Special Warning : אזהרת שימוש

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 
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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 Í ULN or direct bilirubin > 1 Í ULN and AST or ALT > 3 Í 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 
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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 Í ULN. Treatment should be permanently discontinued in patients who develop a concurrent elevation of ALT > 3 Í ULN and a total bilirubin > 2 Í 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 1000 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.

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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’.

Effects on Driving

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.