AKEEGA SMPC 2023

ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
Akeega 50 mg/500 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Each film-coated tablet contains niraparib tosylate monohydrate equivalent to 100 mg of niraparib and
500 mg of abiraterone acetate equivalent to 446 mg of abiraterone.
Excipients with known effect

Each film-coated tablet contains 241 mg of lactose (see section 4.4)
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet).

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

Orange, oval, film-coated tablets (22 mm x 11 mm), debossed with “N 100 A” on one side, and plain
on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Akeega is indicated with prednisone or prednisolone for the treatment of adult patients with metastatic
castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in
whom chemotherapy is not clinically indicated.
4.2 Posology and method of administration
Treatment with niraparib and abiraterone acetate plus prednisone or prednisolone should be initiated
and supervised by specialist physicians experienced in the medical treatment of prostate cancer.
Before initiation of Akeega therapy, positive BRCA status must be established using a validated test
method (see section 5.1).
Posology
The recommended starting dose of Akeega is 200 mg/1 000 mg (two 100 mg niraparib/500 mg
abiraterone 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.
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Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continued
during treatment in patients not surgically castrated.
Dosage of prednisone or prednisolone

Akeega is used with 10 mg prednisone or prednisolone daily.
Duration of treatment
Patients should be treated until disease progression or unacceptable toxicity.
Missed dose
If a dose of either Akeega, prednisone or prednisolone is missed, it should be taken as soon as possible
on the same day with a return to the normal schedule the following day. Extra tablets must not be
taken 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 be
interrupted 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 Akeega
should be interrupted rather than discontinued and supportive management considered. Akeega should
be permanently discontinued if haematological toxicity has not returned to acceptable levels within
28 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 weekly
monitoring for 28 days after restarting dose.
Grade ≥ 3 Withhold Akeega and monitor at least weekly until platelets and neutrophils
recover to Grade 1 or baseline.1 Then resume Akeega or, if warranted, use two
lower strength tablets (50 mg/500 mg).
Weekly monitoring of blood counts is recommended for 28 days after restarting

dose or starting the lower strength dose (two 50 mg/500 mg tablets). When
starting 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 neutrophils
occurrence 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 with

lower strength Akeega. When starting the lower strength dose (two 50
mg/500 mg tablets), please refer to “Recommended monitoring” below for
further 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 3
3
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During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by the
physician 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 and
neutropenia is improved to Grade 1 or resolved to baseline. Treatment may resume at a lower strength
of 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 until
recovered to Grade ≤2. Dose reduction (two 50 mg/500 mg tablets) should be considered if anaemia
persists 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 least
weekly until recovered to Grade ≤ 2. Dose reduction [two lower strength
tablets (50 mg/500 mg)] should be considered if anaemia persists based on
clinical judgment. When starting the lower strength dose, please refer to
“Recommended monitoring” below for further information regarding liver
function.
Second Withhold Akeega, provide supportive management and monitor at least weekly
occurrence 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 with
lower strength Akeega. When starting the lower strength dose, please refer to
“Recommended monitoring” below for further information regarding liver
function.
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 3
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During Akeega treatment interruption, abiraterone acetate and prednisone or prednisolone may be considered by the
physician and given to maintain daily dose of abiraterone acetate (see abiraterone acetate prescribing information).
Hepatotoxicity
For patients who develop ≥ Grade 3 hepatotoxicity (alanine aminotransferase [ALT] increases or
aspartate 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 a
reduced dose level of one regular strength Akeega tablet (equivalent to 100 mg niraparib/500 mg
abiraterone acetate). For patients being re-treated, serum transaminases should be monitored at a
minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the
reduced 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, treatment
should be permanently discontinued.
Permanently discontinue Akeega for patients who develop a concurrent elevation of ALT greater than
3  ULN, and total bilirubin greater than 2  ULN, in the absence of biliary obstruction or other
causes responsible for the concurrent elevation (see section 4.4).
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Recommended monitoring
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 then
every other month for the remainder of treatment to monitor for clinically significant changes in any
haematologic parameter (see section 4.4).
Serum aminotransferases and total bilirubin should be measured prior to starting treatment, every two
weeks for the first three months of treatment and monthly thereafter for the first year and then every
other month for the duration of treatment. When starting the lower strength dose (two tablets) after
dose interruption, liver function should be monitored every two weeks for six weeks due to risk of
increased abiraterone exposure (see section 5.2), before resuming regular monitoring. Serum
potassium should be monitored monthly for the first year and then every other month for the duration
of treatment (see section 4.4).
Blood pressure monitoring should occur weekly for the first two months, monthly for the first year and
then every other month for the duration of treatment.
In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated
with Akeega, consider maintaining the patient’s potassium level at ≥ 4.0 mM.
Special populations
Elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Hepatic impairment
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 when
administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No
dose adjustment can be predicted. The use of Akeega should be cautiously assessed in patients with
moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see
sections 4.4 and 5.2). Akeega is contraindicated in patients with severe hepatic impairment (see
sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is necessary for patients with mild to moderate renal impairment, although close
monitoring of safety events should be conducted with moderate renal impairment due to the potential
for increased niraparib exposure. There are no data on the use of Akeega in patients with severe renal
impairment or end stage renal disease undergoing haemodialysis, Akeega may only be used in patients
with severe renal impairment if the benefit outweighs the potential risk, and the patient should be
carefully monitored for renal function and adverse events (see sections 4.4 and 5.2).
Paediatric population
There is no relevant use of Akeega in the paediatric population.
Method of administration
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 tablets
must be swallowed whole with water, they must not be broken, crushed, or chewed.
Precaution to be taken before manipulating or administering the product

Women who are or may become pregnant should wear gloves when handling the tablets (see section
6.6).
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
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Women who are or may become pregnant (see section 4.6).
Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, 4.4 and 5.2)].
Akeega plus prednisone or prednisolone is contraindicated in combination with Ra-223 treatment.
4.4 Special warnings and precautions for use
Haematological adverse reactions

Haematological adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in
patients 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 of
treatment is recommended to monitor for clinically significant changes in any haematological
parameter 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 not
resolve within 28 days following interruption, Akeega should be discontinued.
Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts should
be used with caution in patients taking Akeega (see section 4.8).
When starting the lower strength dose (two tablets) after dose interruption due to haematological
adverse reactions, liver function should be monitored every two weeks for six weeks due to risk of
increased abiraterone exposure (see section 5.2), before resuming regular monitoring (see section 4.2).
Hypertension
Akeega may cause hypertension and pre-existing hypertension should be adequately controlled before
starting 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 increased
mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a
corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in
incidence and severity of these adverse reactions. Caution is required in treating patients whose
underlying medical conditions might be compromised by hypokalaemia (e.g., those on cardiac
glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent
myocardial infarction or ventricular arrhythmia and those with severe renal impairment). QT
prolongation has been observed in patients experiencing hypokalaemia in association with Akeega
treatment. 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 cardiac
failure, or cardiac events such as ischaemic heart disease), cardiac failure should be treated and cardiac
function optimised. Fluid retention (weight gain, peripheral oedema), and other signs and symptoms of
congestive heart failure should be monitored every two weeks for three months, then monthly
thereafter and abnormalities corrected. Akeega should be used with caution in patients with a history
of cardiovascular disease.
Management of cardiac risk factors (including hypertension, dyslipidaemia, and diabetes) should be
optimised in patients receiving Akeega and these patients should be monitored for signs and symptoms
of cardiac disease.
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Abiraterone acetate, a component of Akeega, increases mineralocorticoid levels and carries a risk for
cardiovascular events. Mineralocorticoid excess may cause hypertension, hypokalaemia, and fluid
retention. Previous androgen deprivation therapy (ADT) exposure as well as advanced age are
additional risks for cardiovascular morbidity and mortality. The MAGNITUDE study excluded
patients with clinically significant heart disease as evidenced by myocardial infarction, arterial and
venous thrombotic events in the past six months, severe or unstable angina, or NYHA Class II to IV
heart failure or cardiac ejection fraction measurement of < 50%. Patients with a history of cardiac
failure should be clinically optimised and appropriate management of symptoms instituted. If there is a
clinically significant decrease in cardiac function, discontinuation of Akeega should be considered.
Infections
In MAGNITUDE, severe infections including COVID-19 infections with fatal outcome occurred more
frequently in patients treated with Akeega. Patients should be monitored for signs and symptoms of
infection. 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 frequency
compared to control. Patients with a prior history of PE or venous thrombosis may be more at risk of a
further occurrence. Patients should be monitored for clinical signs and symptoms of PE. If clinical
features 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 symptoms
including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or
without 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 a
monotherapy in the ovarian cancer population. In the MAGNITUDE study, among prostate cancer
patients 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 medical
management should be instituted.
Hepatotoxicity and hepatic impairment

