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

Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis 

The recommended dose is 5 mg tablets administered twice daily, or one 11 mg extended-release tablet which should not be exceeded.

No dose adjustment is required when used in combination with MTX.

For information on switching between tofacitinib tablets and tofacitinib extended-release tablets see Table 1.

Table 1: Switching between tofacitinib tablets and tofacitinib extended-release tablets Switching between tofacitinib     Treatment with tofacitinib 5 mg tablets twice daily and tofacitinib 5 mg tablets and tofacitinib      11 mg extended-release tablet once daily may be switched between 11 mg extended-release tablet a each other on the day following the last dose of either tablet.
a   See section 5.2 for comparison of pharmacokinetics of extended-release and tablets formulations.



Ulcerative colitis

Induction treatment
The recommended dose is 10 mg given orally twice daily for induction for 8 weeks.
For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.

Maintenance treatment
The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily.

Avoid XELJANZ in patients at increased risk for thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis.



Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known major adverse cardiovascular events (MACE) and malignancy risk factors, unless there is no suitable alternative treatment available (see section 4.4 and 4.8).


For patients with UC who are not at increased risk for VTE, MACE and malignancy (see section 4.4), tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used.

In patients who have responded to treatment with tofacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Retreatment in UC
If therapy is interrupted, restarting treatment with tofacitinib can be considered. If there has been a loss of response, reinduction with tofacitinib 10 mg twice daily may be considered. The treatment interruption period in clinical studies extended up to 1 year. Efficacy may be regained by 8 weeks of 10 mg twice daily therapy (see section 5.1).

Polyarticular JIA and juvenile PsA (children between 2 and 18 years of age) 
Tofacitinib may be used as monotherapy or in combination with MTX.

The recommended dose in patients 2 years of age and older is based upon the following weight categories:

Table 2: 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 interruption and discontinuation in adults patients and paediatric patients 

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 3, 4 and 5 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 patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.



Table 3: 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.

For patients receiving tofacitinib 10 mg twice daily, dosing should be reduced to tofacitinib 5 mg twice daily.

For patients receiving tofacitinib 5 mg twice daily or 11 mg extended- release, 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 adult patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1,200 cells/mm3.
Table 4: Low absolute neutrophil count
Low absolute neutrophil count (ANC) (see section 4.4)
Laboratory Value                                    Recommendation
(cells/mm )
3

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.

For patients receiving tofacitinib 10 mg twice daily, dosing should be reduced to tofacitinib 5 mg twice daily.

For patients receiving tofacitinib 5 mg twice daily or 11 mg extended- release , 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 adult patients with haemoglobin less than 9 g/dL.
It is recommended not to initiate dosing in paediatric patients with haemoglobin less than 10 g/dL 



Table 5: Low haemoglobin value
Low haemoglobin value (see section 4.4)
Laboratory value                                 Recommendation
(g/dL)
Less than or equal to 2 g/dL Dose should be maintained.
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 by half 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) as follows:
•      Tofacitinib dose should be reduced to 5 mg once daily in patients receiving 5 mg twice daily or 11 mg extended release once daily.
•      Tofacitinib dose should be reduced to 5 mg twice daily in patients receiving 10 mg twice daily.

Only in paediatric patients: 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 clinical improvement within this timeframe.

Dose discontinuation in AS

Available data suggest that clinical improvement in AS is observed within 16 weeks of initiation of treatment with tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibiting no clinical improvement within this timeframe.


Special populations
Elderly

No dose adjustment is required in patients 65 years of age and older. There are limited data in patients aged 75 years and older. See section 4.4 for Use in patients 65 years of age and older.




Hepatic impairment
Table 6: Dose adjustment for hepatic impairment
Hepatic          Classification        Dose adjustment in hepatic impairment for different impairment                             strength tablets category
Mild             Child Pugh A          No dose adjustment required.
Moderate         Child Pugh B          Dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg extended release once daily.

Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg 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 7: Dose adjustment for renal impairment
Renal             Creatinine           Dose adjustment in renal impairment for different impairment        clearance            strength tablets 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 once daily when the patients                               indicated dose in the presence of normal renal function is undergoing                             5 mg twice daily or 11 mg extended release once daily.
haemodialysis)
Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is
10 mg twice daily.

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

Paediatric population
The safety and efficacy of tofacitinib in children less than 2 years of age with polyarticular JIA and juvenile PsA has not been established. No data are available.

The safety and efficacy of tofacitinib in children less than 18 years of age with other indications (e.g., ulcerative colitis) has not been established. No data are available.

The safety and efficacy of tofacitinib extended-release formulation in children aged 0 to less than 18 years have not been established. No data are available.

Method of administration

Oral use.
Tofacitinib is given orally with or without food.

For patients who have difficulties swallowing, tofacitinib 5 mg and 10 mg tablets may be crushed and taken with water.


Tofacitinib 11 mg extended-release tablets must be taken whole in order to ensure the entire dose is delivered correctly. They must not be crushed, split, or chewed.