Included as part of the "PRECAUTIONS" Section
Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The
most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see ADVERSE REACTIONS]. Among opportunistic infections, tuberculosis, multidermatomal herpes
zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ.
Avoid use of RINVOQ in patients with an active, serious infection, including localized
infections. Consider the risks and benefits of treatment prior to initiating RINVOQ 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 RINVOQ. Interrupt RINVOQ if a patient develops a serious or opportunistic
infection. A patient who develops a new infection during treatment with RINVOQ 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 RINVOQ should be interrupted if the patient is not responding to antimicrobial therapy.
RINVOQ may be resumed once the infection is controlled.
Patients should be screened for tuberculosis (TB) before starting RINVOQ therapy. RINVOQ
should not be given to patients with active TB. Anti-TB therapy should be considered prior to
initiation of RINVOQ in patients with previously untreated latent TB or active TB in whom an
adequate course of treatment cannot be confirmed, and for patients with a negative test for latent
TB but who have 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.
Monitor patients for the development of signs and symptoms of TB, including patients who
tested negative for latent TB infection prior to initiating therapy.
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis
B virus reactivation, were reported in clinical studies with RINVOQ [see ADVERSE REACTIONS]. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ until the
Screening for viral hepatitis and monitoring for reactivation should be performed in accordance
with clinical guidelines before starting and during therapy with RINVOQ. 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. However, cases of hepatitis B reactivation were still reported in
patients enrolled in the Phase 3 studies of RINVOQ. If hepatitis B virus DNA is detected while
receiving RINVOQ, a liver specialist should be consulted.
Malignancies were observed in clinical studies of RINVOQ [see ADVERSE REACTIONS].
Consider the risks and benefits of RINVOQ treatment prior to initiating therapy in patients with
a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or
when considering continuing RINVOQ in patients who develop a malignancy.
Non-Melanoma Skin Cancer
NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is
recommended for patients who are at increased risk for skin cancer.
Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis,
have occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors,
including RINVOQ. Many of these adverse events were serious and some resulted in death.
Consider the risks and benefits of RINVOQ treatment prior to treating patients who may be at
increased risk of thrombosis. If symptoms of thrombosis occur, patients should be evaluated
promptly and treated appropriately.
Events of gastrointestinal perforation have been reported in clinical studies with RINVOQ,
although the role of JAK inhibition in these events is not known. In these studies, many patients
with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-
Inflammatory Drugs (NSAIDs).
RINVOQ should be used with caution in patients who may be at increased risk for
gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).
Patients presenting with new onset abdominal symptoms should be evaluated promptly for early
identification of gastrointestinal perforation.
Treatment with RINVOQ 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 initiation of or interrupt RINVOQ treatment in patients with a low neutrophil count (i.e.,
ANC less than 1000 cells/mm3) [see DOSAGE AND ADMINISTRATION].
ALC less than 500 cells/mm3 were reported in RINVOQ clinical studies.
Evaluate lymphocyte counts at baseline and thereafter according to routine patient management.
Avoid initiation of or interrupt RINVOQ treatment in patients with a low lymphocyte count (i.e.,
less than 500 cells/mm3) [see DOSAGE AND ADMINISTRATION].
Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ clinical studies.
Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid
initiation of or interrupt RINVOQ treatment in patients with a low hemoglobin level (i.e., less
than 8 g/dL) [see DOSAGE AND ADMINISTRATION].
Treatment with RINVOQ was associated with increases in lipid parameters, including total
cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL)
cholesterol [see ADVERSE REACTIONS]. Elevations in LDL cholesterol decreased to pretreatment
levels in response to statin therapy. The effect of these lipid parameter elevations on
cardiovascular morbidity and mortality has not been determined.
Patients should be monitored 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.
Liver Enzyme Elevations
Treatment with RINVOQ was associated with 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, RINVOQ should be interrupted until this diagnosis is excluded.
Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a
pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused
increases in fetal malformations. Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception during treatment with RINVOQ
and for 4 weeks following completion of therapy [see Use In Specific Populations].
Use of live, attenuated vaccines during, or immediately prior to, RINVOQ therapy is not
recommended. Prior to initiating RINVOQ, it is recommended that patients be brought up to date
with all immunizations, including prophylactic zoster vaccinations, in agreement with current
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients that they may be more likely to develop infections when taking RINVOQ.
Instruct patients to contact their healthcare provider immediately during treatment if they
develop any signs or symptoms of an infection [see WARNINGS AND PRECAUTIONS].
Advise patients that the risk of herpes zoster is increased in patients taking RINVOQ and in
some cases can be serious [see WARNINGS AND PRECAUTIONS].
Inform patients that RINVOQ may increase their risk of certain cancers. Instruct patients to
inform their healthcare provider if they have ever had any type of cancer [see WARNINGS AND PRECAUTIONS].
Advise patients that events of DVT and PE have been reported in clinical studies with RINVOQ.
Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT
or PE [see WARNINGS AND PRECAUTIONS].
Inform patients that RINVOQ may affect certain lab tests, and that blood tests are required
before and during RINVOQ treatment [see WARNINGS AND PRECAUTIONS].
