AKEEGA 100mg / 500mg film-coated tablets medication leaflet

Akeega 50 mg/500 mg film-coated tablets

Akeega 100 mg/500 mg film-coated tablets

Akeega 50 mg/500 mg film-coated tablets

Each film-coated tablet contains niraparib tosylate monohydrate equivalent to 50 mg of niraparib and500 mg of abiraterone acetate equivalent to 446 mg of abiraterone.

Akeega 100 mg/500 mg film-coated tablets

Each film-coated tablet contains niraparib tosylate monohydrate equivalent to 100 mg of niraparib and500 mg of abiraterone acetate equivalent to 446 mg of abiraterone.

Each film-coated tablet contains 241 mg of lactose (see section 4.4)

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Akeega 50 mg/500 mg film-coated tablets

Yellowish orange to yellowish brown, oval, film-coated tablets (22 mm x 11 mm), debossed with “N50 A” on one side, and plain on the other side.

Akeega 100 mg/500 mg film-coated tablets

Orange, oval, film-coated tablets (22 mm x 11 mm), debossed with “N 100 A” on one side, and plainon the other side.

Akeega is indicated with prednisone or prednisolone for the treatment of adult patients with metastaticcastration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) inwhom chemotherapy is not clinically indicated.

Treatment with Akeega plus prednisone or prednisolone should be initiated and supervised byspecialist physicians experienced in the medical treatment of prostate cancer.

Before initiation of Akeega therapy, positive BRCA status must be established using a validated testmethod (see section 5.1).

The recommended starting dose of Akeega is 200 mg/1 000 mg (two 100 mg niraparib/500 mgabiraterone acetate tablets), as a single daily dose at approximately the same time every day (see“Method of administration” below). The 50 mg/500 mg tablet is available for dose reduction.

Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continuedduring treatment in patients not surgically castrated.

Akeega is used with 10 mg prednisone or prednisolone daily.

Patients should be treated until disease progression or unacceptable toxicity.

If a dose of either Akeega, prednisone or prednisolone is missed, it should be taken as soon as possibleon the same day with a return to the normal schedule the following day. Extra tablets must not betaken to make up for the missed dose.

Dose adjustments for adverse reactions

Non-haematological adverse reactions

For patients who develop Grade ≥ 3 non-haematological adverse reactions, treatment should beinterrupted and appropriate medical management should be instituted (see section 4.4). Treatment with

Akeega should not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or baseline.

Haematological adverse reactions

For patients who develop a ≥ Grade 3 or intolerable haematological toxicity, dosing with Akeegashould be interrupted rather than discontinued and supportive management considered. Akeega shouldbe permanently discontinued if haematological toxicity has not returned to acceptable levels within28 days of the dose interruption period.

The dose adjustment recommendations for thrombocytopenia and neutropenia are listed in Table 1.

Table 1: Dose adjustment recommendations for thrombocytopenia and neutropenia

Grade 1 No change, consider weekly monitoring

Grade 2 At least weekly monitoring and consider withholding Akeega until recovery to

Grade 1 or baseline.1 Resume Akeega with recommendation of weeklymonitoring for 28 days after restarting dose.

Grade ≥ 3 Withhold Akeega and monitor at least weekly until platelets and neutrophilsrecover to Grade 1 or baseline.1 Then resume Akeega or, if warranted, use twolower strength tablets (50 mg/500 mg).

Weekly monitoring of blood counts is recommended for 28 days after restartingdose or starting the lower strength dose (two 50 mg/500 mg tablets). Whenstarting the lower strength dose, please refer to “Recommended monitoring”below for further information regarding liver function.

Second Withhold Akeega and monitor at least weekly until platelets and/or neutrophilsoccurrence recover to Grade 1. Further treatment should restart with two lower strength≥ grade 3 tablets (50 mg/500 mg).

Weekly monitoring is recommended for 28 days after resuming treatment withlower strength Akeega. When starting the lower strength dose (two50 mg/500 mg tablets), please refer to “Recommended monitoring” below forfurther information regarding liver function.

If patient was already on lower strength Akeega tablet (50 mg/500 mg),consider treatment discontinuation.

Third occurrence Permanently discontinue treatment.≥ grade 31 During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by thephysician and given to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information).

Further dosing with Akeega may be resumed only when toxicity due to thrombocytopenia andneutropenia is improved to Grade 1 or resolved to baseline. Treatment may resume at a lower strengthof Akeega 50 mg/500 mg (2 tablets). For the most common adverse reactions, see section 4.8.

For Grade ≥ 3 anaemia, Akeega should be interrupted and supportive management provided untilrecovered to Grade ≤ 2. Dose reduction (two 50 mg/500 mg tablets) should be considered if anaemiapersists based on clinical judgment. The dose adjustment recommendations for anaemia are listed in

Table 2.

Table 2: Dose adjustment recommendations for anaemia

Grade 1 No change, consider weekly monitoring.

Grade 2 At least weekly monitoring for 28 days, if baseline anaemia was Grade ≤ 1.

Grade ≥ 3 Withhold Akeega1 and provide supportive management with monitoring at leastweekly until recovered to Grade ≤ 2. Dose reduction [two lower strengthtablets (50 mg/500 mg)] should be considered if anaemia persists based onclinical judgment. When starting the lower strength dose, please refer to“Recommended monitoring” below for further information regarding liverfunction.

Second Withhold Akeega, provide supportive management and monitor at least weeklyoccurrence until recovered to Grade ≤ 2. Further treatment should restart with two lower≥ Grade 3 strength tablets (50 mg/500 mg).

Weekly monitoring is recommended for 28 days after resuming treatment withlower strength Akeega. When starting the lower strength dose, please refer to“Recommended monitoring” below for further information regarding liverfunction.

If patient was already on lower strength Akeega tablet (50 mg/500 mg),consider treatment discontinuation.

