Posology : מינונים

4.2    Posology and method of administration

Lonsurf should be prescribed by physicians experienced in the administration of anticancer therapy.

Posology
The recommended starting dose of Lonsurf in adults, as monotherapy or in combination with bevacizumab, is 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle until disease progression or unacceptable toxicity (see section 4.4).

When Lonsurf is used in combination with bevacizumab for the treatment of metastatic CRC, the dose of bevacizumab is 5 mg/kg of body weight given once every 2 weeks. Please refer to the full product information for bevacizumab.

The dose is calculated according to body surface area (BSA) (see Table 1).
The dose must not exceed 80 mg/dose.

If doses were missed or held, the patient must not make up for missed doses.
Table 1 - Starting dose calculation according to BSA
Tablets per dose                 Total daily
Starting      BSA        Dose in mg                (2x daily)                   dose (mg) dose         (m2)        (2x daily)
15 mg/6.14 mg 20 mg/8.19 mg
35 mg/m2     < 1.07           35                1                   1               70 1.07 - 1.22        40                0                   2               80 1.23 - 1.37        45                3                   0               90 1.38 - 1.52        50                2                   1               100 1.53 - 1.68        55                1                   2               110 1.69 - 1.83        60                0                   3               120 1.84 - 1.98        65                3                   1               130 1.99 - 2.14        70                2                   2               140 2.15 - 2.29        75                1                   3               150
≥ 2.30           80                0                   4               160 
Recommended dose adjustments

Dosing adjustments may be required based on individual safety and tolerability.
A maximum of 3 dose reductions are permitted to a minimum dose of 20 mg/m2 twice daily.
Dose escalation is not permitted after it has been reduced.

In the event of haematological and/or non-haematological toxicities patients should follow the dose interruption, resumption and reduction criteria stated in Table 2, Table 3 and Table 4.

Table 2 - Dose interruption and resumption criteria for haematological toxicities related to myelosuppression
Parameter                         Interruption criteria                Resumption criteriaa Neutrophils                                 < 0.5  109/L                          1.5  109/L Platelets                                   < 50  10 /L
9
 75  109/L a
Resumption criteria applied to the start of the next cycle for all patients regardless of whether or not the interruption criteria were met.


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Table 3 - Recommended dose modifications for Lonsurf in case of haematological and non-haematological adverse reactions
Adverse reaction                      Recommended dose modifications
• Febrile neutropenia                          • Interrupt dosing until toxicity resolves to Grade
• CTCAE* Grade 4 neutropenia                     1 or baseline.
(< 0.5 x 109/L) or thrombocytopenia          • When resuming dosing, decrease the dose (< 25  109/L) that results in more than       level by 5 mg/m2/dose from the previous dose 1 week’s delay in start of next cycle          level (Table 4).
• CTCAE* non-haematologic Grade 3 or           • Dose reductions are permitted to a minimum Grade 4 adverse reaction; except for Grade     dose of 20 mg/m2/dose twice daily or 15 3 nausea and/or vomiting controlled by         mg/m2/dose twice daily in severe renal antiemetic therapy or diarrhoea responsive     impairment.
to antidiarrhoeal medicinal products         • Do not increase dose after it has been reduced.
* Common terminology criteria for adverse events


