Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 08 May 2018
4 CONTRAINDICATIONS ARAVA is contraindicated in: Pregnant women.
Arava may cause fetal
If a woman becomes pregnant while taking this drug, stop ARAVA, apprise the patient of the potential
Patients with known hypersensitivity to leflunomide or any of the other components of ARAVA. Known reactions include anaphylaxis [see
Patients being treated with teriflunomide [see Drug Interactions (7)].
(4, 5.1, 8.1)
(4, 5.2) Hypersensitivity to ARAVA or any of its
(4) Current teriflunomide treatment.
(6.1) To report SUSPECTED
In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with ARAVA administered as either monotherapy or in combination with methotrexate or sulfasalazine.
Patients ranged in age from 19 to 85 years, with an overall median age of 58 years.
Elevation of Liver Enzymes Treatment with ARAVA was associated with elevations of liver enzymes, primarily ALT and AST, in a
2-fold ULN) and usually
Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment.
Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2.
All patients in Trial 1 received folate.
Trial 1 Trial 2 Trial 3 ARAVA PL MTX ARAVA PL SSZ ARAVA MTX 20 mg/day (n= 182) (n=118) 7.5 - 15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2.0 g/day (n=133) 20 mg/day (n=501) 7.5 - 15 mg/wk (n=498) MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal ALT (SGPT) >3-fold ULN (n %) 8 (4.4) 3 (2.5) 5 (2.7) 2 (1.5) 1 (1.1) 2 (1.5) 13 (2.6) 83 (16.7) Reversed to?
2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0-3 Months 6 1 1 2 1 2 7 27 4-6 Months 1 1 3
1 34 7-9 Months 1 1 1
16 10-12 Months
5 6 In
Table 2 displays the
5 % in any ARAVA treatment group).
All patients in Trial 1 received folate; none in Trial 2 received folate.
ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2.0 g/day (n=133) MTX 7.5 - 15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5 - 15 mg/wk (n=498) ARAVA (n=1339)Includes all
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine Diarrhea 27 % 12 % 10 % 20 % 22 % 10 % 17 %
9 % 4 % 4 % 3 % 10 % 4 % 10 % Asthenia 6 % 4 % 5 % 6 % 3 % 3 % 3 % Back
Blood and Lymphatic System: leukocytosis, thrombocytopenia; Cardiovascular: chest
Because these reactions are reported voluntarily from
Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;
2 DOSAGE AND ADMINISTRATION Loading dosage for patients at
(2.1) Maintenance dosage: 20 mg daily.
(2.1)?If 20 mg once daily is not tolerated,
(2.1) Screen patients for active and latent tuberculosis, pregnancy test (females),
Treatment may be initiated with or without a loading dose, depending upon the patient 's risk of ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression.
The loading dosage provides steady-state concentrations more rapidly.
For patients who are at
Subsequently administer 20 mg once daily.
For patients at
Consider dosage reduction to 10 mg once
After stopping ARAVA treatment,
Without use of an accelerated drug
2.2 Evaluation and Testing Prior to Starting ARAVA Prior to starting ARAVA treatment
8 USE IN SPECIFIC POPULATIONS Lactation:
(8.4) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy.
Risk Summary ARAVA is contraindicated for use in pregnant women because of the
In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of and equivalent to the maximum
The background risk of major birth
The background risk in the U.S. general population of
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
Clinical Considerations Fetal/Neonatal
The accelerated drug
Data Animal Data In an embryofetal development study, pregnant
Under these exposure conditions, leflunomide also caused
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
In a pre - and post-natal development study, when female
8.2 Lactation Risk Summary 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
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 (8.1)].
Women receiving ARAVA treatment who wish to become pregnant should
Pregnancy Testing Exclude pregnancy in females of reproductive
8.4 Pediatric Use The
In this population, ARAVA treatment was found not to be
Fourteen pediatric patients
8.5 Geriatric Use Of the total number of subjects in
Given that the kidney plays an
|Agency product number||G162GK9U4W|
|Date Last Revised||29-02-2016|
|Type||HUMAN PRESCRIPTION DRUG|
|Storage and handling||Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light.|
|Marketing authorisation holder||sanofi-aventis U.S. LLC|
EMBRYO-FETAL TOXICITY and HEPATOTOXICITY WARNING:
EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for
Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide.
(5.1, 8.1) Exclude pregnancy prior to initiating ARAVA therapy.
(5.1, 8.3) Advise use of
(5.1, 5.3, 8.3) Stop ARAVA and use an accelerated drug
(5.1, 5.3, 8.1)
(5.2) Monitor ALT levels.
Interrupt ARAVA treatment if ALT elevation > 3 fold
If likely leflunomide-induced, start accelerated drug
(5.2, 5.3) Embryo-Fetal Toxicity ARAVA is contraindicated for use in pregnant women because of the
Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level.
Exclude pregnancy before the start of treatment with ARAVA in females of reproductive
Advise females of reproductive
Stop ARAVA and use an accelerated drug
[see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in
Concomitant use of ARAVA with other potentially hepatotoxic drugs may increase the risk of
Patients with pre-existing
[see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in