Third occurrence Consider discontinuing treatment with Akeega based on clinical judgment.≥ Grade 31 During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by thephysician and given to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information).

For patients who develop ≥ Grade 3 hepatotoxicity (alanine aminotransferase [ALT] increases oraspartate aminotransferase [AST] increases above five times the upper limit of normal [ULN]),treatment with Akeega should be interrupted and liver function closely monitored (see section 4.4).

Re-treatment may take place only after return of liver function tests to the patient’s baseline and at areduced dose level of one regular strength Akeega tablet (equivalent to 100 mg niraparib/500 mgabiraterone acetate). For patients being re-treated, serum transaminases should be monitored at aminimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at thereduced dose of 100 mg/500 mg daily (1 tablet), treatment with Akeega should be discontinued.

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) while on Akeega, treatmentshould be permanently discontinued.

Permanently discontinue Akeega for patients who develop a concurrent elevation of ALT greater than3  ULN, and total bilirubin greater than 2  ULN, in the absence of biliary obstruction or othercauses responsible for the concurrent elevation (see section 4.4).

Complete blood counts should be obtained prior to starting treatment, weekly for the first month,every two weeks for the next two months, followed by monthly monitoring for the first year and thenevery other month for the remainder of treatment to monitor for clinically significant changes in anyhaematologic parameter (see section 4.4).

Serum aminotransferases and total bilirubin should be measured prior to starting treatment, every twoweeks for the first three months of treatment and monthly thereafter for the first year and then everyother month for the duration of treatment. When starting the lower strength dose (two tablets) afterdose interruption, liver function should be monitored every two weeks for six weeks due to risk ofincreased abiraterone exposure (see section 5.2), before resuming regular monitoring. Serumpotassium should be monitored monthly for the first year and then every other month for the durationof treatment (see section 4.4).

Blood pressure monitoring should occur weekly for the first two months, monthly for the first year andthen every other month for the duration of treatment.

In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treatedwith Akeega, consider maintaining the patient’s potassium level at ≥ 4.0 mM.

No dose adjustment is necessary for elderly patients (see section 5.2).

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment (Child-Pugh

Class A). There are no data on the clinical safety and efficacy of multiple doses of Akeega whenadministered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Nodose adjustment can be predicted. The use of Akeega should be cautiously assessed in patients withmoderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (seesections 4.4 and 5.2). Akeega is contraindicated in patients with severe hepatic impairment (seesections pct. 4.3, pct. 4.4 and 5.2).

No dose adjustment is necessary for patients with mild to moderate renal impairment, although closemonitoring of safety events should be conducted with moderate renal impairment due to the potentialfor increased niraparib exposure. There are no data on the use of Akeega in patients with severe renalimpairment or end stage renal disease undergoing haemodialysis, Akeega may only be used in patientswith severe renal impairment if the benefit outweighs the potential risk, and the patient should becarefully monitored for renal function and adverse events (see sections 4.4 and 5.2).

There is no relevant use of Akeega in the paediatric population.

Akeega is for oral use.

The tablets must be taken as a single dose, once daily. Akeega should be taken on an empty stomach,at least 1 hour before or 2 hours after a meal (see section 5.2). For optimal absorption, Akeega tabletsmust be swallowed whole with water, they must not be broken, crushed, or chewed.

Women who are or may become pregnant should wear gloves when handling the tablets (see section6.6).

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

Women who are or may become pregnant (see section 4.6).

Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, pct. 4.4 and 5.2)].

Akeega plus prednisone or prednisolone is contraindicated in combination with Ra-223 treatment.

Haematological adverse reactions

Haematological adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported inpatients treated with Akeega (see section 4.2).

Testing complete blood counts weekly for the first month, every two weeks for the next two months,followed by monthly monitoring for the first year and then every other month for the remainder oftreatment is recommended to monitor for clinically significant changes in any haematologicalparameter while on treatment (see section 4.2).

Based on individual laboratory values, weekly monitoring for the second month may be warranted.

If a patient develops severe persistent haematological toxicity including pancytopenia that does notresolve within 28 days following interruption, Akeega should be discontinued.

Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts shouldbe used with caution in patients taking Akeega (see section 4.8).

When starting the lower strength dose (two tablets) after dose interruption due to haematologicaladverse reactions, liver function should be monitored every two weeks for six weeks due to risk ofincreased abiraterone exposure (see section 5.2), before resuming regular monitoring (see section 4.2).

Akeega may cause hypertension and pre-existing hypertension should be adequately controlled beforestarting Akeega treatment. Blood pressure should be monitored at least weekly for two months,monitored monthly afterwards for the first year and every other month thereafter during treatment with

Akeega.

Hypokalaemia, fluid retention, & cardiovascular adverse reactions due to mineralocorticoid excess

Akeega may cause hypokalaemia and fluid retention (see section 4.8) as a consequence of increasedmineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of acorticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction inincidence and severity of these adverse reactions. Caution is required in treating patients whoseunderlying medical conditions might be compromised by hypokalaemia (e.g., those on cardiacglycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recentmyocardial infarction or ventricular arrhythmia and those with severe renal impairment). QTprolongation has been observed in patients experiencing hypokalaemia in association with Akeegatreatment. Hypokalaemia and fluid retention should be corrected and controlled.

Before treating patients with a significant risk for congestive heart failure (e.g., a history of cardiacfailure, or cardiac events such as ischaemic heart disease), cardiac failure should be treated and cardiacfunction optimised. Fluid retention (weight gain, peripheral oedema), and other signs and symptoms ofcongestive heart failure should be monitored every two weeks for three months, then monthlythereafter and abnormalities corrected. Akeega should be used with caution in patients with a historyof cardiovascular disease.

Management of cardiac risk factors (including hypertension, dyslipidaemia, and diabetes) should beoptimised in patients receiving Akeega and these patients should be monitored for signs and symptomsof cardiac disease.

