Included as part of the PRECAUTIONS section.
ARAVA may cause fetal harm when administered to a
pregnant woman. Teratogenicity and embryo-lethality occurred in animal
reproduction studies with leflunomide at doses lower than the human exposure
level [see Use In Specific Populations].
ARAVA is contraindicated for use in pregnant women [see
CONTRAINDICATIONS]. Exclude pregnancy before starting treatment with ARAVA
in females of reproductive potential [see DOSAGE AND ADMINISTRATION].
Advise females of reproductive potential to use effective contraception during
ARAVA treatment and during an accelerated drug elimination procedure after
ARAVA treatment [see Use In Specific Populations]. If a woman becomes
pregnant while taking ARAVA, stop treatment with ARAVA, apprise the patient of
the potential risk to a fetus, and perform an accelerated drug elimination
procedure to achieve non-detectable plasma concentrations of teriflunomide, the
active metabolite of leflunomide [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite].
Upon discontinuing ARAVA, it is recommended that all
females of reproductive potential undergo an accelerated drug elimination
procedure. Women receiving ARAVA treatment who wish to become pregnant must
discontinue ARAVA and undergo an accelerated drug elimination procedure, which
includes verification that plasma concentrations of the active metabolite of
leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on
animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L
(0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see CONTRAINDICATIONS,
Procedure for Accelerated Elimination of ARAVA and its Active Metabolite, and Use In Specific Populations].
Severe liver injury, including fatal liver failure, has
been reported in some patients treated with ARAVA. Patients with pre-existing
acute or chronic liver disease, or those with serum alanine aminotransferase
(ALT) of greater than twice the upper limits of normal ( > 2xULN) before
initiating treatment, should not be treated with ARAVA. Use caution when ARAVA
is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is
recommended at least monthly for six months after starting ARAVA, and
thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt
ARAVA therapy and investigate the cause. If likely ARAVA-induced, perform the
accelerated drug elimination procedure and monitor liver tests weekly until
normalized [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite] If ARAVA-induced liver injury
is unlikely because some other cause has been found, resumption of ARAVA
therapy may be considered.
If ARAVA and methotrexate are given concomitantly, follow
the American College of Rheumatology (ACR) guidelines for monitoring
methotrexate liver toxicity with ALT, AST, and serum albumin testing.
Procedure For Accelerated Elimination Of ARAVA And Its Active
The active metabolite of leflunomide, teriflunomide, is
eliminated slowly from the plasma [see CLINICAL PHARMACOLOGY].
Use of an accelerated drug elimination procedure will
rapidly reduce plasma concentrations of leflunomide and its active metabolite,
teriflunomide. Therefore, an accelerated elimination procedure should be
considered at any time after discontinuation of ARAVA, and in particular, when
a patient has experienced a severe adverse reaction (e.g., hepatotoxicity,
serious infection, bone marrow suppression, Steven Johnson Syndrome, toxic
epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected
hypersensitivity, or has become pregnant. It is recommended that all women of
childbearing potential undergo an accelerated elimination procedure after
stopping ARAVA treatment.
Without use of an accelerated drug elimination procedure,
it may take up to 2 years to reach plasma teriflunomide concentrations of less
than 0.02 mg/L, the plasma concentration not associated with embryo-fetal
toxicity in animals.
Elimination can be accelerated by the following
- Administer cholestyramine 8 grams orally 3 times daily
for 11 days.
- Alternatively, administer 50 grams of activated
charcoal powder (made into a suspension) orally every 12 hours for 11 days.
Verify plasma teriflunomide concentrations of less than
0.02 mg/L (0.02 μg/mL) by two separate tests at least 14 days apart. If
plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat
cholestyramine and/or activated charcoal treatment.
The duration of accelerated drug elimination treatment
may be modified based on the clinical status and tolerability of the
elimination procedure. The procedure may be repeated as needed, based on
teriflunomide concentrations and clinical status.
Use of the accelerated drug elimination procedure may
potentially result in return of disease activity if the patient had been
responding to ARAVA treatment.
Immunosuppression, Bone Marrow Suppression, And Risk Of Serious
ARAVA is not recommended for patients with severe
immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If
a serious infection occurs, consider interrupting ARAVA therapy and initiating
the accelerated drug elimination procedure [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite].
Medications like ARAVA that have immunosuppression potential may cause patients
to be more susceptible to infections, including opportunistic infections,
especially Pneumocystis jiroveci pneumonia, tuberculosis (including
extra-pulmonary tuberculosis), and aspergillosis. Severe infections including
sepsis, which may be fatal, have been reported in patients receiving ARAVA,
especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of
the reports were confounded by concomitant immunosuppressant therapy and/or
comorbid illness which, in addition to rheumatoid arthritis, may predispose
patients to infection.
Cases of tuberculosis were observed in clinical studies
with teriflunomide, the metabolite of ARAVA. Prior to initiating ARAVA, all
patients should be screened for active and inactive (“latent”) tuberculosis
infection as per commonly used diagnostic tests. ARAVA has not been studied in
patients with a positive tuberculosis screen, and the safety of ARAVA in
individuals with latent tuberculosis infection is unknown. Patients testing
positive in tuberculosis screening should be treated by standard medical
practice prior to therapy with ARAVA and monitored carefully during ARAVA
treatment for possible reactivation of the infection.
