Upadacitinib

Registered South African indications:

• Active rheumatoid arthritis - moderate to severe

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or to any of its excipients
• Pregnancy
• Breastfeeding
• Severe hepatic impairment (Child-Pugh class C)
• Active tuberculosis
  (See additional prescribing points)
• Active serious infections

International manufacturer recommendations

• Hypersensitivity to the active ingredient or to any of its excipients
• Pregnancy
• Severe hepatic impairment (Child-Pugh class C)
• Active tuberculosis
• Active serious infections

Cautions

South African manufacturer recommendations

• Women of childbearing potential and for 4 weeks following the final dose of upadacitinib
• Severe and end-stage renal impairment
• Elderly (≥65 years of age)
• Chronic or recurrent infection
• Those who have been exposed to tuberculosis
• History of a serious or an opportunistic infection
• Those who have resided or travelled in areas of endemic tuberculosis or endemic mycoses
• Underlying conditions that may predispose them to infection
• Known malignancy or development thereof
• Increased risk for skin cancer
• Cardiovascular risk factors
  - Hypertension
  - Hyperlipidaemia
• High risk for deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
  - Elderly
  - Obesity
  - Medical history of DVT and/or PE
  - Patients undergoing major surgery
  - Prolonged immobilisation
• Positive hepatitis C antibody or hepatitis C virus RNA status
• Positive hepatitis B surface antigen or hepatitis B virus DNA status
• Coadministration with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other Janus kinase (JAK) inhibitors
• Coadministration with live vaccines
  (See additional prescribing points)

International manufacturer recommendations

• Women of childbearing potential and for 4 weeks following the final dose of upadacitinib
  - Female paediatric patients who have commenced/ experienced menarche
• Breastfeeding
• Severe and end-stage renal impairment
• Elderly (≥65 years of age)
• Chronic or recurrent infection
• Those who have been exposed to tuberculosis
• History of a serious or an opportunistic infection
• Those who have resided or travelled in areas of endemic tuberculosis or endemic mycoses
• Underlying conditions that may predispose them to infection
• Positive hepatitis C antibody or hepatitis C virus RNA status
• Positive hepatitis B surface antigen or hepatitis B virus DNA status
• Known malignancy or development thereof
• Increased risk for skin cancer
• Diverticular disease
• Cardiovascular risk factors
  - Hypertension
  - Hyperlipidaemia
• High risk for deep vein thrombosis (DVT) and/or pulmonary embolism (PE)
  - Elderly
  - Obesity
  - Medical history of DVT and/or PE
  - Patients undergoing major surgery
  - Prolonged immobilisation
• Coadministration of chronic treatment with medications associated with an increased risk of diverticulitis, such as nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids
• Coadministration with other potent immunosuppressants such as azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other Janus kinase (JAK) inhibitors
• Coadministration with live vaccines
  (See additional prescribing points)

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment with upadacitinib should be initiated and supervised by medical practitioners experienced in the diagnosis and treatment of rheumatoid arthritis

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 drugs (DMARDs)

• Oral (tab): 15mg, dly

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Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is <500 cells/mm³, an absolute neutrophil count (ANC) that is <1000 cells/mm³ or who have haemoglobin (Hb) levels that are <8g/dl

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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 laboratory abnormalities (see additional prescribing points)

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Upadacitinib is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed

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May be used as monotherapy or in combination with methotrexate

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International manufacturer recommendations

Treatment with upadacitinib should be initiated and supervised by physicians experienced in the diagnosis and treatment of conditions for which upadacitinib is indicated

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 DMARDs
Active psoriatic arthritis (Additional agent may be required)
- In patients who have responded inadequately to, or who are intolerant to one or more DMARDs
Active ankylosing spondylitis
- In patients who have responded inadequately to conventional therapy

• Oral (tab): 15mg, dly

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Consideration should be given to discontinuing treatment in patients with ankylosing spondylitis who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks

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May be used as monotherapy or in combination with methotrexate for the indication of active rheumatoid and psoriatic arthritis respectively

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Atopic dermatitis - moderate to severe
- In those who are candidates for systemic therapy

• Oral (tab): 15-30mg, dly based on individual patient presentation; High disease burden OR inadequate response to 15mg, dly: Oral (tab): 30mg, dly; Maintenance: Consider lowest effective dose

