Posology : מינונים

4.2    Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with biliary tract cancer.

FGFR 2 fusion positivity status must be known prior to initiation of Pemazyre therapy. Assessment for FGFR 2 fusion positivity in tumor specimen should be performed with an appropriate diagnostic test.


Posology
The recommended dose is 13.5 mg pemigatinib taken once daily for 14 days followed by 7 days off therapy.

If a dose of pemigatinib is missed by 4 or more hours or vomiting occurs after taking a dose, an additional dose should not be administered and dosing should be resumed with the next scheduled dose.

Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity.

During the use of this medicine phosphate levels should be monitored in accordance with physician’s clinical consideration.

In all patients, a low-phosphate diet should be initiated when serum phosphate level is > 5.5 mg/dL and adding a phosphate-lowering therapy should be considered when level is > 7 mg/dL. The dose of phosphate-lowering therapy should be adjusted until serum phosphate level returns to < 7 mg/dL.
Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals that can lead to hypocalcaemia, soft tissue mineralization, muscle cramps, seizure activity, QT interval prolongation, and arrhythmias (see section 4.4).

Discontinuing phosphate-lowering therapy and diet should be considered during Pemazyre treatment breaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and haemolytic anemia (see section 4.4).

Dose adjustment due to drug interaction

Concomitant use of pemigatinib with strong CYP3A4 inhibitors
Concurrent use of strong CYP3A4 inhibitors, including grapefruit juice, should be avoided during treatment with pemigatinib. If co-administration with a strong CYP3A4 inhibitor is necessary, the dose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily (see sections 4.4 and 4.5).

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management of toxicities.
Pemigatinib dose reductions levels are summarised in table 1.

Table 1:         Recommended pemigatinib dose reduction levels
Dose                                   Dose reduction levels
First                          Second
13.5 mg taken orally once daily 9 mg taken orally once daily    4.5 mg taken orally once daily for 14 days followed by 7 days for 14 days on, followed by      for 14 days on, followed by off therapy                     7 days off therapy              7 days off therapy 
Treatment should be permanently discontinued if patient is unable to tolerate 4.5 mg pemigatinib once daily.

Dose modifications for hyperphosphataemia are provided in table 2.



Table 2:       Dose modifications for hyperphosphataemia
Adverse reaction                             pemigatinib dose modification > 5.5 mg/dL - ≤ 7 mg/dL    •     pemigatinib should be continued at current dose.
> 7 mg/dL - ≤ 10 mg/dL        •     pemigatinib should be continued at current dose, phosphate- lowering therapy should be initiated, serum phosphate should be monitored weekly, dose of phosphate lowering therapy should be adjusted as needed until level returns to < 7 mg/dL.
•     pemigatinib should be withheld if levels do not return to <
7 mg/dL within 2 weeks of starting a phosphate lowering therapy. pemigatinib and phosphate-lowering therapy should be restarted at the same dose when level returns to < 7 mg/dL.
•     Upon recurrence of serum phosphate at > 7 mg/dL with phosphate-lowering therapy, pemigatinib should be reduced 1 dose level.
> 10 mg/dL                    •     pemigatinib should be continued at current dose, phosphate- lowering therapy should be initiated, serum phosphate should be monitored weekly and dose of phosphate lowering therapy should be adjusted as needed until level returns to < 7 mg/dL.
•     pemigatinib should be withheld if levels continue > 10 mg/dL for 1 week. pemigatinib and phosphate-lowering therapy should be restarted 1 dose level lower when serum phosphate is <
7 mg/dL.
•     If there is recurrence of serum phosphate > 10 mg/dL following 2 dose reductions, pemigatinib should be permanently discontinued.

Dose modifications for serous retinal detachment are provided in table 3.

Table 3:         Dose modifications for serous retinal detachment
Adverse reaction                                  pemigatinib dose modification Asymptomatic                    • pemigatinib should be continued at current dose. Monitoring should be performed as described in section 4.4.
Moderate decrease in visual     • pemigatinib should be withheld until resolution. If improved acuity (best corrected visual       on subsequent examination, pemigatinib should be resumed at acuity 20/40 or better or ≤         the next lower dose level.
3 lines of decreased vision     • If it recurs, symptoms persist or examination does not improve, from baseline); limiting            permanent discontinuation of pemigatinib should be considered instrumental activities of          based on clinical status.
daily living
Marked decrease in visual       • pemigatinib should be withheld until resolution. If improved acuity (best corrected visual       on subsequent examination, pemigatinib may be resumed at 2 acuity worse than 20/40 or >        dose levels lower.
3 lines decreased vision from • If it recurs, symptoms persist or examination does not improve, baseline up to 20/200);             permanent discontinuation of pemigatinib should be limiting activities of daily        considered, based on clinical status.
living
Visual acuity worse than        • pemigatinib should be withheld until resolution. If improved 20/200 in affected eye;             on subsequent examination, pemigatinib may be resumed at 2 limiting activities of daily        dose levels lower.
living                          • If it recurs, symptoms persist or examination does not improve, permanent discontinuation of pemigatinib should be considered, based on clinical status.



Special populations

Elderly patients
The dose of pemigatinib is the same in elderly patients as younger adult patients (see section 5.1).
Renal impairment
Dose adjustment is not required for patients with mild, moderate renal impairment or End Stage Renal Disease (ESRD) on haemodialysis. For patients with severe renal impairment, the dose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily (see section 5.2).

Hepatic impairment
Dose adjustment is not required for patients with mild or moderate hepatic impairment. For patients with severe hepatic impairment, the dose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily (see section 5.2).

Paediatric population
The safety and efficacy of Pemazyre in patients less than 18 years of age have not been established.
No data are available.

Method of administration
Pemazyre is for oral use. The tablets should be taken at approximately the same time every day.
Patients should not crush, chew, split or dissolve the tablets. Pemigatinib may be taken with or without food.