Advise pregnant women and females of reproductive potential that exposure to RINVOQ during
pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a
known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Advise females of reproductive potential that effective contraception should
be used during treatment and for 4 weeks following the final dose of upadacitinib [see Use In Specific Populations].
Advise women not to breastfeed during treatment with RINVOQ [see Use In Specific Populations].
Advise patients not to chew, crush, or split RINVOQ tablets [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of upadacitinib was evaluated in Sprague-Dawley rats and Tg.rasH2
mice. No evidence of tumorigenicity was observed in male or female rats that received
upadacitinib for up to 101 weeks at oral doses up to 15 or 20 mg/kg/day, respectively
(approximately 4 and 10 times the MRHD on an AUC basis, respectively). No evidence of
tumorigenicity was observed in male or female Tg.rasH2 mice that received upadacitinib for 26
weeks at oral doses up to 20 mg/kg/day.
Upadacitinib tested negatively in the following genotoxicity assays: the in vitro bacterial
mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral
blood lymphocytes, and in vivo rat bone marrow micronucleus assay.
Impairment Of Fertility
Upadacitinib had no effect on fertility in male or female rats at oral doses up to 50 mg/kg/day in
males and 75 mg/kg/day in females (approximately 42 and 84 times the MRHD in males and
females, respectively, on an AUC basis). However, maintenance of pregnancy was adversely
affected at oral doses of 25 mg/kg/day and 75 mg/kg/day based upon dose-related findings of
increased post-implantation losses (increased resorptions) and decreased numbers of mean viable
embryos per litter (approximately 22 and 84 times the MRHD on an AUC basis, respectively).
The number of viable embryos was unaffected in female rats that received upadacitinib at an oral
dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 2
times the MRHD on an AUC basis).
Use In Specific Populations
The limited human data on use of RINVOQ in pregnant women are not sufficient to evaluate a
drug-associated risk for major birth defects or miscarriage. Based on animal studies, upadacitinib
has the potential to adversely affect a developing fetus.
In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats
and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the maximum
recommended human dose (MRHD), respectively, resulted in dose-related increases in skeletal
malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only),
increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and
rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral
upadacitinib during organogenesis at approximately 0.3 and 2 times the exposure at the MRHD.
In a pre- and post-natal development study in pregnant female rats, oral upadacitinib
administration at exposures approximately 3 times the MRHD resulted in no maternal or
developmental toxicity [see Animal Data].
The estimated background risks of major birth defects and miscarriage for the indicated
population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriages are 2-4% and 15-20%, respectively.
Disease-Associated Maternal and/or Embryo/Fetal Risk
Published data suggest that increased disease activity is associated with the risk of developing
adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes
include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g)
infants, and small for gestational age at birth.
In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25,
and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib
was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula)
at exposures equal to or greater than approximately 1.7 times the MRHD (on an AUC basis at
maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent
forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed
in the absence of maternal toxicity at an exposure approximately 84 times the MRHD (on an
AUC basis at a maternal oral dose of 75 mg/kg/day).
In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of
1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib
was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures
approximately 1.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day).
No developmental toxicity was observed in rats at an exposure approximately 0.3 times the
MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).
In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of
2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19.
Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed
in the presence of maternal toxicity at an exposure approximately 15 times the MRHD (on an
AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased
post-implantation loss that was due to elevated incidences of both total and early resorptions. No
developmental toxicity was observed in rabbits at an exposure approximately 2 times the MRHD
(on an AUC basis at a maternal oral dose of 10 mg/kg/day).
In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at
doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or
developmental toxicity was observed in either mothers or offspring, respectively, at an exposure
approximately 3 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
There are no data on the presence of upadacitinib in human milk, the effects on the breastfed
infant, or the effects on milk production. Available pharmacodynamic/toxicological data in
animals have shown excretion of upadacitinib in milk. When a drug is present in animal milk, it
is likely that the drug will be present in human milk. Because of the potential for serious adverse
reactions in the breastfed infant, advise patients that breastfeeding is not recommended during
treatment with upadacitinib, and for 6 days (approximately 10 half-lives) after the last dose.
A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female
Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater
in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related
material in milk was parent drug.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to starting treatment with
RINVOQ [see Pregnancy].
Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to
pregnant women [see Pregnancy]. Advise female patients of reproductive
potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the
The safety and efficacy of RINVOQ in children and adolescents aged 0 to 18 years have not yet
been established. No data are available.
Of the 4381 patients treated in the five Phase 3 clinical studies, a total of 906 rheumatoid arthritis
patients were 65 years of age or older, including 146 patients 75 years and older. No differences
in effectiveness were observed between these patients and younger patients; however, there was
a higher rate of overall adverse events in the elderly.
No dose adjustment is required in patients with mild, moderate or severe renal impairment. The
use of RINVOQ has not been studied in subjects with end stage renal disease [see CLINICAL PHARMACOLOGY].
No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B)
hepatic impairment. RINVOQ is not recommended for use in patients with severe hepatic
impairment (Child Pugh C) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].