Tofacitinib

Registered South African indications:

• Rheumatoid arthritis - moderate to severe
• Psoriatic arthritis
• Ulcerative colitis - moderately to severely active

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Severe hepatic impairment
• Active tuberculosis
• Serious infections, such as sepsis
• Opportunistic infections

Cautions

• Severe renal impairment
• Moderate hepatic impairment
• Elderly
• Known risk factors for venous thromboembolism (VTE)
  - Previous VTE
  - Patients undergoing major surgery
  - Immobilisation
  - Myocardial infarction (within the previous 3 months)
  - Heart failure
  - Use of combined hormonal contraceptives or hormone replacement therapy
  - Inherited coagulation disorder
  - Malignancy
  - Age
  - Obesity (BMI ≥30)
  - Diabetes
  - Hypertension
  - Smoking status
• Risk factors for infections
  - Rheumatoid arthritis patients taking corticosteroids
  - Recurrent infections
  - History of a serious or an opportunistic infection
  - Resided or travelled in areas of endemic mycoses
  - Underlying conditions that predispose patient to infection
  - >65 years of age
  - Diabetes
• Latent or active tuberculosis infection, or history thereof (where adequate treatment course cannot be confirmed or who test negative but have risk factors for TB infection)
  - Exposure to tuberculosis
  - Resided or travelled in areas of endemic tuberculosis
• Risk factors for viral reactivation of herpes zoster
  - Japanese or Korean patients
  - ALC <1000cells/mm³
  - Long-standing rheumatoid arthritis patients who have previously received two or more biological disease modifying antirheumatic drugs
  - Patients treated with 10mg, 12hrly
• Hepatitis B or C
• Current or history of malignancy other than a successfully treated non-melanoma skin cancer
• Highly active rheumatoid arthritis
• Patients at increased risk for skin cancer
• History of chronic lung disease
• Asian patients with rheumatoid arthritis
• Risk factors for gastrointestinal perforation
  - History of diverticulitis
  - Coadministration with corticosteroids and/or non-steroidal anti-inflammatory drugs
• Risk factors for cardiovascular disorders
  - Hyperlipidaemia
  - Hypertension
• Haemoglobin value <9 g/dL
• Patients with increased alanine aminotransferase or aspartate aminotransferase enzymes
• Patients not up to date with required immunisations (See additional prescribing points)
• Patients with a doubtful or unreliable chickenpox history or those seropositive for varicella zoster virus (VZV)
• Coadministration with live vaccines (See additional prescribing points)
• Coadministration with biologics
  - TNF antagonists
  - Interleukin (IL)-1R antagonists
  - IL-6R antagonists
  - Anti-CD20 monoclonal antibodies
  - IL-17 antagonists
  - IL-12/IL-23 antagonists
  - Anti-integrins
  - Selective co-stimulation modulators
• Coadministration with potent immunosuppressants
  - Azathioprine
  - 6-mercaptopurine
  - Ciclosporin
  - Tacrolimus
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

Forms avail in SA and covered in this monograph: tab

Active rheumatoid arthritis - moderate to severe (additional agent may be required)
- In patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic agents
Active psoriatic arthritis (additional agent required)
- In patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug therapy

• Oral (tab): 5mg, 12hrly; Max: 10mg/24hrs

Active ulcerative colitis - moderately to severely active
- In patients who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent

- Induction treatment

• Oral (tab): 10mg, 12hrly; Treatment duration: 8 weeks

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For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5mg twice daily for maintenance

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Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16

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- Maintenance treatment

• Oral (tab): 5-10mg, 12hrly

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Tofacitinib 10mg twice daily for maintenance treatment is not recommended in patients who have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment available

For patients who are not at increased risk for venous thromboembolism, tofacitinib 10mg, 12hrly may be considered if the patient experiences a decrease in response on tofacitinib 5mg, 12hrly and failed to respond to alternative treatment options for ulcerative colitis

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Tofacitinib 10mg,12hrly for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used

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

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- Retreatment in ulcerative colitis (if therapy is interrupted)

• Oral (tab): 10mg, 12hrly; Treatment duration: 8 weeks

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If therapy is interrupted, restarting treatment with tofacitinib can be considered. If there has been a loss of response, reinduction with tofacitinib 10mg 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 10mg twice daily therapy

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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 and temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women
• Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development
• As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated
• Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose

Breastfeeding

• Contraindicated
• It is not known whether tofacitinib is secreted in human milk. A risk to the breastfed child cannot be excluded
• Tofacitinib was secreted in the milk of lactating rats
• As a precautionary measure, the use of tofacitinib during breastfeeding is contraindicated

Fertility

• Formal studies of the potential effect on human fertility have not been conducted. Tofacitnib impaired female fertility but not male fertility in rats

