Other
Embryo-Fetal Toxicity
ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm. 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 potential. Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment. Stop ARAVA and use an accelerated drug elimination procedure if the patient becomes pregnant. [see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in Special Populations (8.1, 8.3)], and Clinical Pharmacology (12.3)]
Hepatotoxicity
Severe liver injury, including fatal liver failure, has been reported in patients treated with ARAVA. ARAVA is contraindicated in patients with severe hepatic impairment. Concomitant use of ARAVA with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2×ULN before initiating treatment, are at increased risk and should not be treated with ARAVA. Monitor ALT levels at least monthly for six months after starting ARAVA, and thereafter every 6–8 weeks. If leflunomide-induced liver injury is suspected, stop ARAVA treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized. [see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Special Populations (8.6)]
Elevation of Liver Enzymes
Treatment with ARAVA was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. 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. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
| 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 a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.
Most Common Adverse Reactions
The most common adverse reactions in ARAVA-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥ 5% in any ARAVA treatment group).
| Placebo-Controlled Trials | Active-Controlled Trials | All RA Studies | |||||
|---|---|---|---|---|---|---|---|
| Trial 1 and 2 | Trial 3 Only 10% of patients in Trial 3 received folate. 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 controlled and uncontrolled trials with ARAVA (duration up to 12 months). | |
| MTX = methotrexate, PL = placebo, SSZ = sulfasalazine | |||||||
| Diarrhea | 27% | 12% | 10% | 20% | 22% | 10% | 17% |
| Headache | 13% | 11% | 12% | 21% | 10% | 8% | 7% |
| Nausea | 13% | 11% | 19% | 18% | 13% | 18% | 9% |
| Rash | 12% | 7% | 11% | 9% | 11% | 10% | 10% |
| Abnormal Liver Enzymes | 10% | 2% | 4% | 10% | 6% | 17% | 5% |
| Alopecia | 9% | 1% | 6% | 6% | 17% | 10% | 10% |
| Hypertension Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials. | 9% | 4% | 4% | 3% | 10% | 4% | 10% |
| Asthenia | 6% | 4% | 5% | 6% | 3% | 3% | 3% |
| Back Pain | 6% | 3% | 4% | 9% | 8% | 7% | 5% |
| GI/Abdominal Pain | 6% | 4% | 7% | 8% | 8% | 8% | 5% |
| Abdominal Pain | 5% | 4% | 4% | 8% | 6% | 4% | 6% |
| Allergic Reaction | 5% | 2% | 0% | 6% | 1% | 2% | 2% |
| Bronchitis | 5% | 2% | 4% | 7% | 8% | 7% | 7% |
| Dizziness | 5% | 3% | 6% | 5% | 7% | 6% | 4% |
| Mouth Ulcer | 5% | 4% | 3% | 10% | 3% | 6% | 3% |
| Pruritus | 5% | 2% | 3% | 2% | 6% | 2% | 4% |
| Rhinitis | 5% | 2% | 4% | 3% | 2% | 2% | 2% |
| Vomiting | 5% | 4% | 4% | 3% | 3% | 3% | 3% |
| Tenosynovitis | 2% | 0% | 1% | 2% | 5% | 1% | 3% |
Adverse events during a second year of treatment with ARAVA in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
Less Common Adverse Reactions
In addition, in controlled clinical trials, the following adverse events in the ARAVA treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug.
Blood and Lymphatic System: leukocytosis, thrombocytopenia;
Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein;
Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;
Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;
General Disorders: malaise;
Immune System: anaphylactic reaction;
Infection: abscess, flu syndrome, vaginal moniliasis;
Nervous System: dizziness, headache, somnolence;
Respiratory System: dyspnea;
Effect of potent CYP and transporter inducers
Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of ARAVA and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for ARAVA when coadministered with rifampin. Because of the potential for ARAVA concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin [see Clinical Pharmacology (12.3)].
Effect on CYP2C8 substrates
Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking ARAVA, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)].
Effect on warfarin
Coadministration of ARAVA with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of ARAVA, may decrease peak INR by approximately 25%.
Effect on oral contraceptives
Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with ARAVA [see Clinical Pharmacology (12.3)].
Effect on CYP1A2 substrates
Teriflunomide, the active metabolite of ARAVA, may be a weak inducer of CYP1A2 in vivo. In patients taking ARAVA, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3)].
Effect on organic anion transporter 3 (OAT3) substrates
Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking ARAVA, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3)].
Effect on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates
Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking ARAVA, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking ARAVA [see Clinical Pharmacology (12.3)].
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-in-a-study/.
Risk Summary
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 and Precautions (5.3)].
Clinical Considerations
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 (5.3) and Clinical Pharmacology (12.3)].