Hepatotoxicity had been recognised as an important identified risk for abiraterone acetate, a
component of Akeega. The mechanism for hepatotoxicity of abiraterone acetate is not fully
understood. Patients with moderate and severe hepatic impairment (NCI classification) and patients
with 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 was
mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function
tests (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 in

clinical studies, although these were uncommon (see section 4.8). Serum aminotransferase and total
bilirubin levels should be measured prior to starting treatment, every two weeks for the first
three months of treatment, and monthly thereafter. When starting the lower strength dose (two tablets)
after dose interruption, liver function should be monitored every two weeks for six weeks due to risk
of increased abiraterone exposure (see section 5.2), before resuming regular monitoring. If clinical
symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured
immediately. Development of elevated aminotransferases in patients treated with Akeega should be
promptly managed 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
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may take 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 concurrent
elevation of ALT > 3  ULN and a total bilirubin > 2  ULN in the absence of biliary obstruction or
other 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 are
no 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 been
shown to increase the systemic exposure to abiraterone and niraparib (see section 5.2). There are no
data on the clinical safety and efficacy of multiple doses of Akeega when administered to patients with
moderate or severe hepatic impairment. The use of Akeega should be cautiously assessed in patients
with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see
sections 4.2 and 5.2). Akeega should not be used in patients with severe hepatic impairment (see
sections 4.2, 4.3 and 5.2).
Hypoglycaemia
Cases of hypoglycaemia have been reported when abiraterone acetate (a component of Akeega) plus
prednisone or prednisolone was administered to patients with pre-existing diabetes receiving
pioglitazone 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 among
patients who received 300 mg of niraparib (a component of Akeega).
No cases of MDS/AML have been observed in patients treated with 200 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 treatment
interruption 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, and
the patient should be treated appropriately.
Corticosteroid withdrawal and coverage of stress situations

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are
withdrawn from prednisone or prednisolone. If Akeega is continued after corticosteroids are
withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information
above).
In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of
corticosteroids may be indicated before, during and after the stressful situation.
Bone density
Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of
abiraterone acetate (a component of Akeega) in combination with a glucocorticoid could increase this
effect.
Increased fractures and mortality in combination with Radium (Ra) 223 Dichloride
Treatment with Akeega plus prednisone or prednisolone in combination with Ra-223 treatment is
contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased
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mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical
studies with abiraterone acetate, a component of Akeega.
It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after
the last administration of Akeega in combination with prednisone or prednisolone.
Hyperglycaemia
The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured
frequently in patients with diabetes.
Skeletal muscle effects

Cases of myopathy and rhabdomyolysis have not been seen in patients treated with Akeega. In
abiraterone acetate (a component of Akeega) monotherapy studies, most cases developed within the
first six months of treatment and recovered after abiraterone acetate withdrawal. Caution is
recommended in patients concomitantly treated with medicinal products known to be associated with
myopathy/rhabdomyolysis.
Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic
alternative, 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 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 dose, that is to say essentially
‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions
No clinical study evaluating drug interactions has been performed using Akeega. Interactions that have
been 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 abiraterone
acetate 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’s
wort [Hypericum perforatum]) during treatment with Akeega should be avoided unless there is no
therapeutic 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

CYP2D6 substrates
Abiraterone is an inhibitor of CYP2D6. In a clinical study to determine the effects of abiraterone
acetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, the
systemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC24 for
dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%. Dose
reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6
should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol,
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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 of
pioglitazone, a CYP2C8 substrate, was increased by 46% and the AUCs for M-III and M-IV, the
active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with
a single dose of 1 000 mg abiraterone acetate. Patients should be monitored for signs of toxicity
related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Akeega
because of the abiraterone acetate component. Examples of medicinal products metabolised by
CYP2C8 include pioglitazone and repaglinide (see section 4.4).
Pharmacodynamic interactions
Akeega with vaccines or immunosuppressant agents has not been studied.
The data on niraparib, in combination with cytotoxic medicinal products, are limited. Caution should
be taken if Akeega is used in combination with live or live-attenuated vaccines, immunosuppressant
agents or with other cytotoxic medicinal products.
Use with products known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when
administering Akeega with medicinal products known to prolong the QT interval or medicinal
products 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.
Use with spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels.
Use with Akeega is not recommended (see section 5.1).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females

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 required
along with another effective contraceptive method.
Studies in animals have shown reproductive toxicity (see section 5.3).
Pregnancy
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 foetal
harm based on the mechanism of action of both components and findings from animal studies with
abiraterone acetate. Animal developmental and reproductive toxicology studies were not conducted
with niraparib (see section 5.3).
Breast-feeding
Akeega is not for use in women.
Fertility
There are no clinical data on fertility with Akeega. In animal studies, male fertility was reduced with
niraparib or abiraterone acetate but these effects were reversible following treatment cessation (see
section 5.3).
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4.7 Effects on ability to drive and use machines
Akeega has moderate influence on the ability to drive or use machines. Patients who take Akeega may
experience asthenia, fatigue, dizziness or difficulties concentrating. Patients should use caution when
driving or using machines.
4.8 Undesirable effects
Summary of the safety profile

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 all
grades occurring in >10% in the niraparib plus AAP arm were anaemia (50.0%), hypertension
(33.0%), constipation (33.0%), fatigue (29.7%), nausea (24.5%), thrombocytopenia (23.1%), dyspnoea
(17.9%), back pain (17.0%), decreased appetite (15.6%), neutropenia (15.1%), arthralgia (15.1%),
vomiting (14.6%), hypokalaemia (13.7%), dizziness (12.7%), insomnia (11.3%), hyperglycaemia
(11.8%) and urinary tract infection (10.4%). The most frequently observed Grade 3-4 adverse
reactions were anaemia (30.2%), hypertension (15.6%), thrombocytopenia (7.5%), neutropenia (6.6%)
and blood alkaline phosphatase increased (5.7%).
Tabulated list of adverse reactions