Abiraterone acetate, a component of Akeega, increases mineralocorticoid levels and carries a risk forcardiovascular events. Mineralocorticoid excess may cause hypertension, hypokalaemia, and fluidretention. Previous androgen deprivation therapy (ADT) exposure as well as advanced age areadditional risks for cardiovascular morbidity and mortality. The MAGNITUDE study excludedpatients with clinically significant heart disease as evidenced by myocardial infarction, arterial andvenous thrombotic events in the past six months, severe or unstable angina, or NYHA Class II to IVheart failure or cardiac ejection fraction measurement of < 50%. Patients with a history of cardiacfailure should be clinically optimised and appropriate management of symptoms instituted. If there is aclinically significant decrease in cardiac function, discontinuation of Akeega should be considered.

In MAGNITUDE, severe infections including COVID-19 infections with fatal outcome occurred morefrequently in patients treated with Akeega. Patients should be monitored for signs and symptoms ofinfection. Severe infections may occur in absence of neutropenia and/or leukopenia.

Pulmonary embolism (PE)

In MAGNITUDE, cases of PE were reported in patients treated with Akeega with a higher frequencycompared to control. Patients with a prior history of PE or venous thrombosis may be more at risk of afurther occurrence. Patients should be monitored for clinical signs and symptoms of PE. If clinicalfeatures of PE occur, patients should be evaluated promptly, followed by appropriate treatment.

Posterior reversible encephalopathy syndrome (PRES)

PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptomsincluding seizures, headache, altered mental status, visual disturbance, or cortical blindness, with orwithout associated hypertension. A diagnosis of PRES requires confirmation by brain imaging,preferably magnetic resonance imaging (MRI).

There have been reports of PRES in patients receiving 300 mg niraparib (a component of Akeega) as amonotherapy in the ovarian cancer population. In the MAGNITUDE study, among prostate cancerpatients treated with 200 mg of niraparib, there were no PRES cases reported.

In case of PRES, treatment with Akeega should be permanently discontinued and appropriate medicalmanagement should be instituted.

Hepatotoxicity had been recognised as an important identified risk for abiraterone acetate, acomponent of Akeega. The mechanism for hepatotoxicity of abiraterone acetate is not fullyunderstood. Patients with moderate and severe hepatic impairment (NCI classification) and patientswith Child-Turcotte-Pugh Class B and C were excluded from Akeega combination studies.

In the MAGNITUDE study and all combination clinical studies, the risk for hepatotoxicity wasmitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver functiontests (Serum total bilirubin > 1.5  ULN or direct bilirubin > 1  ULN and AST or ALT> 3  ULN).

Marked increases in liver enzymes leading to treatment interruption or discontinuation occurred inclinical studies, although these were uncommon (see section 4.8). Serum aminotransferase and totalbilirubin levels should be measured prior to starting treatment, every two weeks for the firstthree months of treatment, and monthly thereafter for the first year and then every other month for theduration of treatment. When starting the lower strength dose (two tablets) after dose interruption, liverfunction should be monitored every two weeks for six weeks due to risk of increased abirateroneexposure (see section 5.2), before resuming regular monitoring. If clinical symptoms or signssuggestive of hepatotoxicity develop, serum transaminases should be measured immediately.

Development of elevated aminotransferases in patients treated with Akeega should be promptlymanaged with treatment interruption. If at any time the ALT or AST rises above 5 times the ULN,treatment with Akeega should be interrupted and liver function closely monitored. Re-treatment maytake place only after return of liver function tests to the patient’s baseline and at a reduced dose level(see section 4.2).

Treatment should be permanently discontinued in patients with elevations of ALT or AST> 20  ULN. Treatment should be permanently discontinued in patients who develop a concurrentelevation of ALT > 3  ULN and a total bilirubin > 2  ULN in the absence of biliary obstruction orother causes responsible for the concurrent elevation.

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy,treatment with Akeega should be permanently discontinued.

Patients with active or symptomatic viral hepatitis were excluded from clinical studies; thus, there areno data to support the use of Akeega in this population.

Moderate hepatic impairment (Child-Pugh Class B or any AST and TB > 1.5 x - 3 x ULN) has beenshown to increase the systemic exposure to abiraterone and niraparib (see section 5.2). There are nodata on the clinical safety and efficacy of multiple doses of Akeega when administered to patients withmoderate or severe hepatic impairment. The use of Akeega should be cautiously assessed in patientswith moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (seesections 4.2 and 5.2). Akeega should not be used in patients with severe hepatic impairment (seesections 4.2, pct. 4.3 and 5.2).

Cases of hypoglycaemia have been reported when abiraterone acetate (a component of Akeega) plusprednisone or prednisolone was administered to patients with pre-existing diabetes receivingpioglitazone or repaglinide (metabolised by CYP2C8) (see section 4.5). Blood sugar should, therefore,be monitored in patients with diabetes.

Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML)

MDS/AML, including cases with fatal outcome, have been reported in ovarian cancer studies amongpatients who received 300 mg of niraparib (a component of Akeega).

In the MAGNITUDE study, no cases of MDS/AML have been observed in patients treated with200 mg of niraparib and 1 000 mg of abiraterone acetate plus prednisone or prednisolone.

For suspected MDS/AML or prolonged haematological toxicities that has not resolved with treatmentinterruption or dose reduction, the patient should be referred to a haematologist for further evaluation.

If MDS and/or AML is confirmed, treatment with Akeega should be permanently discontinued, andthe patient should be treated appropriately.

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients arewithdrawn from prednisone or prednisolone. If Akeega is continued after corticosteroids arewithdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see informationabove).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose ofcorticosteroids may be indicated before, during and after the stressful situation.

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use ofabiraterone acetate (a component of Akeega) in combination with a glucocorticoid could increase thiseffect.

