Posology : מינונים

2        DOSAGE AND ADMINISTRATION
2.1      Patient Selection
Select patients for treatment of metastatic NSCLC with ZYKADIA based on the presence of ALK positivity in tumor specimens [see Clinical Studies (14.1)].
2.2 Recommended dosage
The recommended dosage of ZYKADIA is 450 mg orally once daily with food until disease progression or unacceptable toxicity. [see Clinical Pharmacology (12.3)].
If a dose of ZYKADIA is missed, make up that dose unless the next dose is due within 12 hours.
If vomiting occurs during the course of treatment, do not administer an additional dose and continue with the next scheduled dose of ZYKADIA.
2.3 Dosage Modifications for Adverse Reactions
Recommendations for dose modifications of ZYKADIA for adverse reactions are provided in Table 2.
Discontinue ZYKADIA for patients unable to tolerate 150 mg daily with food.

Table 1: ZYKADIA Dose Reduction Increments

Dose Reduction Schedule                                        Dose Level 
Starting dose                                        450 mg taken orally once daily with food 
First dose reduction                                 300 mg taken orally once daily with food 
Second dose reduction                                150 mg taken orally once daily with food 


Table 2: ZYKADIA Dose Modifications for Adverse Reactions

Adverse Reaction                                  ZYKADIA Dose Modification Gastrointestinal Adverse Reactions

ZYK SPI 20FEB22 CL V5                                                                             USPI October 2021 Lipase or amylase elevation greater than 2       Withhold and monitor serum lipase and amylase.
times ULN
Resume ZYKADIA with a 150 mg dose reduction after recovery to less than 1.5 times ULN.

Severe or intolerable nausea, vomiting or          Withhold until improved, then resume ZYKADIA with a diarrhea despite optimal antiemetic or             150 mg dose reduction.
antidiarrheal therapy
Hyperglycemia
Persistent hyperglycemia greater than 250 mg/dL Withhold until hyperglycemia is adequately controlled, despite optimal antihyperglycemic therapy       then resume ZYKADIA with a 150 mg dose reduction.

If adequate hyperglycemic control cannot be achieved with optimal medical management, discontinue ZYKADIA.
Pneumonitis
Any Grade treatment-related ILD/pneumonitis         Permanently discontinue ZYKADIA.
Cardiac Arrhythmias
QTc interval greater than 500 msec on at           Withhold until QTc interval is less than 481 msec or least 2 separate ECGs                              recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume ZYKADIA with a 150 mg dose reduction.
QTc interval prolongation in combination with      Permanently discontinue ZYKADIA.
Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia
Symptomatic bradycardia that is not life-          Withhold until recovery to asymptomatic bradycardia or to threatening                                        a heart rate of 60 bpm or above, evaluate concomitant medications known to cause bradycardia, and adjust the dose of ZYKADIA.
Clinically significant bradycardia requiring       Withhold until recovery to asymptomatic bradycardia intervention or life-threatening bradycardia in    or to a heart rate of 60 bpm or above.
patients taking a concomitant medication also known to cause bradycardia or a medication
If the concomitant medication can be adjusted or known to cause hypotension discontinued, resume ZYKADIA with a 150 mg dose reduction, with frequent monitoring.
Life-threatening bradycardia in patients who are Permanently discontinue ZYKADIA.
not taking a concomitant medication also known to cause bradycardia or known to cause hypotension

Hepatotoxicity

ZYK SPI 20FEB22 CL V5                                                                            USPI October 2021 ALT or AST elevation greater than 5 times ULN         Withhold until recovery to baseline or less than or equal to 3 with                                                  times ULN, then resume ZYKADIA with a 150 mg dose total bilirubin elevation less than or equal to 2     reduction.
times ULN

ALT or AST elevation greater than 3 times             Permanently discontinue ZYKADIA.
ULN with total bilirubin elevation greater than 2 times
ULN in the absence of cholestasis or hemolysis

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal; ILD: interstitial lung disease; ECG: electrocardiogram: bpm: beats per minute 

2.4 Dosage Modification for Strong CYP3A4 Inhibitors
Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
If concurrent use of a strong CYP3A inhibitor is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ZYKADIA dose that was taken prior to initiating the strong CYP3A4 inhibitor.


2.5 Dosage Modification for patients with severe hepatic impairment (Child-Pugh C)
For patients with severe hepatic impairment (Child-Pugh C), reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].