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency
categories 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 infestations very common urinary tract infection
common pneumoniae, bronchitis, nasopharyngitis
uncommon urosepsis, conjunctivitis
Blood and lymphatic system very common anaemia, thrombocytopenia, neutropenia,
disorders leukopenia
common lymphopenia
not known pancytopenia7
Immune system disorders not known hypersensitivity (including anaphylaxis)7
Metabolism and nutrition very common decreased appetite, hypokalaemia
disorders common hypertriglyceridaemia
Psychiatric disorders very common insomnia
common depression, anxiety
uncommon confusional state, cognitive impairment8
Nervous system disorders very common dizziness
common headache
uncommon dysgeusia
not known posterior reversible encephalopathy syndrome
(PRES)7
Cardiac disorders common tachycardia, palpitations, atrial fibrillation, cardiac
failure1, myocardial infarction
uncommon angina pectoris2, QT prolongation
Vascular disorders very common hypertension
not known hypertensive crisis7
Endocrine disorders not known adrenal insufficiency9
Respiratory, thoracic and very common dyspnoea
mediastinal disorders common cough, pulmonary embolism, pneumonitis
uncommon epistaxis
not known allergic alveolitis9
Gastrointestinal disorders very common constipation, nausea, vomiting
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Table 3: Adverse reactions identified in clinical studies
System Organ Class Frequency Adverse reaction
common abdominal pain3, dyspepsia, diarrhoea, abdominal
distention, stomatitis, dry mouth
uncommon mucosal inflammation
Hepatobiliary disorders common hepatitis4
uncommon acute hepatic failure
Skin and subcutaneous tissue common rash5
disorders uncommon photosensitivity
Musculoskeletal and connective very common back pain, arthralgia
tissue disorders common myalgia
not known myopathy9, rhabdomyolysis9
Renal and urinary disorders common haematuria
General disorders and very common fatigue, asthenia
administration site conditions common oedema peripheral
Investigations very common blood alkaline phosphatase increased, weight
decreased
common blood creatinine increased, AST increased, ALT
increased
uncommon gamma-glutamyl transferase increased
Injury, poisoning and procedural very common fractures6
complications
1
Includes cardiac failure congestive, cor pulmonale, left ventricular dysfunction
2
Includes coronary artery disease, acute coronary syndrome
3
Includes abdominal pain upper
4
Includes hepatitis acute, fulminant, hepatic cytolysis, hepatotoxicity
5
Includes rash, erythema, dermatitis, rash maculo-papular, rash pruritic
6
Includes osteoporosis and osteoporosis-related fractures
7
Not observed with Akeega. Reported in post-marketing experience with niraparib monotherapy
8
Not observed with Akeega. Reported with niraparib monotherapy
9
Not observed with Akeega. Reported in post-marketing experience with abiraterone monotherapy
Description of selected adverse reactions

Haematological toxicities
Haematological toxicities (anaemia, thrombocytopenia and neutropenia) including laboratory findings
are the most frequent adverse reactions attributable to niraparib (a component of Akeega). These
toxicities generally occurred within the first two months of treatment with the incidence decreasing
over time.
In the MAGNITUDE study and other Akeega studies, the following haematological parameters were
inclusion criteria: absolute neutrophil count (ANC) ≥ 1 500 cells/μL; platelets ≥ 100 000 cells/μL and
haemoglobin ≥ 9 g/dL. Haematological adverse reactions were managed with laboratory monitoring
and dose modifications (see sections 4.2 and 4.4).
Anaemia
Anaemia was the most frequent adverse reaction (50.0%) and most commonly observed Grade 3-4
event (30.2%) in the MAGNITUDE study. Anaemia occurred early during the course of therapy
(median time to onset of 59 days). In the MAGNITUDE study, dose interruptions occurred in 22.6%
and dose reductions in 13.7% of patients. Twenty-seven percent of patients received at least one
anaemia-related transfusion. Anaemia caused discontinuation in a relatively small number of patients
(2.4%).
Thrombocytopenia
In the MAGNITUDE study, 23.1% of treated patients reported thrombocytopenia while 7.5% of
patients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was
56 days. In the MAGNITUDE study, thrombocytopenia was managed with dose modification
(interruption 10.8% and reduction in 2.8%) and platelet transfusion (2.4%) where appropriate (see
12
section 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.4% of
patients experienced a nonlife-threatening bleeding event.
Neutropenia
In the MAGNITUDE study, 15.1% of patients experienced neutropenia with Grade 3-4 neutropenia
reported in 6.6% of patients. Median time from first dose to first report of neutropenia was 54 days.
Neutropenia led to treatment interruption in 6.6% of patients and dose reduction in 1.4%. There were
no treatment discontinuations due to neutropenia. In the MAGNITUDE study, 0.9% of patients had a
concurrent infection.
Hypertension
Hypertension is an adverse reaction for both components of Akeega and patients with uncontrolled
hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg) were
excluded in all combination studies. Hypertension was reported in 33% of patients of whom 15.6%
had Grade ≥ 3. The median time to onset of hypertension was 60.5 days. Hypertension was managed
with adjunctive medicinal products.
Patients should have blood pressure controlled before initiating Akeega and blood pressure should be
monitored on treatment (see section 4.4).
Cardiac events
In the MAGNITUDE study, the incidence of TEAEs of cardiac disorder (all grades) was similar in
both arms, except for the arrhythmia category, where AEs were observed in 13.7% of patients in the
niraparib plus AAP arm and 7.6% of patients in the placebo plus AAP arm (see section 4.4). Higher
frequency of arrhythmias was largely due to low grade events of palpitations, tachycardias and atrial
arrhythmias.
The median time to onset of the events of arrhythmias was 105 days in the niraparib plus AAP arm
and 262 days in the placebo plus AAP arm. Events of arrhythmia were resolved in 62% of patients in
the niraparib plus AAP arm and 63% of subjects in the placebo plus AAP arm.
The incidence of cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure
congestive was 2.4% in the niraparib plus AAP arm vs 1.9% in placebo plus AAP arm. The median
time to onset of the AESI of cardiac failure was 206 days in the niraparib plus AAP arm and 83 days
in the placebo plus AAP arm. Events of cardiac failure were resolved in 20% of patients the niraparib
plus AAP arm and 25% of patients in the placebo plus AAP arm.
The grouped term of ischemic heart disease (included preferred terms of angina pectoris, acute
myocardial infarction, acute coronary syndrome, unstable angina, and arteriosclerosis coronary artery)
occurred in 4.2% of the niraparib plus AAP arm vs 4.3% in the placebo plus AAP arm. The median
time to onset of the AESI of ischemic heart disease was 538 days in the niraparib plus AAP arm and
257 days in the placebo plus AAP arm. Events of ischemic heart disease were resolved in 78% of
patients in both arms.
Hepatotoxicity
The overall incidence of hepatotoxicity in the MAGNITUDE study was similar for the niraparib plus
AAP (12.7%) and placebo plus AAP (12.8%) arms (see sections 4.2 and 4.4). The majority of these
events were low grade aminotransferase elevations. Grade 3 events occurred in 1.4% of patients and a
Grade 4 event occurred in only one patient (0.5%). The incidence of SAEs was also 0.9%. The median
time to onset of hepatotoxicity in the MAGNITUDE study was 34 days. Hepatotoxicity was managed
with dose interruptions in 0.9% and dose reduction in 0.5% of patients. In the MAGNITUDE study,
0.5% of patients discontinued treatment due to hepatotoxicity.
No studies have been conducted in paediatric patients with Akeega.
13
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 national reporting system
listed in Appendix V.
4.9 Overdose
There is no specific treatment in the event of Akeega overdose. In the event of an overdose, physicians
should follow general supportive measures and should treat patients symptomatically, including
monitoring for arrhythmias, hypokalaemia and signs and symptoms of fluid retention. Liver function
also should be assessed.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK
Mechanism of action
Akeega is a combination of niraparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and
abiraterone acetate (a prodrug of abiraterone), a CYP17 inhibitor targeting two oncogenic
dependencies 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 may
involve 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). This
enzyme is expressed in, and is required for, androgen biosynthesis in testicular, adrenal and prostatic
tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone
precursors, 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 affect
androgen production by the adrenals or in the tumour. Treatment with abiraterone decreases serum
testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or
orchiectomy).
Pharmacodynamic effects
Abiraterone acetate
Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by
the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the
CYP17 enzyme required for androgen biosynthesis.
Clinical efficacy and safety