Increased fractures and mortality in combination with Radium (Ra) 223 Dichloride

Treatment with Akeega plus prednisone or prednisolone in combination with Ra-223 treatment iscontraindicated (see section 4.3) due to an increased risk of fractures and a trend for increasedmortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinicalstudies with abiraterone acetate, a component of Akeega.

It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days afterthe last administration of Akeega in combination with prednisone or prednisolone.

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measuredfrequently in patients with diabetes.

Cases of myopathy and rhabdomyolysis have not been seen in patients treated with Akeega. Inabiraterone acetate (a component of Akeega) monotherapy studies, most cases developed within thefirst six months of treatment and recovered after abiraterone acetate withdrawal. Caution isrecommended in patients concomitantly treated with medicinal products known to be associated withmyopathy/rhabdomyolysis.

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeuticalternative, due to risk of decreased exposure of abiraterone (see section 4.5).

Lactose and sodium

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinalproduct.

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

No clinical study evaluating drug interactions has been performed using Akeega. Interactions that havebeen identified in studies with individual components of Akeega (niraparib or abiraterone acetate)determine the interactions that may occur with Akeega.

Effects of other medicinal products on niraparib or abiraterone acetate

CYP3A4 inducers and inhibitors

Abiraterone is a CYP3A4 substrate. In a clinical study in healthy subjects pretreated with the strong

CYP3A4 inducer rifampicin, 600 mg daily for six days, followed by a single dose of abirateroneacetate 1 000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of

CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John’swort [Hypericum perforatum]) during treatment with Akeega should be avoided unless there is notherapeutic alternative (see section 4.4).

In a separate clinical study in healthy subjects, co-administration of ketoconazole, a strong inhibitor of

CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

Effects of niraparib or abiraterone acetate on other medicinal products

Abiraterone is an inhibitor of CYP2D6. In a clinical study to determine the effects of abirateroneacetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, thesystemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC24 fordextrorphan, the active metabolite of dextromethorphan, increased approximately 33%. Dosereduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol,propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine,oxycodone and tramadol.

CYP2C8 substrates

Abiraterone is an inhibitor of CYP2C8. In a clinical study in healthy subjects, the AUC ofpioglitazone, a CYP2C8 substrate, was increased by 46% and the AUCs for M-III and M-IV, theactive metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together witha single dose of 1 000 mg abiraterone acetate. Patients should be monitored for signs of toxicityrelated to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Akeegabecause of the abiraterone acetate component. Examples of medicinal products metabolised by

CYP2C8 include pioglitazone and repaglinide (see section 4.4).

Akeega with vaccines or immunosuppressant agents has not been studied.

The data on niraparib, in combination with cytotoxic medicinal products, are limited. Caution shouldbe taken if Akeega is used in combination with live or live-attenuated vaccines, immunosuppressantagents or with other cytotoxic medicinal products.

Since androgen deprivation treatment may prolong the QT interval, caution is advised whenadministering Akeega with medicinal products known to prolong the QT interval or medicinalproducts able to induce torsades de pointes, such as class IA (e.g., quinidine, disopyramide) or class III(e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,moxifloxacin, antipsychotics, etc.

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels.

Use with Akeega is not recommended (see section 5.1).

It is not known whether components of Akeega or their metabolites are present in semen.

During treatment and for four months after the last dose of Akeega:

- A condom is required if the patient is engaged in sexual activity with a pregnant woman.

- If the patient is engaged in sex with a woman of childbearing potential, a condom is requiredalong with another effective contraceptive method.

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

Akeega is not for use in women (see section 4.3).

There are no data from the use of Akeega in pregnant women. Akeega has the potential to cause foetalharm based on the mechanism of action of both components and findings from animal studies withabiraterone acetate. Animal developmental and reproductive toxicology studies were not conductedwith niraparib (see section 5.3).

Akeega is not for use in women.

There are no clinical data on fertility with Akeega. In animal studies, male fertility was reduced withniraparib or abiraterone acetate but these effects were reversible following treatment cessation (seesection 5.3).

Akeega has moderate influence on the ability to drive or use machines. Patients who take Akeega mayexperience asthenia, fatigue, dizziness or difficulties concentrating. Patients should use caution whendriving or using machines.

The overall safety profile of Akeega is based on data from a Phase 3, randomised, double-blind,placebo-controlled study, MAGNITUDE cohort 1 (N=212). The most common adverse reactions of allgrades occurring in >10% in the niraparib plus AAP arm were anaemia (52.4%), hypertension(34.0%), constipation (34.0%), fatigue (31.1%), nausea (25.0%), thrombocytopenia (24.1%), dyspnoea(18.9%), arthralgia (18.4%), back pain (17.9%), asthenia (17.0%), neutropenia (16.0%), decreasedappetite (15.6%), hypokalaemia (15.6%), vomiting (15.1%), dizziness (13.2%), abdominal pain(12.7%), hyperglycaemia (12.7%), blood alkaline phosphatase increased (11.8%), weight decreased(11.8%), insomnia (11.3%), leukopenia (10.8%), lymphopenia (10.8%), blood creatinine increased(10.4%), and urinary tract infection (10.4%). The most frequently observed Grade 3-4 adversereactions were anaemia (30.7%), hypertension (16.5%), thrombocytopenia (8.5%), neutropenia(6.6%), blood alkaline phosphatase increased (5.7%), and hypokalaemia (5.7%).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories are defined as follows: 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); and not known(frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse reactions identified in clinical studies

System Organ Class Frequency Adverse reaction

Infections and very common urinary tract infectioninfestations common pneumoniae, bronchitis, nasopharyngitisuncommon urosepsis, conjunctivitis

Blood and lymphatic very common anaemia, thrombocytopenia, neutropenia,system disorders leukopenia, lymphopenianot known pancytopenia7

Immune system not known hypersensitivity (including anaphylaxis)7disorders

Endocrine disorders not known adrenal insufficiency9

Metabolism and very common decreased appetite, hypokalaemia,nutrition disorders hyperglycaemiacommon hypertriglyceridaemia

