Posology : מינונים

4.2 Posology and method of administration

Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which tofacitinib is indicated.

Posology

Tofacitinib may be used as monotherapy or in combination with methotrexate (MTX).
The recommended dose in patients 2 years of age and older is based upon the following weight categories:

Table 1: Tofacitinib dose for patients with polyarticular juvenile idiopathic arthritis and juvenile PsA two years of age and older
Body weight (kg)                                   Dose regimen
10 - < 20                        3.2 mg (3.2 mL of oral solution) twice daily 20 - < 40                          4 mg (4 mL of oral solution) twice daily
≥ 40               5 mg (5 mL of oral solution or 5 mg film-coated tablet) twice daily 
Patients ≥ 40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution.

Dose adjustment

No dose adjustment is required when used in combination with MTX.
Dose interruption and discontinuation

Available data suggest that clinical improvement is observed within 18 weeks of initiation of treatment with tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. As described in Tables 2, 3 and 4 below, 
 recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities (see section 4.4).

It is recommended not to initiate dosing in paediatric patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.

Table 2: Low absolute lymphocyte count
Low absolute lymphocyte count (ALC) (see section 4.4)
Laboratory value                                Recommendation
(cells/mm3)
ALC greater than or equal  Dose should be maintained.
to 750
ALC 500-750                For persistent (2 sequential values in this range on routine testing) decrease in this range, dosing should be reduced or interrupted until ALC is greater than 750.

For patients receiving tofacitinib 5 mg twice daily, dosing should be interrupted.

When ALC is greater than 750, treatment should be resumed as clinically appropriate.
ALC less than 500             If laboratory value confirmed by repeat testing within 7 days, dosing should be discontinued.

It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1,200 cells/mm3.

Table 3: Low absolute neutrophil count
Low absolute neutrophil count (ANC) (see section 4.4)
Laboratory Value                                 Recommendation
(cells/mm3)
ANC greater than 1,000     Dose should be maintained.
ANC 500-1,000              For persistent (2 sequential values in this range on routine testing) decreases in this range, dosing should be reduced or interrupted until ANC is greater than 1,000.

For patients receiving tofacitinib 5 mg twice daily, dosing should be interrupted.

When ANC is greater than 1,000, treatment should be resumed as clinically appropriate.
ANC less than 500             If laboratory value confirmed by repeat testing within 7 days, dosing should be discontinued.

It is recommended not to initiate dosing in paediatric patients with haemoglobin less than 10 g/dL.



Table 4: Low haemoglobin value
Low haemoglobin value (see section 4.4)
Laboratory value                                 Recommendation
(g/dL)
Less than or equal to        Dose should be maintained.
2 g/dL decrease and greater than or equal to 9.0 g/dL
Greater than 2 g/dL          Dosing should be interrupted until haemoglobin values have decrease or less than        normalised.
8.0 g/dL
(confirmed by repeat testing)

Interactions

Tofacitinib total daily dose should be reduced to 5 mg film-coated tablet once daily or weight-based equivalent once daily in patients receiving 5 mg film-coated tablets or weight-based equivalent twice daily in patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.5).

Special populations

Elderly
The safety and efficacy of tofacitinib oral solution has not been established in the elderly.

Hepatic impairment

Table 5: Dose adjustment for hepatic impairment
Hepatic          Classification       Dose adjustment in hepatic impairment for oral impairment                            solution category
Mild             Child Pugh A         No dose adjustment required.
Moderate         Child Pugh B         Dose should be reduced to 5 mg or weight-based equivalent once daily when the indicated dose in the presence of normal hepatic function is 5 mg or weight-based equivalent twice daily (see section 5.2).
Severe           Child Pugh C         Tofacitinib should not be used in patients with severe hepatic impairment (see section 4.3).




Renal impairment
Table 6: Dose adjustment for renal impairment
Renal             Creatinine          Dose adjustment in renal impairment for oral impairment        clearance           solution category
Mild              50-80 mL/min        No dose adjustment required.
Moderate          30-49 mL/min        No dose adjustment required.
Severe (including < 30 mL/min         Dose should be reduced to 5 mg or weight-based patients                              equivalent once daily when the indicated dose in the undergoing                            presence of normal renal function is 5 mg or haemodialysis)                        weight-based equivalent twice daily.

Patients with severe renal impairment should remain on a reduced dose even after haemodialysis (see section 5.2).

Paediatric population (children below 2 years of age)
The safety and efficacy of tofacitinib in children below 2 years of age has not been established. No data are available.

Method of administration

Oral use.
Tofacitinib oral solution should be administered using the included press-in bottle adapter and oral dosing syringe.

Tofacitinib is given orally with or without food.