Posology : מינונים

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/1000 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.


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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



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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 /500 (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.



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Permanently discontinue Akeega for patients who develop a concurrent elevation of ALT greater than 3 Í ULN, and total bilirubin greater than 2 Í 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.



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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).