Psychiatric disorders very common insomniacommon depression, anxietyuncommon confusional statenot known cognitive impairment8

Nervous system very common dizzinessdisorders common headache, cognitive disorderuncommon dysgeusianot known posterior reversible encephalopathy syndrome(PRES)7

Cardiac disorders common tachycardia, palpitations, atrial fibrillation,cardiac failure1, myocardial infarction, anginapectoris2uncommon QT prolongation

Vascular disorders very common hypertensionnot known hypertensive crisis7very common dyspnoea

Respiratory, thoracic common cough, pulmonary embolism, pneumonitisand mediastinal uncommon epistaxisdisorders not known allergic alveolitis9

Gastrointestinal very common constipation, nausea, vomiting, abdominal pain3disorders common dyspepsia, diarrhoea, abdominal distention,stomatitis, dry mouthuncommon mucosal inflammation

Hepatobiliary disorders common hepatic failure4

Skin and subcutaneous common rash5tissue disorders uncommon photosensitivity

Musculoskeletal and very common back pain, arthralgiaconnective tissue common myalgiadisorders not known myopathy9, rhabdomyolysis9

Renal and urinary common haematuriadisorders

General disorders and very common fatigue, astheniaadministration site common oedema peripheralconditions

Investigations very common blood alkaline phosphatase increased, weightdecreased, blood creatinine increasedcommon AST increased, ALT increaseduncommon gamma-glutamyl transferase increased

Injury, poisoning and common fractures6proceduralcomplications1 Includes cardiac failure congestive, cor pulmonale, left ventricular dysfunction2 Includes coronary artery disease, acute coronary syndrome3 Includes abdominal pain upper, abdominal pain lower4 Includes hepatic cytolysis, hepatotoxicity, hepatic failure5 Includes rash, erythema, dermatitis, rash maculo-papular, rash pruritic6 Includes osteoporosis and osteoporosis-related fractures7 Not observed with Akeega. Reported in post-marketing experience with niraparib monotherapy8 Not observed with Akeega. Reported with niraparib monotherapy9 Not observed with Akeega. Reported in post-marketing experience with abiraterone monotherapy

Haematological toxicities (anaemia, thrombocytopenia and neutropenia) including laboratory findingsare the most frequent adverse reactions attributable to niraparib (a component of Akeega). Thesetoxicities generally occurred within the first three months of treatment with the incidence decreasingover time.

In the MAGNITUDE study and other Akeega studies, the following haematological parameters wereinclusion criteria: absolute neutrophil count (ANC) ≥ 1 500 cells/μL; platelets ≥ 100 000 cells/μL andhaemoglobin ≥ 9 g/dL. Haematological adverse reactions were managed with laboratory monitoringand dose modifications (see sections 4.2 and 4.4).

Anaemia was the most frequent adverse reaction (52.4%) and most commonly observed Grade 3-4event (30.7%) in the MAGNITUDE study. Anaemia occurred early during the course of therapy(median time to onset of 64 days). In the MAGNITUDE study, dose interruptions occurred in 24.1%and dose reductions in 13.7% of patients. Twenty-seven percent of patients received at least oneanaemia-related red blood cell transfusion. Anaemia caused discontinuation in a relatively smallnumber of patients (2.8%).

In the MAGNITUDE study, 24.1% of treated patients reported thrombocytopenia while 8.5% ofpatients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was71 days. In the MAGNITUDE study, thrombocytopenia was managed with dose modification(interruption 11.3% and reduction in 2.8%) and platelet transfusion (3.8%) where appropriate (seesection 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.9% ofpatients experienced a nonlife-threatening bleeding event.

In the MAGNITUDE study, 16.0% of patients experienced neutropenia with Grade 3-4 neutropeniareported in 6.6% of patients. Median time from first dose to first report of neutropenia was 65 days.

Neutropenia led to treatment interruption in 6.6% of patients and dose reduction in 1.4%. There wereno treatment discontinuations due to neutropenia. In the MAGNITUDE study, 0.9% of patients had aconcurrent infection.

Hypertension is an adverse reaction for both components of Akeega and patients with uncontrolledhypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg) wereexcluded in all combination studies. Hypertension was reported in 34% of patients of whom 16.5%had Grade ≥ 3. The median time to onset of hypertension was 60.5 days. Hypertension was managedwith adjunctive medicinal products.

Patients should have blood pressure controlled before initiating Akeega and blood pressure should bemonitored on treatment (see section 4.4).

In the MAGNITUDE study, the incidence of TEAEs of cardiac disorder (all grades) was similar inboth arms, except for the arrhythmia category, where AEs were observed in 13.2% of patients in theniraparib plus AAP arm and 7.6% of patients in the placebo plus AAP arm (see section 4.4). Higherfrequency of arrhythmias was largely due to low grade events of palpitations, tachycardias and atrialarrhythmias.

The median time to onset of the events of arrhythmias was 81 days in the niraparib plus AAP arm and262 days in the placebo plus AAP arm. Events of arrhythmia were resolved in 64.3% of patients in theniraparib plus AAP arm and 62.5% of subjects in the placebo plus AAP arm.

The incidence of cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failurecongestive was 2.8% in the niraparib plus AAP arm vs 1.9% in placebo plus AAP arm. The mediantime to onset of the AESI of cardiac failure was 312 days in the niraparib plus AAP arm and 83 daysin the placebo plus AAP arm. Events of cardiac failure were resolved in 16.7% of patients in theniraparib plus AAP arm and 25% of patients in the placebo plus AAP arm.

The grouped term of ischaemic heart disease (included preferred terms of angina pectoris, acutemyocardial infarction, acute coronary syndrome, unstable angina, and arteriosclerosis coronary artery)occurred in 5.2% of the niraparib plus AAP arm vs 4.7% in the placebo plus AAP arm. The mediantime to onset of the AESI of ischaemic heart disease was 684 days in the niraparib plus AAP arm and296 days in the placebo plus AAP arm. Events of ischaemic heart disease were resolved in 81.8% ofpatients in the niraparib plus AAP arm and 80% of patients in the placebo plus AAP arm.