Data
Animal Data
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 with 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.
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 potential for serious adverse reactions in a breastfed infant from ARAVA, advise a nursing woman to discontinue breastfeeding during treatment with ARAVA.
Pregnancy Testing
Exclude pregnancy in females of reproductive potential before starting treatment with ARAVA.
Contraception
Females
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 (5.3)].
Absorption
Following oral administration, peak teriflunomide concentrations occurred between 6 –12 hours after dosing. Due to the very long half-life of teriflunomide (18–19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.
Effect of Food
Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
Distribution
Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
Elimination
Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18–19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal. 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, due to individual variation in drug clearance [see Warnings and Precautions (5.3)]. After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.
Metabolism
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism. In vivo, leflunomide is metabolized to one primary (teriflunomide) and many minor metabolites. In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely detectable in plasma.
Excretion
Teriflunomide, the active metabolite of leflunomide, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.
Specific Populations
Gender. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.
Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Drug Interaction Studies
Drug interaction studies have been conducted with both ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
The Potential Effect of Other Drugs on ARAVA
- Potent CYP and transporter inducers:
- An in vivo interaction study with ARAVA and cimetidine (non-specific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure.
- CYP2C8 Substrates
- CYP1A2 Substrates
- OAT3 Substrates
- BCRP and OATP1B1/1B3 Substrates
- Oral Contraceptives
- Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).
- Of the potential for fetal harm if ARAVA is taken during pregnancy.
- To notify their healthcare provider immediately if a pregnancy occurs or is suspected.
- To use effective contraception during treatment with ARAVA and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions (5.1, 5.3), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.3)].
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when ARAVA was given alone [see Drug Interactions (7)].
The Potential Effect of ARAVA on Other Drugs
There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7)].
Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo [see Drug Interactions (7)].
There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) [see Drug Interactions (7)].
There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7)].
Trial 1
Trial 1, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. The primary analysis was at 52 weeks with blinded treatment to 104 weeks.
Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.
Trial 2
Trial 2 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of Trial 2 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine.
Of the 168 patients who completed 12 months of treatment, 146 patients (87%) entered a 1-year extension study of double blind active treatment; (60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Trial 3
Trial 3 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.
Of the 736 patients who completed 52 weeks of treatment in study Trial 3, 612 (83%) entered the double-blind, 1-year extension study (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.
Clinical Trial Results
Clinical Response
The ACR20 Responder at Endpoint rates are shown in Figure 1. ARAVA was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study Trial 1 (at the primary 12 months endpoint) and Trial 2 (at 6 month endpoint). ACR20 Responder at Endpoint rates with ARAVA treatment were consistent across the 6 and 12 month studies (41 – 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. ARAVA treatment effect was evident by 1 month, stabilized by 3 – 6 months, and continued throughout the course of treatment as shown in Figure 1.
Figure 1. Percentage of ACR20 Responders at Endpoint in Patients with Active RA in Trials 1, 2, and 3
Figure 1 (Arava 03)
| Comparisons | 95%Confidence Interval | p Value | |
|---|---|---|---|
| Trial 1 | ARAVA vs. Placebo | (12, 32) | <0.0001 |
| Methotrexate vs. Placebo | (8, 30) | <0.0001 | |
| ARAVA vs. Methotrexate | (-4, 16) | NS | |
| Trial 2 | ARAVA vs. Placebo | (7, 33) | 0.0026 |
| Sulfasalazine vs. Placebo | (4, 29) | 0.0121 | |
| ARAVA vs. Sulfasalazine | (-8, 16) | NS | |
| Trial 3 | ARAVA vs. Methotrexate | (-19, -7) | <0.0001 |
Figure 2. ACR20 Responders over Time in Patients with Active RA in Trial 1*
Figure 2 (Arava 04)
ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 3). Mean change for the individual components of the ACR Responder Index are shown in Table 4.
| Study and Treatment Group | ACR20 | ACR50 | ACR70 |
|---|---|---|---|
| Placebo-Controlled Studies | |||
| Trial 1 (12 months) | |||
| ARAVA (n=178) n is the number of ITT patients for whom adequate data were available to calculate the indicated rates. | 52 p<0.001 ARAVA vs placebo | 34 | 20 |
| Placebo (n=118) | 26 | 8 | 4 |
| Methotrexate (n=180) | 46 | 23 | 9 |
| Trial 2 (6 months) | |||
| ARAVA (n=130) | 55 | 33 | 10 p<0.02 ARAVA vs placebo |
| Placebo (n=91) | 29 | 14 | 2 |
| Sulfasalazine (n=132) | 57 | 30 | 8 |
| Non-Placebo Active-Controlled Studies | |||
| Trial 3 (12 months) | |||
| ARAVA (n=495) | 51 | 31 | 10 |
| Methotrexate (n=489) | 65 | 44 | 16 |
Table 4 shows the results of the components of the ACR response criteria for Trial 1, Trial 2 and Trial 3. ARAVA was significantly superior to placebo in all components of the ACR Response criteria in study Trial 1 and Trial 2. In addition, Arava was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between ARAVA and the active comparators.