First-line treatment of mCRPC patients with BRCA 1/2 mutations
The efficacy of Akeega was established in a randomised placebo-controlled multicentre Phase 3
clinical study of patients with mCRPC, MAGNITUDE (Study 64091742PCR3001).
14
MAGNITUDE was a Phase 3, randomised, double-blind, placebo-controlled, multicentre study that
evaluated 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 that
consisted of 423 patients with mCRPC and select HRR gene mutations, who were randomised (1:1) to
receive either niraparib plus AAP (N=212) or placebo plus AAP (N=211) orally daily. Treatment was
continued until disease progression, unacceptable toxicity, or death.
Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a
short duration of prior AAP (up to 4 months) and ongoing ADT, were eligible. Plasma, blood, and/or
tumour tissue samples for all patients were tested by validated next generation sequencing tests to
determine 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 patients
with a non-BRCA1/2 mutation (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) enrolled
in the study (99 received Akeega).
The primary endpoint was radiographic progression free survival (rPFS) as determined by blinded
independent 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 (bone
lesions). Time to symptomatic progression (TSP), time to cytotoxic chemotherapy (TCC), and overall
survival (OS) were included as secondary efficacy endpoints.
In the All HRR Population, the primary efficacy results with a median follow-up of 18.6 months
showed 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 0
or 1 at study entry. All patients who had not received prior orchiectomy continued background
androgen deprivation therapy with a GnRH analogue.
15
Table 4: Summary of demographics and baseline characteristics in the MAGNITUDE
study Cohort 1 (BRCA)
Total
N=225
n (%)
Age (years)
< 65 76 (33.8)
≥ 65-74 96 (42.7)
≥ 75 53 (23.6)
Median 68.0
Range 43-100
Race
Caucasian 162 (72.0)
Asian 38 (16.9)
Black 3 (1.3)
Unknown 22 (9.8)
Stratification factors
Past taxane-based chemotherapy exposure 55 (24.4)
Past AR-targeted therapy exposure 11 (4.9)
Prior AAP use 59 (26.2)
Baseline disease characteristics
Gleason score ≥ 8 155 (69.2)
Bone involvement 192 (85.3)
Visceral disease (liver, lung, adrenal gland, other) 48 (21.3)
Metastasis stage at initial diagnosis (M1) 120 (53.3)
Median time from initial diagnosis to randomization (years) 2.26
Median time from mCRPC to first dose (years) 0.27
BPI-SF pain score at baseline (last score before first dose)
0 114 (50.7)
1 to 3 91 (40.4)
>3 20 (8.9)
A statistically significant improvement in BICR-assessed rPFS was observed in the primary analysis
for BRCA subjects treated with niraparib plus AAP, compared with BRCA subjects treated with
placebo 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 Placebo
Endpoints (N=113) (N=112)
Radiographic Progression-free Survival1
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 Survival2
Hazard Ratio (95% CI) 0.881 (0.582, 1.335)
1
Primary analysis/Interim analysis (data cut-off: 08OCT2021), with 18.6 months median follow-up
2
Interim analysis 2 (data cut-off: 17JUN2022), with 26.8 months median follow-up
NE = Not estimable
16
Figure 1: Kaplan-Meier Plot of BICR assessed radiologic progression-free survival in the BRCA
population (MAGNITUDE, primary analysis)
The European Medicines Agency has waived the obligation to submit the results of studies with Akeega
in all subsets of the paediatric population in prostate malignant neoplasms. See section 4.2 for
information on paediatric use.
5.2 Pharmacokinetic properties
Co-administration of niraparib and abiraterone has no impact on the exposures of the individual
moeities. The AUC and Cmax are comparable for niraparib and abiraterone when administered as
Akeega regular strength (100 mg/500 mg) film-coated tablet or as combination of individual
components when compared to respective monotherapy exposures.
Absorption
Akeega
In mCRPC patients, under fasted and modified fasted conditions, upon administration of multiple
doses of Akeega tablets, the maximum plasma concentration was achieved within a median of 3 hours
for 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 in
mCRPC 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) taking
individual single agents (100 mg niraparib capsule and 4 x 250 mg abiraterone acetate tablets) (see
section 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 single
agents.
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 high
17
permeability and bioavailability, the risk of clinically relevant interactions with medicinal products
that 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, results
in 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 of
meals, taking abiraterone acetate with meals has the potential to result in highly variable exposures.
Therefore, abiraterone acetate must not be taken with food.
Distribution
Based on population pharmacokinetic analysis, the apparent volume of distribution of niraparib and
abiraterone 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%.
Biotransformation
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 major
circulating metabolites. The potential to inhibit CYP3A4 at the intestinal level has not been
established at relevant niraparib concentrations. Niraparib weakly induces CYP1A2 at high
concentrations in vitro.
Abiraterone acetate
Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed
by CEs to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and
oxidation 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 of
metabolites of abiraterone. Of 15 detectable metabolites, two main metabolites, abiraterone sulphate
and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
Abiraterone is an inhibitor of the hepatic drug metabolising enzymes CYP2D6 and CYP2C8 (see
section 4.5).
Elimination
Akeega
The mean t½ of niraparib and abiraterone when given in combination were approximately 62 hours and
20 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 oral
administration of a single 300 mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) of
the dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accounted
for 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47.0%) of the dose. In
pooled samples collected over six days, 40.0% of the dose was recovered in the urine primarily as
metabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib. The
metabolite M1 is a substrate of Multidrug And Toxin Extrusion (MATE) 1 and 2.
18
Abiraterone acetate
Following oral administration of 14C-abiraterone acetate 1 000 mg, approximately 88% of the
radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present
in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the
administered 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-oxide
abiraterone sulphate, were shown to inhibit the hepatic uptake transporter Organic Anion Transport
Polypeptide 1B1 (OATP1B1) and as a consequence, the plasma exposures of medicinal products
eliminated by OATP1B1 may increase. There are no clinical data available to confirm transporter
OATP1B1 based interaction.
Special populations
Hepatic impairment
Based on the population pharmacokinetic analysis of data from clinical studies where prostate cancer
patients 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 hepatic
impairment, 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) following
administration of a single 300 mg dose.
The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n = 8) or

moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy
control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by
approximately 1.11-fold and 3.6-fold in subjects with mild and moderate pre-existing hepatic
impairment, respectively.
In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existing
severe (n = 8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal
hepatic function. The AUC of abiraterone increased by approximately 7-fold and the fraction of free
drug increased by 1.8-fold in subjects with severe hepatic impairment compared to subjects with
normal hepatic function. There is no clinical experience using Akeega in patients with moderate and
severe hepatic impairment (see section 4.2).
Renal impairment
patients received niraparib alone or niraparib/AA in combination, patients with mild (creatinine
clearance 60-90 mL/min, n=337) and moderate (creatinine clearance 30-60 mL/min, n=114) renal
impairment had mildly reduced niraparib clearance compared to individuals with normal renal
function (up to 13% higher exposure in mild and 13-40% higher exposure in moderate renal
impairment).
The pharmacokinetics of abiraterone was compared in patients with end-stage renal disease on a stable
haemodialysis 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 with
end-stage renal disease on dialysis. There is no clinical experience using Akeega in patients with
severe renal impairment (see section 4.2).
19
Weight, age and race
patients received niraparib or abiraterone acetate alone or in combination:
 Body weight did not have a clinically meaningful influence on the exposure of niraparib (body
weight 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) and
abiraterone (age range 19-85 years).
 There is insufficient data to conclude on the impact of race on the pharmacokinetics of niraparib
and abiraterone.
No studies have been conducted to investigate the pharmacokinetics of Akeega in paediatric patients.
5.3 Preclinical safety data
Akeega
Non-clinical studies with Akeega have not been performed. The nonclinical toxicology data are based
on findings in studies with niraparib and abiraterone acetate individually.
Niraparib
In vitro, niraparib inhibited the dopamine transporter at concentration levels below human exposure
levels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in
cortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical
relevance of these findings is not known. No effect on behavioural and/or neurological parameters
have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levels
similar to or below expected therapeutic exposure levels.
Decreased spermatogenesis was observed in both rats and dogs at exposure levels below therapeutic
exposure 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 in
an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus
assay. This clastogenicity is consistent with genomic instability resulting from the primary
pharmacology 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 reproductive
organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete
or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are
consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or
were shown to be resolving after a 4-week recovery period.
In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was
completely reversible in four to 16 weeks after abiraterone acetate was stopped.
In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced
foetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate
was not teratogenic.
In these fertility and developmental toxicity studies performed in the rat, all effects were related to the
pharmacological activity of abiraterone.
20
Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal
no special hazard for humans based on conventional studies of safety pharmacology, repeated dose
toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a
6-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 is
considered related to the pharmacological action of abiraterone and rat-specific. Abiraterone acetate
was not carcinogenic in female rats.
Environmental risk assessment (ERA)

The active substance, abiraterone, shows an environmental risk for the aquatic environment, especially
to fish (see section 6.6).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients

Tablet core
Colloidal anhydrous silica
Crospovidone
Hypromellose
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Sodium lauryl sulfate
Film-coating
Iron oxide black (E172)
Iron oxide red (E172)
Iron oxide yellow (E172)
Sodium lauryl sulphate
Glycerol monocaprylocaprate
Polyvinyl alcohol
Talc
Titanium dioxide (E171)

Tablet core
Colloidal anhydrous silica
Crospovidone
Hypromellose
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Sodium lauryl sulfate
Film-coating
Iron oxide red (E172)
Iron oxide yellow (E172)
Sodium lauryl sulphate
Glycerol monocaprylocaprate
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
21
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs each containing 28
film-coated tablets in a PVdC/PE/PVC blister with an aluminum push-through foil.
6.6 Special precautions for disposal and other handling
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 (see
section 4.6).
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements. This medicinal product may pose a risk to the aquatic environment (see section 5.3).
7. MARKETING AUTHORISATION HOLDER
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/23/1722/001
EU/1/23/1722/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
22
ANNEX II
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE

SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE
FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT
23
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer(s) responsible for batch release
Janssen Cilag SpA

Via C. Janssen,
Borgo San Michele
Latina 04100
Italy
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION
 Periodic safety update reports (PSURs)
The requirements for submission of PSURs for this medicinal product are set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
and any subsequent updates published on the European medicines web-portal.
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within
six months following authorisation.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT
 Risk management plan (RMP)
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the
marketing authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:

 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.
 Obligation to conduct post-authorisation measures
The MAH shall complete, within the stated timeframe, the below measures:
Description Due date

Post-authorisation efficacy study (PAES): In order to further characterise the Q1 2024
efficacy of Akeega, to be used in combination with prednisone or prednisolone
for the treatment of adult patients with metastatic castration resistant prostate
cancer (mCRPC) and BRCA1/2 mutations (germline and/or somatic) in whom
chemotherapy is not clinically indicated, the MAH should submit the final overall
survival data and other long-term endpoints from the MAGNITUDE study.
24
ANNEX III
LABELLING AND PACKAGE LEAFLET
25
A. LABELLING
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON 50 mg/500 mg (28 days)

niraparib/abiraterone acetate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 50 mg niraparib and 500 mg abiraterone acetate.
3. LIST OF EXCIPIENTS
Contains lactose.
See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
56 film-coated tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Take Akeega at least two hours after eating. Do not eat any food for at least one hour after taking
Akeega.
Swallow the tablets whole. Do not break, crush, or chew tablets.
Read the package leaflet before use.
Oral use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Women who are or may become pregnant should handle Akeega with gloves.
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
27
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Discard unused contents appropriately in accordance with local requirements.
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/23/1722/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Akeega 50 mg/500 mg
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC
SN
NN
28
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
OUTER WALLET 50 mg/500 mg (28 days)

Akeega.
Oral use.
(1) Press and hold
(2) Pull out

29
8. EXPIRY DATE
EXP

APPROPRIATE
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/23/1722/001
13. BATCH NUMBER
Lot
Akeega 50 mg/500 mg
30
31
MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
INNER WALLET 50 mg/500 mg (28 days)

2. NAME OF THE MARKETING AUTHORISATION HOLDER
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Fold over to close
Flip open
32
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER 50 mg/500 mg (Blister sealed in inner wallet)

3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON 100 mg/500 mg (28 days)

Contains lactose.
See leaflet for further information.
Akeega.
Oral use.

8. EXPIRY DATE
EXP
34

APPROPRIATE
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/23/1722/002
13. BATCH NUMBER
Lot
Akeega 100 mg/500 mg
2D barcode carrying the unique identifier included.
PC
SN
NN
35
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
OUTER WALLET 100 mg/500 mg (28 days)

Akeega.
Oral use.
(1) Press and hold
(2) Pull out

36
8. EXPIRY DATE
EXP

APPROPRIATE
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/23/1722/002
13. BATCH NUMBER
Lot
Akeega 100 mg/500 mg
37
38
MINIMUM PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
INNER WALLET 100 mg/500 mg (28 days)

3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Fold over to close
Flip open
39
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER 100 mg/500 mg (Blister sealed in inner wallet)

3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
40
B. PACKAGE LEAFLET
41
Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor or pharmacist.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet (see section 4).
What is in this leaflet
1. What Akeega is and what it is used for

2. What you need to know before you take Akeega
3. How to take Akeega
4. Possible side effects
5. How to store Akeega
6. Contents of the pack and other information
Akeega is a medicine that contains two active substances: niraparib and abiraterone acetate, and works
in two different ways.
Akeega is used to treat adult men with prostate cancer who have changes in certain genes and whose
prostate cancer has spread to other parts of the body and no longer responds to medical or surgical
treatment that lowers testosterone (also called metastatic castration-resistant prostate cancer).
Niraparib is a type of cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme
called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged
DNA. When PARP is blocked, cancer cells cannot repair their DNA, resulting in tumour cell death
and helping to control the cancer.
Abiraterone stops your body from making testosterone; this can slow the growth of prostate cancer.
When you take this medicine, your doctor will also prescribe another medicine called prednisone or
prednisolone. This is to lower your chances of getting high blood pressure, having too much water in
your body (fluid retention), or having reduced levels of a chemical known as potassium in your blood.
Do not take Akeega:

 if you are allergic to niraparib or abiraterone acetate or any of the other ingredients of this
medicine - listed in section 6.
 if you are a woman who is or can become pregnant.
 if you have severe liver damage.
 in combination with Ra-223 treatment (which is used to treat prostate cancer). This is because
of a possible increase in the risk of bone fracture or death.
42
Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking this medicine.
Warnings and precautions

Talk to your doctor or pharmacist before or while taking this medicine if you have:
 low blood cell counts. Signs and symptoms you need to look out for include fatigue, fever or
infection, and abnormal bruising or bleeding. Akeega may also lower your blood cell counts.
Your doctor will test your blood regularly throughout your treatment.
 high blood pressure or heart failure or low blood potassium (low blood potassium may increase
the risk of heart rhythm problems), have had other heart or blood vessel problems, have an
irregular or rapid heart rate, shortness of breath, gained weight rapidly, or swelling in the feet,
ankles, or legs. Your doctor will measure your blood pressure regularly throughout your
treatment.
 headaches, vision changes, confusion, or seizure. These may be signs of a rare neurological side
effect named posterior reversible encephalopathy syndrome (PRES) that has been associated
with use of niraparib, an active ingredient of Akeega.
 high fever, fatigue and other signs and symptoms of severe infection.
 blood clots in the lungs, or have had them in the past.
 liver problems.
 low or high levels of sugar in the blood.
 muscle weakness and/or muscle pain.
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking
this medicine.
If you develop low blood-cell counts for a long period of time while taking Akeega, this may be a sign
of more serious problems with the bone marrow such as ‘myelodysplastic syndrome’ (MDS) or ‘acute
myeloid leukaemia’ (AML). Your doctor may want to test your bone marrow to check for these
problems.
Before taking Akeega, also talk to your doctor or pharmacist about:

 the effect Akeega may have on your bones.
 taking prednisone or prednisolone (another medicine you must take with Akeega)
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking this
medicine.
Blood monitoring
Akeega may affect your liver, but you may not notice any symptoms of liver problems. When you are
taking this medicine, your doctor will therefore check your blood periodically to look for any effects
on your liver.
Children and adolescents

This medicine is not for use in children and adolescents. If Akeega is accidentally swallowed by a
child or adolescent, take them to the hospital immediately and take this package leaflet with you to
show to the emergency doctor.
Other medicines and Akeega

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines. This is because Akeega can affect the way some other medicines work. Also, some other
medicines can affect the way Akeega works.
Treatment with medicines that stop the body from producing testosterone, may increase the risk of
heart rhythm problems. Tell your doctor if you are receiving medicine:
 to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol);
43
 known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and
part of drug addiction detoxification; moxifloxacin, an antibiotic; antipsychotics, used for
serious mental illnesses.
Tell your doctor if you are taking any of the medicines listed above.
Akeega with food