The overall incidence of hepatotoxicity in the MAGNITUDE study was similar for the niraparib plus

AAP (14.2%) and placebo plus AAP (12.8%) arms (see sections 4.2 and 4.4). The majority of theseevents were low grade aminotransferase elevations. Grade 3 events occurred in 1.4% of patients in theniraparib plus AAP arm and a Grade 4 event occurred in only one patient (0.5%). The incidence of

SAEs was also 1.4%. The median time to onset of hepatotoxicity in the MAGNITUDE study was43 days. Hepatotoxicity was managed with dose interruptions in 1.9% and dose reduction in 0.9% ofpatients. In the MAGNITUDE study, 0.9% of patients discontinued treatment due to hepatotoxicity.

No studies have been conducted in paediatric patients with Akeega.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment in the event of Akeega overdose. In the event of an overdose, physiciansshould follow general supportive measures and should treat patients symptomatically, includingmonitoring for arrhythmias, hypokalaemia and signs and symptoms of fluid retention. Liver functionalso should be assessed.

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK52

Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), andabiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenicdependencies in patients with mCRPC and HRR gene mutations.

Niraparib

Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2,which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity mayinvolve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes,resulting in DNA damage, apoptosis and cell death.

Abiraterone acetate

Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor.

Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). Thisenzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatictumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosteroneprecursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the

C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals(see section 4.4).

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.

Androgen deprivation therapies, such as treatment with luteinising hormone releasing hormone(LHRH) analogues or orchiectomy, decrease androgen production in the testes but do not affectandrogen production by the adrenals or in the tumour. Treatment with abiraterone decreases serumtestosterone to undetectable levels (using commercial assays) when given with LHRH analogues (ororchiectomy).

Abiraterone acetate

Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved bythe use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the

CYP17 enzyme required for androgen biosynthesis.

First-line treatment of mCRPC patients with BRCA 1/2 mutations

The efficacy of Akeega was established in a randomised placebo-controlled multicentre Phase 3clinical study of patients with mCRPC, MAGNITUDE (Study 64091742PCR3001).

MAGNITUDE was a Phase 3, randomised, double-blind, placebo-controlled, multicentre study thatevaluated treatment with the combination of niraparib (200 mg) and abiraterone acetate (1 000 mg)plus prednisone (10 mg) daily versus AAP standard of care. Efficacy data are based on Cohort 1 thatconsisted of 423 patients with mCRPC and select HRR gene mutations, who were randomised (1:1) toreceive either niraparib plus AAP (N=212) or placebo plus AAP (N=211) orally daily. Treatment wascontinued until disease progression, unacceptable toxicity, or death.

Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for ashort duration of prior AAP (up to 4 months) and ongoing ADT, were eligible. Plasma, blood, and/ortumour tissue samples for all patients were tested by validated next generation sequencing tests todetermine germline and/or somatic HRR gene mutation status. There were 225 subjects with a

BRCA1/2 mutation enrolled in the study (113 received Akeega). There were an additional 198 patientswith a non-BRCA1/2 mutation (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) enrolledin the study (99 received Akeega).

The primary endpoint was radiographic progression free survival (rPFS) as determined by blindedindependent central radiology (BICR) review based on Response Evaluation Criteria In Solid Tumours(RECIST) 1.1 (soft and tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bonelesions). Time to symptomatic progression (TSP), time to cytotoxic chemotherapy (TCC), and overallsurvival (OS) were included as secondary efficacy endpoints.

In the All HRR Population, the primary efficacy results with a median follow-up of 18.6 monthsshowed statistically significant improvement in BICR-assessed rPFS with a HR =0.729 (95% CI:0.556, 0.956; p=0.0217).

Table 4 summarises the demographics and baseline characteristics of BRCA patients enrolled in

Cohort 1 of the MAGNITUDE study. The median PSA at diagnosis was 41.07 ug/L (range 01-12080).

All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0or 1 at study entry. All patients who had not received prior orchiectomy continued backgroundandrogen deprivation therapy with a GnRH analogue.

Table 4: Summary of demographics and baseline characteristics in the MAGNITUDEstudy Cohort 1 (BRCA)

Akeega+P1 Placebo+AAP1 Total

N=113 N=112 N=225n (%) n (%) n (%)

Age (years)< 65 39 (34.5) 37 (33.0) 76 (33.8)≥ 65-74 44 (38.9) 52 (46.4) 96 (42.7)≥ 75 30 (26.5) 23 (20.5) 53 (23.6)

Median 67.0 68.0 68.0

Range 45-100 43-88 43-100

Caucasian 78 (69.0) 84 (75.0) 162 (72.0)

Asian 18 (15.9) 20 (17.9) 38 (16.9)

Black 3 (2.7) 0 3 (1.3)

Unknown 14 (12.4) 8 (7.1) 22 (9.8)

Stratification factors

Past taxane-based chemotherapy exposure 26 (23.0) 29 (25.9) 55 (24.4)

Past AR-targeted therapy exposure 6 (5.3) 5 (4.5) 11 (4.9)

Prior AAP use 30 (26.5) 29 (25.9) 59 (26.2)

Baseline disease characteristics

Gleason score ≥ 8 83 (74.1) 72 (64.3) 155 (69.2)

Bone involvement 99 (87.6) 93 (83.0) 192 (85.3)

Visceral disease (liver, lung, adrenal gland,26 (23.0) 22 (19.6) 48 (21.3)other)

Metastasis stage at initial diagnosis (M1) 70 (61.9) 50 (44.6) 120 (53.3)

Median time from initial diagnosis to2.00 2.31 2.26randomisation (years)

Median time from mCRPC to first dose0.27 0.28 0.27(years)

BPI-SF pain score last score before first dose)0 57 (50.4) 57 (50.9) 114 (50.7)1 to 3 51 (45.1) 40 (35.7) 91 (40.4)> 3 5 (4.4) 15 (13.4) 20 (8.9)

ECOG Performance Status Score0 69 (61.1) 80 (71.4) 149 (66.2)1 44 (38.9) 32 (28.6) 76 (33.8)1 P=prednisone or prednisolone

A statistically significant improvement in BICR-assessed rPFS was observed in the primary analysisfor BRCA subjects treated with niraparib plus AAP, compared with BRCA subjects treated withplacebo plus AAP. Key efficacy results in the BRCA population are presented in Table 5. The Kaplan-

Meier curves for BICR assessed rPFS in the BRCA population are shown in Figure 1.

