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 Akeega 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.

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

It is recommended that patients are treated with Akeega 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 occurrence ≥ grade 3

Withhold Akeega and monitor at least weekly until platelets and/or neutrophils recover to Grade 1. Further treatment should restart with two lower 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 (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 ≥ grade 3

Permanently discontinue treatment.

1 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 occurrence ≥ Grade 3

Withhold Akeega, provide supportive management and monitor at least weekly until recovered to Grade ≤ 2. Further treatment should restart with two lower 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 ≥ Grade 3

Consider discontinuing treatment with Akeega based on clinical judgment.

1 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).

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.

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.

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 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. 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 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).

In the MAGNITUDE study, 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 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, 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).

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 (52.4%), hypertension (34.0%), constipation (34.0%), fatigue (31.1%), nausea (25.0%), thrombocytopenia (24.1%), dyspnoea (18.9%), arthralgia (18.4%), back pain (17.9%), asthenia (17.0%), neutropenia (16.0%), decreased appetite (15.6%), hypokalaemia (15.6%), vomiting (15.1%), dizziness (13.2%), abdominal pain (12.7%), hyperglycaemia (12.7%), blood alkaline phosphatase increased (11.8%), weight decreased (11.8%), insomnia (11.3%), leukopenia (10.8%), lymphopenia (10.8%), blood creatinine increased (10.4%), and urinary tract infection (10.4%). The most frequently observed Grade 3-4 adverse reactions were anaemia (30.7%), hypertension (16.5%), thrombocytopenia (8.5%), neutropenia (6.6%), blood alkaline phosphatase increased (5.7%), and hypokalaemia (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 disorders

very common

anaemia, thrombocytopenia, neutropenia, leukopenia, lymphopenia

not known

pancytopenia7

Immune system disorders

not known

hypersensitivity (including anaphylaxis)7

Endocrine disorders

not known

adrenal insufficiency9

Metabolism and nutrition disorders

very common

decreased appetite, hypokalaemia, hyperglycaemia

common

hypertriglyceridaemia

Psychiatric disorders

very common

insomnia

common

depression, anxiety

uncommon

confusional state

not known

cognitive impairment8

Nervous system disorders

very common

dizziness

common

headache, cognitive disorder

uncommon

dysgeusia

not known

posterior reversible encephalopathy syndrome (PRES)7

Cardiac disorders

common

tachycardia, palpitations, atrial fibrillation, cardiac failure1, myocardial infarction, angina pectoris2

uncommon

QT prolongation

Vascular disorders

very common

hypertension

not known

hypertensive crisis7

Respiratory, thoracic and mediastinal disorders

very common

dyspnoea

common

cough, pulmonary embolism, pneumonitis

uncommon

epistaxis

not known

allergic alveolitis9

Gastrointestinal disorders

very common

constipation, nausea, vomiting, abdominal pain3

common

dyspepsia, diarrhoea, abdominal distention, stomatitis, dry mouth

uncommon

mucosal inflammation

Hepatobiliary disorders

common

hepatic failure4

Skin and subcutaneous tissue disorders

common

rash5

uncommon

photosensitivity

Musculoskeletal and connective tissue disorders

very common

back pain, arthralgia

common

myalgia

not known

myopathy9, rhabdomyolysis9

Renal and urinary disorders

common

haematuria

General disorders and administration site conditions

very common

fatigue, asthenia

common

oedema peripheral

Investigations

very common

blood alkaline phosphatase increased, weight decreased, blood creatinine increased

common

AST increased, ALT increased

uncommon

gamma-glutamyl transferase increased

Injury, poisoning and procedural complications

common

fractures6

1 Includes cardiac failure congestive, cor pulmonale, left ventricular dysfunction

2 Includes coronary artery disease, acute coronary syndrome

3 Includes abdominal pain upper, abdominal pain lower

4 Includes hepatic cytolysis, hepatotoxicity, hepatic failure

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

Thrombocytopenia

In the MAGNITUDE study, 24.1% of treated patients reported thrombocytopenia while 8.5% of patients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was 71 days. In the MAGNITUDE study, thrombocytopenia was managed with dose modification (interruption 11.3% and reduction in 2.8%) and platelet transfusion (3.8%) where appropriate (see section 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.9% of patients experienced a nonlife-threatening bleeding event.

Neutropenia

In the MAGNITUDE study, 16.0% 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 65 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 34% of patients of whom 16.5% 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 13.2% 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 81 days in the niraparib plus AAP arm and 262 days in the placebo plus AAP arm. Events of arrhythmia were resolved in 64.3% of patients in the niraparib plus AAP arm and 62.5% of subjects in the placebo plus AAP arm.

The incidence of cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive was 2.8% 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 312 days in the niraparib plus AAP arm and 83 days in the placebo plus AAP arm. Events of cardiac failure were resolved in 16.7% of patients in the niraparib plus AAP arm and 25% of patients in the placebo plus AAP arm.

The grouped term of ischaemic heart disease (included preferred terms of angina pectoris, acute myocardial infarction, acute coronary syndrome, unstable angina, and arteriosclerosis coronary artery) occurred in 5.2% of the niraparib plus AAP arm vs 4.7% in the placebo plus AAP arm. The median time to onset of the AESI of ischaemic heart disease was 684 days in the niraparib plus AAP arm and 296 days in the placebo plus AAP arm. Events of ischaemic heart disease were resolved in 81.8% of patients in the niraparib plus AAP arm and 80% of patients in the placebo plus AAP arm.

Hepatotoxicity

The overall incidence of hepatotoxicity in the MAGNITUDE study was similar for the niraparib plus AAP (14.2%) and placebo plus AAP (12.8%) arms (see sections 4.2 and 4.4). The majority of these events were low grade aminotransferase elevations. Grade 3 events occurred in 1.4% of patients in the niraparib plus AAP arm and a Grade 4 event occurred in only one patient (0.5%). The incidence of SAEs was also 1.4%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 43 days. Hepatotoxicity was managed with dose interruptions in 1.9% and dose reduction in 0.9% of patients. In the MAGNITUDE study, 0.9% of patients discontinued treatment due to hepatotoxicity.

Paediatric population

No studies have been conducted in paediatric patients with Akeega.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.