 This medicine must not be taken with food (see section 3, “Taking Akeega”), as this may
increase your risk of side effects.
Pregnancy and breast-feeding

 This medicine may cause harm to the unborn child if it is taken by women who are pregnant.
 Women who are pregnant or who may become pregnant should wear gloves if they need to
touch or handle Akeega.
Contraception for men using Akeega
 If you are having sex with a woman who can become pregnant, use a condom and another
effective birth control method. Use contraception during treatment and for 4 months after
stopping. Talk to your doctor if you have any questions about contraception.
 If you are having sex with a pregnant woman, use a condom to protect the unborn child.
Driving and using machines

Taking Akeega may make you feel weak, unfocused, tired or dizzy. This may influence your ability to
drive and use machines. Use caution when driving or using machines.
Akeega contains lactose and sodium

 Akeega contains lactose. If you have been told by your doctor that you have an intolerance to
some sugars, contact your doctor before taking this medicine.
 This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
How much to take

The recommended starting dose is 200 mg/1 000 mg once a day.
Taking Akeega
 Take this medicine by mouth.
 Do not take Akeega with food.
 Take Akeega tablets as a single dose once daily on an empty stomach at least one hour before
or at least two hours after eating (see section 2, “Akeega with food”).
 Swallow the tablets whole with water. Do not break, crush, or chew the tablets. This will ensure
the medicine works as well as possible.
 Akeega is taken with a medicine called prednisone or prednisolone.
o Take the prednisone or prednisolone exactly as your doctor has told you.
o You need to take prednisone or prednisolone every day while you are taking Akeega.
o The amount of prednisone or prednisolone you take may need to be changed if you have a
medical emergency. Your doctor will tell you if you need to change the amount of
prednisone or prednisolone you take. Do not stop taking prednisone or prednisolone
unless your doctor tells you to.
Your doctor may also prescribe other medicines while you are taking Akeega.
44
If you take more Akeega than you should
If you take more tablets than you should contact your doctor. You may have an increased risk of side
effects.
If you forget to take Akeega

If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you
remember on the same day.
If you forget to take Akeega or prednisone or prednisolone for more than one day - talk to your doctor
straight away.
Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
If you stop taking Akeega

Do not stop taking Akeega or prednisone or prednisolone unless your doctor tells you to.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects

Stop taking Akeega and seek medical attention immediately if you notice any of the following
symptoms:
Very common (may affect more than 1 in 10 people)

 Bruising or bleeding for longer than usual if you hurt yourself - these may be signs of a low
blood platelet count (thrombocytopenia).
 Being short of breath, feeling very tired, having pale skin, or fast heartbeat - these may be signs
of a low red blood cell count (anaemia).
 Fever or infection – low white blood cell count (neutropenia) can increase your risk for
infection. Signs may include fever, chills, feeling weak or confused, cough, pain or burning
feeling when passing urine. Some infections can be serious and may lead to death.
 Muscle weakness, muscle twitching or a pounding heart beat (palpitations). These may be signs
that the level of potassium in your blood is low (hypokalaemia).
 Increased level of the enzyme ‘alkaline phosphatase’ in the blood
Not known (cannot be estimated) – not reported with the use of Akeega but reported with use of
niraparib or abiraterone acetate (components of Akeega)
 Allergic reaction (including severe allergic reaction that can be life-threatening). Signs include:
raised and itchy rash (hives) and swelling-sometimes of the face or mouth (angioedema),
causing difficulty in breathing, and collapse or loss of consciousness.
 A sudden increase in blood pressure, which may be a medical emergency that could lead to
organ damage or can be life-threatening.
Other side effects

Talk to your doctor if you get any other side effects. These can include:
Very common (may affect more than 1 in 10 people):

 urinary tract infection
 low number of white blood cells (leukopenia), seen in blood tests
45
 decreased appetite
 difficulty sleeping (insomnia)
 feeling dizzy
 shortness of breath
 constipation
 feeling sick (nausea)
 vomiting
 back pain
 joint pain
 feeling very tired
 feeling weak
 weight loss
 bone fractures
Common (may affect up to 1 in 10 people):

 pneumoniae
 lung infection (bronchitis)
 infection of the nose and throat (nasopharyngitis)
 low number of a type of white blood cell (lymphopenia), seen in blood tests
 high level of a type of fat (hypertriglyceridemia) in the blood
 depression
 feeling anxious
 headache
 fast heart beat
 fast or uneven heart beat (palpitations)
 irregular heart beat (atrial fibrillation)
 heart failure, causing shortness of breath and swollen legs
 heart attack
 cough
 blood clot in the lungs, causing chest pain and shortness of breath
 inflamed lungs
 stomach pain
 indigestion
 diarrhoea
 bloating
 sores in the mouth
 dry mouth
 inflamed liver (hepatitis) based on blood tests
 skin rash
 muscle aches
 blood in the urine
 swollen hands, ankles, or feet
 increased level of ‘creatinine’ in the blood
 increased level of the enzyme ‘aspartate aminotransferase’ in the blood
 increased level of the enzyme ‘alanine aminotransferase’ in the blood
Uncommon (may affect up to 1 in 100 people):

 severe infection (sepsis) that spreads from the urinary tract throughout the body
 inflamed eye (conjunctivitis)
 feeling confused
 difficulty thinking, remembering information, or solving problems (cognitive impairment)
 change in sense of taste
 chest discomfort, often brought on by physical activity
 abnormal ECG (electrocardiogram), which could be a sign of heart problems
46
 nose bleeds
 inflammation of the protective linings in the body cavities, such as the nose, mouth, or digestive
system
 sudden liver failure
 increased sensitivity of the skin to sunlight
 increased level of ‘gamma-glutamyltransferase’ in the blood
 low numbers of all types of blood cells (pancytopenia)
 brain condition with symptoms including seizures (fits), headache, confusion, and changes in
vision (posterior reversible encephalopathy syndrome or PRES), which is a medical emergency
that could lead to organ damage or can be life-threatening
 adrenal gland problems (related to salt and water problems) where too little hormone is
produced which may cause problems like weakness, tiredness, loss of appetite, nausea,
dehydration and skin changes
 inflamed lungs caused by an allergic reaction (allergic alveolitis)
 muscle disease (myopathy), which may cause muscle weakness, stiffness or spasms
 breakdown of muscle tissue (rhabdomyolysis), which may cause muscle cramps or pains,
tiredness and dark urine
Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects, you can help provide more information on the safety
of this medicine.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the container (blister foil, inner
wallet, outer wallet, and carton) after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
What Akeega contains

 The active substances are niraparib and abiraterone acetate. Each film-coated tablet contains
50 mg niraparib and 500 mg abiraterone acetate.
 The other ingredients of the tablet core are colloidal anhydrous silica, crospovidone,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium
lauryl sulfate. The film-coating contains iron oxide black (E172), iron oxide red (E172), iron
oxide yellow (E172), sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol,
talc, and titanium dioxide (E171) (see section 2, Akeega contains lactose and sodium).
What Akeega looks like and contents of the pack

Akeega film-coated tablets are yellowish orange to yellowish brown oval tablet, debossed with “N 50
A” on one side and plain on the other side.
47
Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs of 28 film-coated
tablets each.
Marketing Authorisation Holder

Turnhoutseweg 30
B-2340 Beerse
Belgium
Manufacturer
Janssen Cilag SpA
Via C. Janssen,
Borgo San Michele
Latina 04100
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB "JOHNSON & JOHNSON"
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
[email protected] [email protected]
България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
Česká republika Magyarország

Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]
Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf: +45 4594 8282 Tel: +356 2397 6000
[email protected]
Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: +49 2137 955 955 Tel: +31 76 711 1111
Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε. Janssen-Cilag Pharma GmbH
Tηλ: +30 210 80 90 000 Tel: +43 1 610 300
48
España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]
France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]
Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]
Ireland Slovenija
Janssen Sciences Ireland UC Johnson & Johnson d.o.o.
Tel: 1 800 709 122 Tel: +386 1 401 18 00
Ísland Slovenská republika

