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Serious and sometimes fatal infections have been reported in patients receiving Upadacitinib. The most frequent serious infections reported with Upadacitinibv included pneumonia and cellulitis,Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with Upadacitinib. Avoid use of Upadacitinib in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Upadacitinib in patients:
• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Upadacitinib. Interrupt Upadacitinib 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 should be interrupted if the patient is not responding to antimicrobial therapy. Upadacitinib may be resumed once the infection is controlled.
In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Upadacitinib.
Malignancies, including lymphomas, were observed in clinical trials of Upadacitinib.In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers.
A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Upadacitinib, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.
Non-Melanoma Skin Cancer NMSCs have been reported in patients treated with Upadacitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen.
In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction(MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated withTNF blockers. Patients who are current or past smokers are at additional increased risk.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Upadacitinib, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue Upadacitinib in patients that have experienced a myocardial infarction or stroke.
Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including Upadacitinib. Many of these adverse events were serious and some resulted in death.
In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.
If symptoms of thrombosis occur, patients should discontinue Upadacitinib and be evaluated promptly and treated appropriately. Avoid Upadacitinib in patients that may be at increased risk of thrombosis.
Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving Upadacitinib in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue Upadacitinib and institute appropriate therapy.
Gastrointestinal perforations have been reported in clinical trials with Upadacitinib. Monitor Upadacitinib-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Evaluate promptly patients presenting with new onset abdominal pain for early identification of gastrointestinal perforation.
Treatment with Upadacitinib was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3).
Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid Upadacitinib initiation and interrupt Upadacitinib treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3) .
ALC less than 500 cells/mm3 were reported in Upadacitinib-treated patients in clinical trials.
Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid Upadacitinib initiation or interrupt Upadacitinib treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3).
Decreases in hemoglobin levels to less than 8 g/dL were reported in Upadacitinib-treated patients in clinical trials.
Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid Upadacitinib initiation or interrupt Upadacitinib treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL).
Treatment with Upadacitinib was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia.
Treatment with Upadacitinib was associated with increased incidence of liver enzyme elevations compared to treatment with placebo.
Evaluate liver enzymes 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 should be interrupted until this diagnosis is excluded.
Based on findings in animal studies, Upadacitinib may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations. Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with Upadacitinib and for 4 weeks following completion of therapy.
Avoid use of live vaccines during or immediately prior to Upadacitinib therapy initiation. Prior to initiating Upadacitinib, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.
from FDA，2023.04