| Components | Placebo-Controlled Studies | Non-placebo Controlled Study | ||||||
|---|---|---|---|---|---|---|---|---|
| Trial 1 (12 months) | Trial 2 Non-US (6 months) | Trial 3 Non-US (12 months) | ||||||
| Leflunomide | Methotrexate | Placebo | Leflunomide | Sulfasalazine | Placebo | Leflunomide | Methotrexate | |
| Tender joint count Based on 28 joint count | -7.7 | -6.6 | -3.0 | -9.7 | -8.1 | -4.3 | -8.3 | -9.7 |
| Swollen joint count | -5.7 | -5.4 | -2.9 | -7.2 | -6.2 | -3.4 | -6.8 | -9.0 |
| Patient global assessment Visual Analog Scale - 0=Best; 10=Worst | -2.1 | -1.5 | 0.1 | -2.8 | -2.6 | -0.9 | -2.3 | -3.0 |
| Physician global assessment | -2.8 | -2.4 | -1.0 | -2.7 | -2.5 | -0.8 | -2.3 | -3.1 |
| Physical function/disability (MHAQ/HAQ) | -0.29 | -0.15 | 0.07 | -0.50 | -0.29 | -0.04 | -0.37 | -0.44 |
| Pain intensity | -2.2 | -1.7 | -0.5 | -2.7 | -2.0 | -0.9 | -2.1 | -2.9 |
| Erythrocyte Sedimentation rate | -6.26 | -6.48 | 2.56 | -7.48 | -16.56 | 3.44 | -10.12 | -22.18 |
| C-reactive protein | -0.62 | -0.50 | 0.47 | -2.26 | -1.19 | 0.16 | -1.86 | -2.45 |
| Not included in the ACR Responder Index | ||||||||
| Morning Stiffness (min) | -101.4 | -88.7 | 14.7 | -93.0 | -42.4 | -6.8 | -63.7 | -86.6 |
Maintenance of effect
After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years). ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment.
Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of Arava treatment in all three trials.
Radiographic Response
The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. ARAVA was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine.
Figure 3. Change in Sharp Score in Patients with Active RA in Trials 1, 2, and 3
Figure 3 (Arava 05)
| Comparisons | 95% Confidence Interval | p Value | |
|---|---|---|---|
| Trial 1 | ARAVA vs. Placebo | (-4.0, -1.1) | 0.0007 |
| Methotrexate vs. Placebo | (-2.6, -0.2) | 0.0196 | |
| ARAVA vs. Methotrexate | (-2.3, 0.0) | 0.0499 | |
| Trial 2 | ARAVA vs. Placebo | (-6.2, -1.8) | 0.0004 |
| Sulfasalazine vs. Placebo | (-6.9, 0.0) | 0.0484 | |
| ARAVA vs. Sulfasalazine | (-3.3, 1.2) | NS | |
| Trial 3 | ARAVA vs. Methotrexate | (-2.2, 7.4) | NS |
Physical Function Response
The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. ARAVA was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.
The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In Trial 1, at 12 months, ARAVA provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.
Figure 4. Change in Functional Ability Measure in Patients with Active RA in Trials 1, 2, and 3*
Figure 4 (Arava 06)
| Comparison | 95% Confidence Interval | p Value | |
|---|---|---|---|
| Trial 1 | ARAVA vs. Placebo | (-0.58, -0.29) | 0.0001 |
| ARAVA vs. Methotrexate | (-0.34, -0.07) | 0.0026 | |
| Trial 2 | ARAVA vs. Placebo | (-0.67, -0.36) | <0.0001 |
| ARAVA vs. Sulfasalazine | (-0.33, -0.03) | 0.0163 | |
| Trial 3 | ARAVA vs. Methotrexate | (0.01, 0.16) | 0.0221 |
Maintenance of effect
The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.
Embryo-Fetal Toxicity
Advise females of reproductive potential
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy [see Use in Specific Populations (8.1)].
Lactation
Advise nursing women to discontinue breastfeeding during treatment with ARAVA [see Use in Specific Populations (8.2)].
Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly report if they develop a skin rash or mucous membrane lesions.
Advise patients of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
Advise patients that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness.
Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.
Release date: February 2016
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