute febrile neutrophilic dermatosis was not observed in the clinical trial with Inaqovi, however it was observed in clinical trials with IV decitabine (all Grades) at a frequency of uncommon (< 1%)

y Not applicable (Grade 3-4): Adverse drug reaction has not been observed with either Inaqovi or IV decitabine in both clinical trials and post-market

z Grouped terms include chills and pyrexia

CTCAE= Common Terminology Criteria for Adverse Events

Description of selected adverse reactions

Haematologic adverse drug reactions

The most commonly reported haematologic adverse drug reactions associated with treatment included leukopaenia, thrombocytopaenia, anaemia, neutropaenia and febrile neutropaenia. These adverse drug reactions are manifestations of myelosuppression and may present as pancytopenia.

Serious bleeding-related adverse drug reactions, such as gastrointestinal haemorrhage and cerebral haemorrhage in the context of severe thrombocytopaenia, were reported in patients receiving treatment. Bleeding may also occur with the eyes, skin, and mucous membranes (mouth and anorectal).

Haematological adverse drug reactions must be managed by routine monitoring of CBCs and early administration of supportive treatments as required. Supportive treatments include administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia and transfusions for anaemia or thrombocytopaenia according to institutional guidelines. For situations where treatment must be delayed, see section 4.2.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving treatment.

Gastrointestinal disorders

Occurrences of enterocolitis, including neutropaenic colitis, have been reported during treatment. Enterocolitis may lead to septic complications and may be associated with fatal outcome.

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving intravenous decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving intravenous decitabine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction. Differentiation syndrome may occur with or without concomitant leucocytosis. Capillary leak syndrome and coagulopathy can also occur (see section 4.4).

Other special populations

Elderly

Of the 80 patients in clinical studies who received Inaqovi, 39% were younger than 75 years, and 61% were 75 years and older. No overall differences in safety or effectiveness were observed between patients aged 75 years and older and younger patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

Overdose could cause increased myelosuppression and neutropaenia-related infections such as pneumonia and sepsis.

Management

There is no known antidote for overdose with the medicinal product. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.