Pancytopenia, agranulocytosis and thrombocytopenia have
been reported in patients receiving ARAVA alone. These events have been
reported most frequently in patients who received concomitant treatment with
methotrexate or other immunosuppressive agents, or who had recently
discontinued these therapies; in some cases, patients had a prior history of a
significant hematologic abnormality.
Patients taking ARAVA should have platelet, white blood
cell count and hemoglobin or hematocrit monitored at baseline and monthly for
six months following initiation of therapy and every 6- to 8 weeks thereafter.
If used with concomitant methotrexate and/or other potential immunosuppressive
agents, chronic monitoring should be monthly. If evidence of bone marrow
suppression occurs in a patient taking ARAVA, stop treatment with ARAVA, and perform
an accelerated drug elimination procedure to reduce the plasma concentration of
the ARAVA active metabolite, teriflunomide [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite].
In any situation in which the decision is made to switch
from ARAVA to another anti-rheumatic agent with a known potential for
hematologic suppression, it would be prudent to monitor for hematologic
toxicity, because there will be overlap of systemic exposure to both compounds.
Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, And
Drug Reactions With Eosinophilia And Systemic Symptoms
Rare cases of Stevens-Johnson syndrome and toxic
epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms
(DRESS) have been reported in patients receiving ARAVA. If a patient taking
ARAVA develops any of these conditions, stop ARAVA treatment and perform an
accelerated drug elimination procedure [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite].
Malignancy And Lymphoproliferative Disorders
The risk of malignancy, particularly lymphoproliferative
disorders, is increased with the use of some immunosuppression medications.
There is a potential for immunosuppression with ARAVA. No apparent increase in
the incidence of malignancies and lymphoproliferative disorders was reported in
the clinical trials of ARAVA, but larger dosages and longer-term studies would
be needed to determine whether there is an increased risk of malignancy or
lymphoproliferative disorders with ARAVA.
Cases of peripheral neuropathy have been reported in
patients receiving ARAVA and in clinical studies with teriflunomide, the active
metabolite of leflunomide. Most patients recovered after discontinuation of
treatment, but some patients had persistent symptoms. Age older than 60 years,
concomitant neurotoxic medications, and diabetes may increase the risk for
peripheral neuropathy. If a patient taking ARAVA develops a peripheral
neuropathy, consider discontinuing ARAVA therapy and performing an accelerated
drug elimination procedure [see DOSAGE AND ADMINISTRATION].
Interstitial Lung Disease
Interstitial lung disease and worsening of pre-existing
interstitial lung disease have been reported during treatment with ARAVA and
has been associated with fatal outcomes [see ADVERSE REACTIONS]. The
risk of ARAVA-associated interstitial lung disease is increased in patients
with a history of interstitial lung disease. Interstitial lung disease is a
potentially fatal disorder that may occur acutely at any time during therapy
and has a variable clinical presentation. New onset or worsening pulmonary
symptoms, such as cough and dyspnea, with or without associated fever, may be a
reason for discontinuation of ARAVA therapy and for further investigation as appropriate.
If discontinuation of ARAVA is necessary, consider performing an accelerated
drug elimination procedure [see Procedure for Accelerated Elimination of ARAVA and its Active Metabolite].
No clinical data are available on the efficacy and safety
of vaccinations during ARAVA treatment. Vaccination with live vaccines is,
however, not recommended. The long half-life of the active metabolite of ARAVA
should be considered when contemplating administration of a live vaccine after
Blood Pressure Monitoring
In placebo-controlled studies with the active metabolite
of ARAVA, teriflunomide, elevations in blood pressure were observed in some
subjects. Blood pressure should be checked before starting treatment with ARAVA
and monitored periodically thereafter [See ADVERSE REACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No evidence of carcinogenicity was observed in a 2-year
bioassay in rats at oral doses of leflunomide up to the maximally tolerated
dose of 6 mg/kg (approximately 1/40 the maximum human teriflunomide systemic
exposure based on AUC). However, male mice in a 2-year bioassay exhibited an
increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose
studied (1.7 times the human teriflunomide exposure based on AUC). Female mice,
in the same study, exhibited a dose-related increased incidence of
bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately
1/10 the human teriflunomide exposure based on AUC). The significance of the
findings in mice relative to the clinical use of ARAVA is not known.
Leflunomide was not mutagenic in the Ames assay, the
unscheduled DNA synthesis assay, or in the HGPRT gene mutation assay. In
addition, leflunomide was not clastogenic in the in vivo mouse micronucleus
assay or in the in vivo Chinese hamster bone marrow cell cytogenic test.
However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was
mutagenic in the Ames assay and in the HGPRT gene mutation assay, and was
clastogenic in the in vitro Chinese hamster cell chromosomal aberration assay.
TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in
vivo Chinese hamster bone marrow cell cytogenic test.
