AKEEGA Film-coated tablet Ref.[50974] Active ingredients: Abiraterone Niraparib

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 x ULN or direct bilirubin > 1 x ULN and AST or ALT > 3 x 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 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 x ULN. Treatment should be permanently discontinued in patients who develop a concurrent elevation of ALT > 3 x ULN and a total bilirubin > 2 x 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 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’.

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 AUC_s 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).

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)

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.

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:

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 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.

Paediatric population

No studies have been conducted in paediatric patients with Akeega.

Not applicable.