Table 5: Efficacy results from the BRCA population of the MAGNITUDE study

Akeega+P1 Placebo+AAP1

Endpoints (N=113) (N=112)

Radiographic Progression-free Survival2

Event of disease progression or death (%) 45 (39.8%) 64 (57.1%)

Median, months (95% CI) 16.6 (13.9, NE) 10.9 (8.3, 13.8)

Hazard Ratio (95% CI) 0.533 (0.361, 0.789)p-value 0.0014

Overall Survival3

Hazard Ratio (95% CI) 0.788 (0.554, 1.120)1 P=prednisone or prednisolone2 Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up3 Final Analysis (data cut-off: 15May2023), with 35.9 months median follow-up

NE = Not estimable

Figure 1: Kaplan-Meier Plot of BICR assessed radiologic progression-free survival in the BRCApopulation (MAGNITUDE, primary analysis)

Figure 2: Kaplan-Meier Plot of Overall Survival (MAGNITUDE Cohort 1, BRCA, final analysis)

The European Medicines Agency has waived the obligation to submit the results of studies with Akeegain all subsets of the paediatric population in prostate malignant neoplasms. See section 4.2 forinformation on paediatric use.

Co-administration of niraparib and abiraterone has no impact on the exposures of the individualmoieties. The AUC and Cmax are comparable for niraparib and abiraterone when administered as Akeegaregular strength (100 mg/500 mg) film-coated tablet or as combination of individual components whencompared to respective monotherapy exposures.

Akeega

In mCRPC patients, under fasted and modified fasted conditions, upon administration of multipledoses of Akeega tablets, the maximum plasma concentration was achieved within a median of 3 hoursfor niraparib, and a median of 1.5 hours for abiraterone.

In a relative bioavailability study, the maximum (Cmax) and total (AUC0-72h) exposure of abiraterone inmCRPC patients (n=67) treated with Akeega lower strength film-coated tablets (2 x 50 mg/500 mg)was 33% and 22% higher, respectively, when compared to exposures in patients (n=67) takingindividual single agents (100 mg niraparib capsule and 4 x 250 mg abiraterone acetate tablets) (seesection 4.2). The inter-subject variability (%CV) in exposures were 80.4% and 72.9%, respectively.

Niraparib exposure was comparable between Akeega lower strength film-coated tablets and singleagents.

Niraparib

The absolute bioavailability of niraparib is approximately 73%. Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its highpermeability and bioavailability, the risk of clinically relevant interactions with medicinal productsthat inhibit these transporters is unlikely.

Abiraterone acetate

Abiraterone acetate is rapidly converted in vivo to abiraterone (see section 5.1).

Administration of abiraterone acetate with food, compared with administration in a fasted state, resultsin up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone,depending on the fat content of the meal. Given the normal variation in the content and composition ofmeals, taking abiraterone acetate with meals has the potential to result in highly variable exposures.

Therefore, abiraterone acetate must not be taken with food.

Based on population pharmacokinetic analysis, the apparent volume of distribution of niraparib andabiraterone were 1 117 L and 25 774 L, respectively, indicative of extensive extravascular distribution.

Niraparib

Niraparib was moderately protein-bound in human plasma (83.0%), mainly with serum albumin.

Abiraterone acetate

The plasma protein binding of 14C-abiraterone in human plasma is 99.8%.

Niraparib

Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite,

M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the majorcirculating metabolites. The potential to inhibit CYP3A4 at the intestinal level has not beenestablished at relevant niraparib concentrations. Niraparib weakly induces CYP1A2 at highconcentrations in vitro.

Abiraterone acetate

Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysedby CEs to abiraterone, which then undergoes metabolism including sulphation, hydroxylation andoxidation primarily in the liver. Abiraterone is a substrate of CYP3A4 and sulfotransferase 2A1(SULT2A1). The majority of circulating radioactivity (approximately 92%) is found in the form ofmetabolites of abiraterone. Of 15 detectable metabolites, two main metabolites, abiraterone sulphateand N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.

Abiraterone is an inhibitor of the hepatic drug metabolising enzymes CYP2D6 and CYP2C8 (seesection 4.5).

Akeega

The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and20 hours, respectively, and apparent CL/F of niraparib and abiraterone were 16.7 L/h and 1673 L/h,respectively based on the population pharmacokinetic analysis in subjects with mCRPC.

Niraparib

Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oraladministration of a single 300 mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) ofthe dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accountedfor 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47.0%) of the dose. Inpooled samples collected over six days, 40.0% of the dose was recovered in the urine primarily asmetabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib. Themetabolite M1 is a substrate of Multidrug And Toxin Extrusion (MATE) 1 and 2.

Abiraterone acetate

Following oral administration of 14C-abiraterone acetate 1 000 mg, approximately 88% of theradioactive dose is recovered in faeces and approximately 5% in urine. The major compounds presentin faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of theadministered dose, respectively).