Leflunomide had no effect on fertility or reproductive
performance in either male or female rats at oral doses up to 4.0 mg/kg
(approximately 1/30 the human teriflunomide exposure based on AUC) [see Use
in Specific Populations].
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care
providers and patients are encouraged to report pregnancies by calling
1-877-311-8972 or visit http://www.pregnancystudies.org/participate-ina-study/.
ARAVA is contraindicated for use in pregnant women
because of the potential for fetal harm. In animal reproduction studies, oral
administration of leflunomide during organogenesis at a dose of 1/10 of and
equivalent to the maximum recommended human dose (MRHD) based on AUC,
respectively in rats and rabbits, caused teratogenicity (rats and rabbits) and
embryo-lethality (rats) [see Data]. Pregnancy exposure registry data are
not available at this time to inform the presence or absence of drug-associated
risk with the use of ARAVA during pregnancy. The background risk of major birth
defects and miscarriage for the indicated populations is unknown. The
background risk in the U.S. general population of major birth defects is 2-4%
and of miscarriage is 15-20% of clinically recognized pregnancies. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking this
drug, stop treatment with ARAVA, apprise the patient of the potential hazard to
a fetus, and perform the accelerated drug elimination procedure to achieve
teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see WARNINGS
Fetal/Neonatal Adverse Reactions
Lowering the plasma concentration of the active
metabolite, teriflunomide, by instituting an accelerated drug elimination
procedure as soon as pregnancy is detected may decrease the risk to the fetus
from ARAVA. The accelerated drug elimination procedure includes verification
that the plasma teriflunomide concentration is less than 0.02 mg/L. [see WARNINGS
AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
In an embryofetal development study, pregnant rats
administered leflunomide during organogenesis from gestation days 7 to 19 at a
dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of
15 mg/kg), teratogenic effects, most notably anophthalmia or microophthalmia
and internal hydrocephalus, were observed. Under these exposure conditions,
leflunomide also caused a decrease in the maternal body weight and an increase
in embryolethality with a decrease in fetal body weight for surviving fetuses.
In an embryofetal development study, pregnant rabbits administered leflunomide
during organogenesis from gestation days 6 to 18 at a dose approximately
equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a
teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide
was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10
of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in
both rats and rabbits).
In a pre- and post-natal development study, when female
rats were treated leflunomide at a dose that was approximately 1/100 of the
MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days
before mating and continuing until the end of lactation, the offspring
exhibited marked (greater than 90%) decreases in postnatal survival.
Clinical lactation studies have not been conducted to
assess the presence of ARAVA in human milk, the effects of ARAVA on the
breastfed child, or the effects of ARAVA on milk production. Because of the
potential for serious adverse reactions in a breastfed infant from ARAVA,
advise a nursing woman to discontinue breastfeeding during treatment with
Females And Males Of Reproductive Potential
ARAVA may cause fetal harm when administered during
pregnancy. Advise females of the potential risk to the fetus. Advise females to
notify their healthcare provider immediately if pregnancy occurs or is
suspected during treatment [see Use in Specific Populations]. Women
receiving ARAVA treatment who wish to become pregnant should discontinue ARAVA
and undergo an accelerated drug elimination procedure to achieve plasma
teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see WARNINGS
Exclude pregnancy in females of reproductive potential
before starting treatment with ARAVA.
Advise females of reproductive potential to use effective
contraception during treatment with ARAVA and while undergoing a drug
elimination procedure until verification that the plasma teriflunomide concentration
is less than 0.02 mg/L [see WARNINGS AND PRECAUTIONS].
The safety and effectiveness of ARAVA in pediatric
patients have not been established.
The safety and effectiveness of ARAVA in the treatment of
polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a
single multicenter, double-blind, active-controlled trial in 94 pediatric
patients (1:1 randomization) with polyarticular course juvenile idiopathic
arthritis (JIA) as defined by the American College of Rheumatology (ACR). In
this population, ARAVA treatment was found not to be effective.
The safety of ARAVA was studied in 74 patients with
polyarticular course JIA ranging in age from 3-17 years (47 patients from the
active-controlled study and 27 from an open-label safety and pharmacokinetic
study). The most common adverse events included abdominal pain, diarrhea,
nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia,
rash, headache, and dizziness. Less common adverse events included anemia,
hypertension, and weight loss. Fourteen pediatric patients experienced ALT
and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal,
five between 3 and 8-fold the upper limit of normal.
Of the total number of subjects in controlled clinical
trials (Trials 1, 2, and 3) of ARAVA, 234 subjects were 65 years and over [see Clinical
Studies]. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled
out. No dosage adjustment is needed in patients over 65.
Dedicated studies of the effect of hepatic impairment on
leflunomide pharmacokinetics have not been conducted. Given the need to
metabolize leflunomide into the active species, the role of the liver in drug
elimination/recycling, and the possible risk of increased hepatic toxicity, the
use of ARAVA in patients with hepatic impairment is not recommended.
Dedicated studies of the effect of renal impairment on
leflunomide pharmacokinetics have not been conducted. Given that the kidney
plays an important role in drug elimination, caution should be used when ARAVA
is administered to these patients.