Janssen-Cilag AB Johnson & Johnson, s.r.o.
c/o Vistor hf. Tel: +421 232 408 400
Sími: +354 535 7000
[email protected]
Italia Suomi/Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
Κύπρος Sverige
Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB
Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]
Latvija United Kingdom (Northern Ireland)

UAB "JOHNSON & JOHNSON" filiāle Latvijā Janssen Sciences Ireland UC
Tel: +371 678 93561 Tel: +44 1 494 567 444
This leaflet was last revised in MM/YYYY.
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
49
Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor or pharmacist.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet (see section 4).
What is in this leaflet

Akeega is a medicine that contains two active substances: niraparib and abiraterone acetate, and works
in two different ways.
Akeega is used to treat adult men with prostate cancer who have changes in certain genes and whose
prostate cancer has spread to other parts of the body and no longer responds to medical or surgical
treatment that lowers testosterone (also called metastatic castration-resistant prostate cancer).
Niraparib is a type of cancer medicine called a PARP inhibitor. PARP inhibitors block an enzyme
called poly [adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged
DNA. When PARP is blocked, cancer cells cannot repair their DNA, resulting in tumour cell death
and helping to control the cancer.
Abiraterone stops your body from making testosterone; this can slow the growth of prostate cancer.
When you take this medicine, your doctor will also prescribe another medicine called prednisone or
prednisolone. This is to lower your chances of getting high blood pressure, having too much water in
your body (fluid retention), or having reduced levels of a chemical known as potassium in your blood.
Do not take Akeega:

 if you are allergic to niraparib or abiraterone acetate or any of the other ingredients of this
medicine - listed in section 6.
 if you are a woman who is or can become pregnant.
 if you have severe liver damage.
 in combination with Ra-223 treatment (which is used to treat prostate cancer). This is because
of a possible increase in the risk of bone fracture or death.
50
Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking this medicine.
Warnings and precautions

Talk to your doctor or pharmacist before or while taking this medicine if you have:
 low blood cell counts. Signs and symptoms you need to look out for include fatigue, fever or
infection, and abnormal bruising or bleeding. Akeega may also lower your blood cell counts.
Your doctor will test your blood regularly throughout your treatment.
 high blood pressure or heart failure or low blood potassium (low blood potassium may increase
the risk of heart rhythm problems), have had other heart or blood vessel problems, have an
irregular or rapid heart rate, shortness of breath, gained weight rapidly, or swelling in the feet,
ankles, or legs. Your doctor will measure your blood pressure regularly throughout your
treatment.
 headaches, vision changes, confusion, or seizure. These may be signs of a rare neurological side
effect named posterior reversible encephalopathy syndrome (PRES) that has been associated
with use of niraparib, an active ingredient of Akeega.
 high fever, fatigue and other signs and symptoms of severe infection.
 blood clots in the lungs, or have had them in the past.
 liver problems.
 low or high levels of sugar in the blood.
 muscle weakness and/or muscle pain.
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking
this medicine.
If you develop low blood cell counts for a long period of time while taking Akeega, this may be a sign
of more serious problems with the bone marrow such as ‘myelodysplastic syndrome’ (MDS) or ‘acute
myeloid leukaemia’ (AML). Your doctor may want to test your bone marrow to check for these
problems.
Before taking Akeega, also talk to your doctor or pharmacist about:

 the effect Akeega may have on your bones.
 taking prednisone or prednisolone (another medicine you must take with Akeega).
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking this
medicine.
Blood monitoring
Akeega may affect your liver, but you may not notice any symptoms of liver problems. When you are
taking this medicine, your doctor will therefore check your blood periodically to look for any effects
on your liver.
Children and adolescents

This medicine is not for use in children and adolescents. If Akeega is accidentally swallowed by a
child or adolescent, take them to the hospital immediately and take this package leaflet with you to
show to the emergency doctor.
Other medicines and Akeega

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines. This is because Akeega can affect the way some other medicines work. Also, some other
medicines can affect the way Akeega works.
Treatment with medicines that stop the body from producing testosterone, may increase the risk of
heart rhythm problems. Tell your doctor if you are receiving medicine:
 to treat heart rhythm problems (e.g., quinidine, procainamide, amiodarone and sotalol);
51
 known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and
part of drug addiction detoxification; moxifloxacin, an antibiotic; antipsychotics, used for
serious mental illnesses.
Tell your doctor if you are taking any of the medicines listed above.
Akeega with food

 This medicine must not be taken with food (see section 3, “Taking Akeega”), as this may
increase your risk of side effects.
Pregnancy and breast-feeding

 This medicine may cause harm to the unborn child if it is taken by women who are pregnant.
 Women who are pregnant or who may become pregnant should wear gloves if they need to
touch or handle Akeega.
Contraception for men using Akeega
 If you are having sex with a woman who can become pregnant, use a condom and another
effective birth control method. Use contraception during treatment and for 4 months after
stopping. Talk to your doctor if you have any questions about contraception.
 If you are having sex with a pregnant woman, use a condom to protect the unborn child.
Driving and using machines

Taking Akeega may make you feel weak, unfocused, tired or dizzy. This may influence your ability to
drive and use machines. Use caution when driving or using machines.
Akeega contains lactose and sodium

 Akeega contains lactose. If you have been told by your doctor that you have an intolerance to
some sugars, contact your doctor before taking this medicine.
 This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
How much to take

The recommended starting dose is 200 mg/1,000 mg (two tablets) once a day.
Taking Akeega
 Take this medicine by mouth.
 Do not take Akeega with food.
 Take Akeega tablets as a single dose once daily on an empty stomach at least one hour before
or at least two hours after eating (see section 2, “Akeega with food”).
 Swallow the tablets whole with water. Do not break, crush, or chew the tablets. This will ensure
the medicine works as well as possible.
 Akeega is taken with a medicine called prednisone or prednisolone.
o Take the prednisone or prednisolone exactly as your doctor has told you.
o You need to take prednisone or prednisolone every day while you are taking Akeega.
o The amount of prednisone or prednisolone you take may need to be changed if you have a
medical emergency. Your doctor will tell you if you need to change the amount of
prednisone or prednisolone you take. Do not stop taking prednisone or prednisolone
unless your doctor tells you to.
Your doctor may also prescribe other medicines while you are taking Akeega.
52
If you take more Akeega than you should
If you take more tablets than you should contact your doctor. You may have an increased risk of side
effects.
If you forget to take Akeega

If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you
remember on the same day.
If you forget to take Akeega or prednisone or prednisolone for more than one day - talk to your doctor
straight away.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Akeega

Do not stop taking Akeega or prednisone or prednisolone unless your doctor tells you to.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects

Stop taking Akeega and seek medical attention immediately if you notice any of the following
symptoms:
Very common (may affect more than 1 in 10 people)

 Bruising or bleeding for longer than usual if you hurt yourself - these may be signs of a low
blood platelet count (thrombocytopenia).
 Being short of breath, feeling very tired, having pale skin, or fast heartbeat - these may be signs
of a low red blood cell count (anaemia).
 Fever or infection – low white blood cell count (neutropenia) can increase your risk for
infection. Signs may include fever, chills, feeling weak or confused, cough, pain or burning
feeling when passing urine. Some infections can be serious and may lead to death.
 Muscle weakness, muscle twitching or a pounding heart beat (palpitations). These may be signs
that the level of potassium in your blood is low (hypokalaemia).
 Increased level of the enzyme ‘alkaline phosphatase’ in the blood
 Allergic reaction (including severe allergic reaction that can be life-threatening). Signs include:
raised and itchy rash (hives) and swelling-sometimes of the face or mouth (angioedema),
causing difficulty in breathing, and collapse or loss of consciousness.
 A sudden increase in blood pressure, which may be a medical emergency that could lead to
organ damage or can be life-threatening.
Other side effects