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Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas

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Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment

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For all indications; treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is <0.5x10⁹ cells/l, an absolute neutrophil count (ANC) that is <1x10⁹cells/l or who have haemoglobin (Hb) levels that are <8g/dl

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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 laboratory abnormalities (see additional prescribing points)

---

Upadacitinib is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly

Paed. forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

• Not established for use in children below 18 years

International manufacturer recommendations

Atopic dermatitis - moderate to severe
- In those who are candidates for systemic therapy

Younger than 12 years

• Not established for use

12 years and older

• Oral (tab): ≥30kg: 15mg, dly

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Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas

---

Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment

---

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is <0.5x10⁹ cells/l, an absolute neutrophil count (ANC) that is <1 x10⁹cells/l or who have haemoglobin (Hb) levels that are <8g/dl

---

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 laboratory abnormalities (see additional prescribing points)

---

Upadacitinib is to be taken orally once daily with or without food and may be taken at any time of the day. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly

Pregnancy 

South African manufacturer recommendations

• Contraindicated
• There are no or limited data on the use of upadacitinib in pregnant women
• Studies in animals have shown reproductive toxicity
• Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero
• If a patient becomes pregnant while taking upadacitinib the patient should be informed of the potential risk to the foetus
• Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib

International manufacturer recommendations

• Contraindicated
• There are no or limited data on the use of upadacitinib in pregnant women
• Studies in animals have shown reproductive toxicity
• Upadacitinib was teratogenic in rats and rabbits with effects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero
• If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potential risk to the foetus
• Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib
• Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Mothers taking upadacitinib should not breastfeed their babies
• It is unknown whether upadacitinib /metabolites are excreted in human milk
• Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk
• A risk to newborns/infants cannot be excluded

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether upadacitinib/metabolites are excreted in human milk
• Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk
• A risk to newborns/infants cannot be excluded
• Upadacitinib should not be used during breastfeeding
• A decision must be made whether to discontinue breastfeeding or to discontinue upadacitinib therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• The effect of upadacitinib on human fertility has not been evaluated
• Animal studies do not indicate effects with respect to fertility

Renal Impairment

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe/ End-stage: Caution; no information available 

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; dose adjustment recommended  
  Oral (tab): 15mg, dly; Max: 15mg/24hrs
• End-stage: Caution; no information available 

Hepatic Impairment

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended 
• Severe (Child-Pugh class C): Contraindicated 

Elderly

South African manufacturer recommendations

• ≥65 years: Caution; no dose adjustment recommended 
• ≥75 years: Caution; no information available 
  As there is a higher incidence of infections in the elderly ≥75 years of age, caution should be used when treating this population

International manufacturer recommendations

• ≥65 years: Atopic dermatitis: Caution; dose adjustment recommended 
  Oral (tab): 15mg, dly; Max: 15mg/24hrs
• ≥65 years: Active rheumatoid arthritis/ Active psoriatic arthritis/ Active ankylosing spondylitis: Caution; no dose adjustment recommended 
  As there is a higher incidence of infections in the elderly ≥65 years of age, caution should be used when treating this population
• ≥75 years: Caution; no information available 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue
• Headache
• Bacterial meningitis

Respiratory Disorders

• Upper respiratory tract infections
• Bronchitis
• Influenza
• Cough
• Pneumonia
• Cryptococcosis

Gastrointestinal Disorders

• Abdominal pain
• Nausea
• Oral candidiasis
• Oesophageal candidiasis
• Diverticulitis
  (See additional prescribing points)

Hepatobiliary Disorders

• Increased alanine transaminase ≥3 x ULN
• Increased aspartate transaminase ≥3 x ULN

Genitourinary Disorders

• Urinary tract infections

Endocrine and Metabolic Disorders

• Hypercholesterolaemia
  - Elevations in LDL cholesterol, HDL cholesterol and total cholesterol
• Hypertriglyceridaemia
• Increased weight

Musculoskeletal Disorders

• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Acne
• Urticaria
• Folliculitis
• Cellulitis
• Non-melanoma skin cancer
• Eczema herpeticum

Immune, Blood and Lymphatic System Disorders

• Herpes zoster
  - Multidermatomal herpes zoster
• Herpes simplex
• Anaemia
• Neutropaenia
• Pyrexia
• Infections
  - Serious infections (sometimes fatal)
  (See additional prescribing points)
• Opportunistic infections
  - Tuberculosis
• Malignancy