Renal Impairment

• Mild to moderate (CrCl 30-80ml/min): No dose adjustment recommended
• Severe (including haemodialysis) (CrCl <30ml/min): Caution; dose adjustment recommended
  Dose should be reduced to 5mg, dly when the indicated dose in normal renal function is 5mg, 12hrly
  Dose should be reduced to 5mg, 12hrly when the indicated dose in normal renal function is 10mg, 12hrly
  Patients with severe renal impairment should remain on a reduced dose even after haemodialysis

Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
• Moderate (Child-Pugh Class B): Caution; dose adjustment recommended
  Dose should be reduced to 5mg, dly when the indicated dose in normal hepatic function is 5mg, 12hrly
  Dose should be reduced to 5mg, 12hrly when the indicated dose in normal hepatic function is 10mg, 12hrly
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• Caution; no dose adjustment recommended
  There are limited data in patients aged ≥75 years

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
• Paraesthesia
• Fatigue

Cardiovascular Disorders

• Hypertension
• Venous thromboembolism (including pulmonary embolism and deep vein thrombosis)

Respiratory Disorders

• Cough
• Dyspnoea
• Sinus congestion

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Diarrhoea
• Gastritis
• Dyspepsia

Hepatobiliary Disorders

• Hepatic steatosis
• Increased hepatic enzymes
• Increased transaminases
• Abnormal hepatic function test
• Increased gamma glutamyl-transferase

Endocrine and Metabolic Disorders

• Dyslipidaemia
• Hyperlipidaemia
• Dehydration
• Increased blood creatinine phosphokinase
• Increased blood creatinine
• Increased blood cholesterol
• Increased low density lipoprotein
• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Musculoskeletal pain
• Joint swelling
• Tendonitis  
• Ligament sprain
• Muscle strain

Skin and Subcutaneous Tissue Disorders

• Non-melanoma skin cancers
• Rash
• Erythema
• Pruritis

Immune, Blood and Lymphatic System Disorders

• Pneumonia
• Influenza
• Herpes zoster
• Urinary tract infection
• Sinusitis
• Bronchitis
• Nasopharyngitis
• Pharyngitis
• Tuberculosis
• Diverticulitis
• Pyelonephritis
• Cellulitis
• Herpes simplex
• Viral gastroenteritis
• Viral infection
• Sepsis
• Urosepsis
• Disseminated tuberculosis
• Necrotising fasciitis
• Bacteraemia
• Staphylococcal bacteraemia
• Pneumocystis jirovecii pneumonia
• Pneumococcal pneumonia
• Encephalitis
• Atypical mycobacterial infection
• Cytomegalovirus infection
• Bacterial arthritis
• Central nervous system tuberculosis
• Cryptococcal meningitis
• Mycobacterium avium complex infection
• Anaemia
• Leukopenia
• Lymphopenia
• Neutropenia
• Drug hypersensitivity
• Angioedema
• Urticaria
• Fever
• Peripheral oedema

• CYP3A4 inhibitors
• Ketoconazole
• Tacrolimus
• Ciclosporin
• CYP2C19 inhibitors
• Fluconazole
• CYP3A4 inducers
• Rifampicin
• Live vaccines (See additional prescribing points)

• Full blood count
• Lipid profile
• Hepatic function
• Viral hepatitis screening
• Heart rate
• Blood pressure

Additional observations

• Signs and symptoms of infections (including tuberculosis)
• Abdominal symptoms
• Skin examinations

Medicine interactions and dose adjustment recommendations

• 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) as follows:
  - Tofacitinib dose should be reduced to 5mg once daily in patients receiving 5mg twice daily
  - Tofacitinib dose should be reduced to 5mg twice daily in patients receiving 10mg twice daily

Immunisation status 

• Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines
• Prophylactic zoster vaccination should be considered in accordance with vaccination guidelines. Particular consideration should be given to patients with longstanding rheumatoid arthritis  who have previously received two or more biological disease-modifying antirheumatic drugs. If live zoster vaccine is administered; it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus (VZV). If the history of chickenpox is considered doubtful or unreliable it is recommended to test for antibodies against VZV

Coadministration with live vaccines

• It is recommended that live vaccines not be given concurrently with tofacitinib. The decision to use live vaccines prior to tofacitinib treatment should take into account the pre-existing immunosuppression in a given patient
• Vaccination with live vaccines should occur at least 2 weeks but preferably 4 weeks prior to initiation of tofacitinib or in accordance with current vaccination guidelines regarding immunomodulatory medicinal products. No data are available on the secondary transmission of infection by live vaccines to patients receiving tofacitinib

Tofacitinib is a potent, selective inhibitor of the JAK family. In enzymatic assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In contrast, tofacitinib has a high degree of selectivity against other kinases in the human genome. In human cells, tofacitinib preferentially inhibits signaling by heterodimeric cytokine receptors that associate with JAK3 and/or JAK1 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib attenuates signaling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and type II interferons, which will result in modulation of the immune and inflammatory response.

Tablet 5mg

• Xeljanz (Pfizer Laboratories) originator