Effects of niraparib or abiraterone on transporters

Niraparib inhibits P-gp weakly with an IC50=161 μM. Niraparib is an inhibitor of BCRP, Organic

Cation Transporter 1 (OCT1), MATE-1 and 2 with IC50 values of 5.8 μM, 34.4 μM, 0.18 μM and≤ 0.14 μM, respectively. The major metabolites of abiraterone, abiraterone sulphate and N-oxideabiraterone sulphate, were shown to inhibit the hepatic uptake transporter Organic Anion Transport

Polypeptide 1B1 (OATP1B1) and as a consequence, the plasma exposures of medicinal productseliminated by OATP1B1 may increase. There are no clinical data available to confirm transporter

OATP1B1 based interaction.

Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancerpatients received niraparib alone or niraparib/AA in combination, mild hepatic impairment (NCI-

ODWG criteria, n=231) did not affect the exposure of niraparib.

In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepaticimpairment, niraparib AUCinf in patients with moderate hepatic impairment (n=8) was 1.56 (90%

CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) followingadministration of a single 300 mg dose.

The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n=8) ormoderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy controlsubjects. Systemic exposure to abiraterone after a single oral 1 000 mg dose increased byapproximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre-existing hepaticimpairment, respectively.

In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existingsevere (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normalhepatic function. The AUC of abiraterone increased by approximately 7-fold and the fraction of freedrug increased by 1.8-fold in subjects with severe hepatic impairment compared to subjects withnormal hepatic function. There is no clinical experience using Akeega in patients with moderate andsevere hepatic impairment (see section 4.2).

Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancerpatients received niraparib alone or niraparib/AA in combination, patients with mild (creatinineclearance 60-90 mL/min, n=337) and moderate (creatinine clearance 30-60 mL/min, n=114) renalimpairment had mildly reduced niraparib clearance compared to individuals with normal renalfunction (up to 13% higher exposure in mild and 13-40% higher exposure in moderate renalimpairment).

The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stablehaemodialysis schedule (n=8) versus matched control subjects with normal renal function (n=8).

Systemic exposure to abiraterone after a single oral 1 000 mg dose did not increase in subjects withend-stage renal disease on dialysis. There is no clinical experience using Akeega in patients withsevere renal impairment (see section 4.2).

Weight, age and race

Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancerpatients received niraparib or abiraterone acetate alone or in combination:

- Body weight did not have a clinically meaningful influence on the exposure of niraparib (bodyweight range: 43.3-165 kg) and abiraterone (body weight range: 56.0-135 kg).

- Age had no significant impact on the pharmacokinetics of niraparib (age range 45-90 years) andabiraterone (age range 19-85 years).

- There is insufficient data to conclude on the impact of race on the pharmacokinetics of nirapariband abiraterone.

No studies have been conducted to investigate the pharmacokinetics of Akeega in paediatric patients.

Akeega

Non-clinical studies with Akeega have not been performed. The nonclinical toxicology data are basedon findings in studies with niraparib and abiraterone acetate individually.

Niraparib

In vitro, niraparib inhibited the dopamine transporter at concentration levels below human exposurelevels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites incortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinicalrelevance of these findings is not known. No effect on behavioural and/or neurological parametershave been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levelssimilar to or below expected therapeutic exposure levels.

Decreased spermatogenesis was observed in both rats and dogs at exposure levels below therapeuticexposure levels and were largely reversible within four weeks of cessation of dosing.

Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but was clastogenic inan in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleusassay. This clastogenicity is consistent with genomic instability resulting from the primarypharmacology of niraparib and indicates potential for genotoxicity in humans.

Reproductive and developmental toxicity studies have not been conducted with niraparib.

Carcinogenicity studies have not been conducted with niraparib.

Abiraterone acetate

In animal toxicity studies, circulating testosterone levels were significantly reduced. As a result,reduction in organ weights and morphological and/or histopathological changes in the reproductiveorgans, and the adrenal, pituitary and mammary glands were observed. All changes showed completeor partial reversibility. The changes in the reproductive organs and androgen-sensitive organs areconsistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed orwere shown to be resolving after a 4-week recovery period.

In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which wascompletely reversible in four to 16 weeks after abiraterone acetate was stopped.

In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reducedfoetal weight and survival. Effects on the external genitalia were observed though abiraterone acetatewas not teratogenic.

In these fertility and developmental toxicity studies performed in the rat, all effects were related to thepharmacological activity of abiraterone.

Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data revealno special hazard for humans based on conventional studies of safety pharmacology, repeated dosetoxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a6-month study in the transgenic (Tg.rasH2) mouse. In a 24-month carcinogenicity study in the rat,abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding isconsidered related to the pharmacological action of abiraterone and rat-specific. Abiraterone acetatewas not carcinogenic in female rats.

The active substance, abiraterone, shows an environmental risk for the aquatic environment, especiallyto fish (see section 6.6).

Akeega 50 mg/500 mg film-coated tablets

Colloidal anhydrous silica

Crospovidone

Hypromellose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Sodium lauryl sulfate

Iron oxide black (E172)

Iron oxide red (E172)

Iron oxide yellow (E172)

Sodium lauryl sulphate

Glycerol monocaprylocaprate

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Akeega 100 mg/500 mg film-coated tablets

Colloidal anhydrous silica

Crospovidone

Hypromellose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Sodium lauryl sulfate

Iron oxide red (E172)

Iron oxide yellow (E172)

Sodium lauryl sulphate

Glycerol monocaprylocaprate

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Not applicable.

30 months.

This medicinal product does not require any special storage conditions.

Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs each containing28 film-coated tablets in a PVdC/PE/PVC blister with an aluminium push-through foil.

Based on its mechanism of action, this medicinal product may harm a developing foetus. Therefore,women who are or may become pregnant should handle Akeega with protection, e.g., gloves (seesection 4.6).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. This medicinal product may pose a risk to the aquatic environment (see section 5.3).

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/23/1722/001

EU/1/23/1722/002

Date of first authorisation: 19 April 2023

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.