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Table 4 - Dose reductions according to BSA
Tablets per dose
Reduced             BSA         Dose in mg                (2x daily)             Total daily 2 dose              (m )          (2x daily)                                      dose (mg) 15 mg/6.14 mg 20 mg/8.19 mg
Level 1 dose reduction: From 35 mg/m2 to 30 mg/m2
30 mg/m2          < 1.09              30             2               0               60 1.09 - 1.24           35             1               1               70 1.25 - 1.39           40             0               2               80 1.40 - 1.54           45             3               0               90 1.55 - 1.69           50             2               1               100 1.70 - 1.94           55             1               2               110 1.95 - 2.09           60             0               3               120 2.10 - 2.28           65             3               1               130
≥ 2.29             70             2               2               140 2           2
Level 2 dose reduction: From 30 mg/m to 25 mg/m
25 mg/m2          < 1.10             25a            2a               1a              50a
1.10 - 1.29           30             2               0               60 1.30 - 1.49           35             1               1               70 1.50 - 1.69           40             0               2               80 1.70 - 1.89           45             3               0               90 1.90 - 2.09           50             2               1               100 2.10 - 2.29           55             1               2               110
≥ 2.30             60             0               3               120 Level 3 dose reduction: From 25 mg/m2 to 20 mg/m2
20 mg/m2          < 1.14              20             0               1               40
1.14 – 1.34          25 a
2 a
1a
50a
1.35 – 1.59           30             2               0               60 1.60 – 1.94           35             1               1               70 1.95 – 2.09           40             0               2               80 2.10 – 2.34           45             3               0               90
≥ 2.35             50             2               1               100 a
At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and 2 x 15 mg/6.14 mg tablets in the evening.


Special populations
Renal impairment

• Mild renal impairment (CrCl 60 to 89 mL/min) or moderate renal impairment (CrCl 30 to 59 mL/min) No adjustment of the starting dose is recommended in patients with mild or moderate renal impairment (see sections 4.4 and 5.2).

• Severe renal impairment (CrCl 15 to 29 mL/min)
For patients with severe renal impairment a starting dose of 20 mg/m2 twice daily is recommended (see section 4.4 and 5.2). One dose reduction to a minimum dose of 15 mg/m2 twice daily is permitted based on individual safety and tolerability (see Table 5). Dose escalation is not permitted after it has been reduced.
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In the event of haematological and/or no-haemtological toxicities patients should follow the dose interruption, resumption and reduction criteria stated in Table 2, Table 3 and Table 5.

Table 5 – Starting dose and dose reduction in patients with severe renal impairment according to BSA

Reduced          BSA (m2)        Dose in mg             Tablets per dose             Total daily dose                             (2x daily)                (2x daily)               dose (mg) 15 mg/6.14 mg 20 mg/8.19 mg
Starting dose
20 mg/m2           < 1.14          20               0               1                 40
1.14 – 1.34     25a              2a              1a                50a 1.35 – 1.59     30               2               0                 60 1.60 – 1.94     35               1               1                 70 1.95 – 2.09     40               0               2                 80 2.10 – 2.34     45               3               0                 90
≥ 2.35          50               2               1                 100 Dose reduction: From 20 mg/m2 to 15 mg/m2
15 mg/m2           < 1.15          15               1               0                 30 1.15 – 1.49     20               0               1                 40 a               a               a
1.50 – 1.84     25               2               1                 50a 1.85 – 2.09     30               2               0                 60 2.10 – 2.34     35               1               1                 70
≥ 2.35          40               0               2                 80 a
At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and 2 x 15 mg/6.14 mg tablets in the evening.

• End stage renal disease (CrCl below 15 mL/min or requiring dialysis) Administration is not recommended in patients with end stage renal disease as there are no data available for these patients (see section 4.4).

Hepatic impairment

• Mild hepatic impairment
No adjustment of the starting dose is recommended in patients with mild hepatic impairment (see section 5.2).

• Moderate or severe hepatic impairment
Administration is not recommended in patients with baseline moderate or severe hepatic impairment (National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin >1.5 x ULN) as, a higher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderate hepatic impairment, although this is based on very limited data (see sections 4.4 and 5.2).

Elderly

No adjustment of the starting dose is required in patients ≥ 65 years old (see sections 4.8, 5.1 and 5.2).
Efficacy and safety data in patients over 75 years old is limited.


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Paediatric population
There is no relevant use of Lonsurf in the paediatric population for the indications of metastatic colorectal cancer and metastatic gastric cancer.

Race

No adjustment of the starting dose is required on the basis of patient’s race (see sections 5.1 and 5.2).
There is limited data on Lonsurf in Black/African American patients but there is no biological rationale to expect any difference between this subgroup and the overall population.

Method of administration

Lonsurf is for oral use. The tablets must be taken with a glass of water within 1 hour after completion of the morning and evening meals.