Talk to your doctor if you get any other side effects. These can include:
Very common (may affect more than 1 in 10 people):

 urinary tract infection
 low number of white blood cells (leukopenia), seen in blood tests
53
 decreased appetite
 difficulty sleeping (insomnia)
 feeling dizzy
 shortness of breath
 constipation
 feeling sick (nausea)
 vomiting
 back pain
 joint pain
 feeling very tired
 feeling weak
 weight loss
 bone fractures
Common (may affect up to 1 in 10 people):

 pneumoniae
 lung infection (bronchitis)
 infection of the nose and throat (nasopharyngitis)
 low number of a type of white blood cell (lymphopenia), seen in blood tests
 high level of a type of fat (hypertriglyceridemia) in the blood
 depression
 feeling anxious
 headache
 fast heart beat
 fast or uneven heart beat (palpitations)
 irregular heart beat (atrial fibrillation)
 heart failure, causing shortness of breath and swollen legs
 heart attack
 cough
 blood clot in the lungs, causing chest pain and shortness of breath
 inflamed lungs
 stomach pain
 indigestion
 diarrhoea
 bloating
 sores in the mouth
 dry mouth
 inflamed liver (hepatitis) based on blood tests
 skin rash
 muscle aches
 blood in the urine
 swollen hands, ankles, or feet
 increased level of ‘creatinine’ in the blood
 increased level of the enzyme ‘aspartate aminotransferase’ in the blood
 increased level of the enzyme ‘alanine aminotransferase’ in the blood
Uncommon (may affect up to 1 in 100 people):

 severe infection (sepsis) that spreads from the urinary tract throughout the body
 inflamed eye (conjunctivitis)
 feeling confused
 difficulty thinking, remembering information, or solving problems (cognitive impairment)
 change in sense of taste
 chest discomfort, often brought on by physical activity
 abnormal ECG (electrocardiogram), which could be a sign of heart problems
54
 nose bleeds
 inflammation of the protective linings in the body cavities, such as the nose, mouth, or digestive
system
 sudden liver failure
 increased sensitivity of the skin to sunlight
 increased level of ‘gamma-glutamyltransferase’ in the blood
 low numbers of all types of blood cells (pancytopenia)
 brain condition with symptoms including seizures (fits), headache, confusion, and changes in
vision (posterior reversible encephalopathy syndrome or PRES), which is a medical emergency
that could lead to organ damage or can be life-threatening
 adrenal gland problems (related to salt and water problems) where too little hormone is
produced which may cause problems like weakness, tiredness, loss of appetite, nausea,
dehydration and skin changes
 inflamed lungs caused by an allergic reaction (allergic alveolitis)
 muscle disease (myopathy), which may cause muscle weakness, stiffness or spasms
 breakdown of muscle tissue (rhabdomyolysis), which may cause muscle cramps or pains,
tiredness and dark urine
Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects, you can help provide more information on the safety
of this medicine.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the container (blister foil, inner
wallet, outer wallet, and carton) after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
What Akeega contains

 The active substances are niraparib and abiraterone acetate. Each film-coated tablet contains
100 mg niraparib and 500 mg abiraterone acetate.
 The other ingredients of the tablet core are colloidal anhydrous silica, crospovidone,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium
lauryl sulfate. The film-coating contains iron oxide red (E172), iron oxide yellow (E172),
sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium
dioxide (E171) (see section 2, Akeega contains lactose and sodium)
What Akeega looks like and contents of the pack

Akeega film-coated tablets are orange oval tablets, debossed with “N 100 A” on one side and plain on
the other side.
55
Each 28-day carton contains 56 film-coated tablets in two cardboard wallet packs of 28 film-coated
tablets each.
Marketing Authorisation Holder

Turnhoutseweg 30
B-2340 Beerse
Belgium
Manufacturer
Janssen Cilag SpA
Via C. Janssen,
Borgo San Michele
Latina 04100
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien Lietuva
Janssen-Cilag NV UAB "JOHNSON & JOHNSON"
Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88
България Luxembourg/Luxemburg
„Джонсън & Джонсън България” ЕООД Janssen-Cilag NV
Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11
Česká republika Magyarország

Janssen-Cilag s.r.o. Janssen-Cilag Kft.
Tel: +420 227 012 227 Tel.: +36 1 884 2858
[email protected]
Danmark Malta
Janssen-Cilag A/S AM MANGION LTD
Tlf: +45 4594 8282 Tel: +356 2397 6000
[email protected]
Deutschland Nederland
Janssen-Cilag GmbH Janssen-Cilag B.V.
Tel: +49 2137 955 955 Tel: +31 76 711 1111
Eesti Norge
UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS
Tel: +372 617 7410 Tlf: +47 24 12 65 00
Ελλάδα Österreich
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε. Janssen-Cilag Pharma GmbH
Tηλ: +30 210 80 90 000 Tel: +43 1 610 300
56
España Polska
Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o.
Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00
[email protected]
France Portugal
Janssen-Cilag Janssen-Cilag Farmacêutica, Lda.
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600
[email protected]
Hrvatska România
Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL
Tel: +385 1 6610 700 Tel: +40 21 207 1800
[email protected]
Ireland Slovenija
Janssen Sciences Ireland UC Johnson & Johnson d.o.o.
Tel: 1 800 709 122 Tel: +386 1 401 18 00
Ísland Slovenská republika

Janssen-Cilag AB Johnson & Johnson, s.r.o.
c/o Vistor hf. Tel: +421 232 408 400
Sími: +354 535 7000
[email protected]
Italia Suomi/Finland
Janssen-Cilag SpA Janssen-Cilag Oy
Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300
Κύπρος Sverige
Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB
Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00
[email protected]
Latvija United Kingdom (Northern Ireland)

UAB "JOHNSON & JOHNSON" filiāle Latvijā Janssen Sciences Ireland UC
Tel: +371 678 93561 Tel: +44 1 494 567 444
This leaflet was last revised in MM/YYYY.
Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
57

AKEEGA SMPC 2023

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AKEEGA SMPC 2023

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

Akeega 50 mg/500 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Akeega 50 mg/500 mg film-coated tablets

Akeega 100 mg/500 mg film-coated tablets

Excipients with known effect

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Akeega 50 mg/500 mg film-coated tablets

Akeega 100 mg/500 mg film-coated tablets

4.1 Therapeutic indications

4.2 Posology and method of administration

Dosage of prednisone or prednisolone

Dose adjustments for adverse reactions

Haematological adverse reactions

Table 1: Dose adjustment recommendations for thrombocytopenia and neutropenia

Weekly monitoring of blood counts is recommended for 28 days after restarting

Weekly monitoring is recommended for 28 days after resuming treatment with

Third occurrence Permanently discontinue treatment.

Table 2: Dose adjustment recommendations for anaemia

Precaution to be taken before manipulating or administering the product

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

4.4 Special warnings and precautions for use

Haematological adverse reactions

Pulmonary embolism (PE)

Posterior reversible encephalopathy syndrome (PRES)

Hepatotoxicity and hepatic impairment

Marked increases in liver enzymes leading to treatment interruption or discontinuation occurred in

Treatment should be permanently discontinued in patients with elevations of ALT or AST

Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML)

Corticosteroid withdrawal and coverage of stress situations

Skeletal muscle effects

Interactions with other medicinal products

Lactose and sodium

Effects of other medicinal products on niraparib or abiraterone acetate

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

Effects of niraparib or abiraterone acetate on other medicinal products

Use with products known to prolong QT interval

Use with spironolactone

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

4.8 Undesirable effects

Summary of the safety profile

Tabulated list of adverse reactions

Table 3: Adverse reactions identified in clinical studies

Description of selected adverse reactions

5.1 Pharmacodynamic properties

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

Clinical efficacy and safety

5.2 Pharmacokinetic properties

Effects of niraparib or abiraterone on transporters

The pharmacokinetics of abiraterone was examined in subjects with pre-existing mild (n = 8) or

5.3 Preclinical safety data

Carcinogenicity studies have not been conducted with niraparib.

Environmental risk assessment (ERA)

6.1 List of excipients

Akeega 50 mg/500 mg film-coated tablets

Akeega 100 mg/500 mg film-coated tablets