• Strong CYP3A4 inhibitors (chronic treatment)
• Ketoconazole
• Itraconazole
• Posaconazole
• Voriconazole
• Clarithromycin
• Strong CYP3A4 inducers
• Rifampicin
• Phenytoin

Other interactions

• Grapefruit
• Grapefruit juice

• Lymphocyte count
• Neutrophil count
• Haemoglobin
• Hepatic function
• Lipid profile
• Viral hepatitis status
• Latent and active tuberculosis screening

Specific cases may require

• Pregnancy status

Additional observations

• Signs and symptoms of infection (including tuberculosis)
• Skin examinations
• Symptoms of thrombosis

Vaccination

• No data are available on the response to vaccination with live vaccines in patients receiving upadacitinib
• Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy is not recommended
• Prior to initiating upadacitinib, it is recommended that patients be brought up to date with all immunisations, including prophylactic zoster vaccinations, in agreement with current immunisation guidelines

Tuberculosis (TB)

• Patients should be screened for tuberculosis before starting upadacitinib therapy
• Upadacitinib should not be given to patients with active TB
• Anti-TB therapy should be considered prior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with risk factors for TB infection
• Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient
• Patients should be monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy

Serious infections

• Serious and sometimes fatal infections have been reported in patients receiving upadacitinib
• Upadacitinib should not be initiated in patients with an active, serious infection, including localised infections
• Consider the risks and benefits of treatment prior to initiating upadacitinib in patients: 
• Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with upadacitinib
• Upadacitinib therapy should be interrupted if a patient develops a serious or opportunistic infection
• A patient who develops a new infection during treatment with upadacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding to antimicrobial therapy
• Upadacitinib therapy may be resumed once the infection is controlled and only following a careful consideration of benefit-risk

Viral reactivation

• Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported in clinical studies
• The risk of herpes zoster appears to be higher in Japanese patients treated with upadacitinib
• If a patient develops herpes zoster, interruption of upadacitinib therapy should be considered until the episode resolves
• Screening for viral hepatitis and monitoring for reactivation should be performed before starting and during therapy with upadacitinib
• Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies
• Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical studies
• If hepatitis B virus DNA is detected while receiving upadacitinib, a liver specialist should be consulted

Malignancy

• The risk of malignancies, including lymphoma is increased in patients with rheumatoid arthritis
• Immunomodulatory medicinal agents may increase the risk of malignancies, including lymphoma
• The clinical data are currently limited and long-term studies are ongoing
• Malignancies were observed in clinical studies of upadacitinib
• The risks and benefits of upadacitinib treatment should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing upadacitinib therapy in patients who develop a malignancy

Diverticulitis

• Events of diverticulitis have been reported in clinical trials and from post marketing sources
• Diverticulitis may cause gastrointestinal perforation
• Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis: nonsteroidal anti inflammatory drugs, corticosteroids, and opioids
• Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation

Hepatic transaminase elevations

• Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo
• Evaluate at baseline and thereafter according to routine patient management
• Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury
• If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded

Management of laboratory abnormalities

Laboratory measure	Action	Monitoring guidance
ANC	Treatment should be interrupted if ANC is <1000 cells/mm3 and may be restarted once ANC returns above this value	Evaluate at baseline and thereafter according to routine patient management
ALC	Treatment should be interrupted if ALC is <500 cells/mm3 and may be restarted once ALC returns above this value
Hb	Treatment should be interrupted if Hb is <8 g/dl and may be restarted once Hb returns above this value
Hepatic transaminases	Treatment should be temporarily interrupted if drug-induced liver injury is suspected
Lipids	Patients should be managed according to international clinical guidelines for hyperlipidaemia	12 weeks after initiation of treatment and thereafter according to international clinical guidelines for hyperlipidaemia

Upadacitinib is a selective and reversible Janus Kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit cytokine or growth factor signals involved in a broad range of cellular processes including inflammatory responses, hematopoiesis and immune surveillance. The JAK family of enzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylate and activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn, modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signals while JAK2 is important for red blood cell maturation and JAK3 signals play a role in immune surveillance and lymphocyte function. In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2.

Tablet 15mg

• Rinvoq (AbbVie) originator