Generic Name: leflunomide
Dosage Form: tablet, film coated
Arava® Tablets
(leflunomide)
10 mg, 20 mg, 100 mg
Pregnancy
Pregnancy must be excluded before the start of treatment with Arava. Arava is contraindicated in pregnant women, or women of childbearing potential who are not using reliable contraception. (see CONTRAINDICATIONS and WARNINGS.) Pregnancy must be avoided during Arava treatment or prior to the completion of the drug elimination procedure after Arava treatment.
Hepatotoxicity
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) >2×ULN 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 while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of Arava therapy may be considered. (SEE WARNINGS – HEPATOTOXICITY).
Arava Description
Arava® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:
Arava is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).
Arava - Clinical Pharmacology
Mechanism of Action
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Pharmacokinetics
Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite.
Absorption
Following oral administration, peak levels of the active metabolite, M1, occurred between 6 – 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.
| Maintenance (Loading) Dose | |||
|---|---|---|---|
| Parameter | 5 mg (50 mg) | 10 mg (100 mg) | 25 mg (100 mg) |
| |||
| C24 (Day 1) (µg/mL)* | 4.0 ± 0.6 | 8.4 ± 2.1 | 8.5 ± 2.2 |
| C24 (ss) (µg/mL)† | 8.8 ± 2.9 | 18 ± 9.6 | 63 ± 36 |
| t1/2(DAYS) | 15 ± 3 | 14 ± 5 | 18 ± 9 |
Relative to an oral solution, Arava tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.
Distribution
M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.
Metabolism
Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.
Elimination
The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.
In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day. (See PRECAUTIONS - General - Need for Drug Elimination). Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.
Special Populations
Gender
Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.
Age
Age has been shown to cause a change in the in vivo pharmacokinetics of M1 (see CLINICAL PHARMACOLOGY – Special Populations - Pediatrics).
Smoking
A population based pharmacokinetic analysis of the phase III 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.
Chronic Renal Insufficiency
In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when Arava is administered to these patients.
Hepatic Insufficiency
Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. 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 leflunomide in patients with hepatic insufficiency is not recommended.
Pediatrics
The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients.
| N | Body Weight (kg) | CL (mL/h) |
|---|---|---|
| 10 | <20 | 18 ± 9.8 [6.8–37] |
| 30 | 20–40 | 18 ± 9.5 [4.2–43] |
| 33 | >40 | 26 ± 16 [9.7–93.6] |
In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.
In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 – 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. (See PRECAUTIONS – Drug Interactions).
Methotrexate
Coadministration, in 30 patients, of Arava (100 mg/day × 2 days followed by 10 – 20 mg/day) with methotrexate (10 – 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity (see PRECAUTIONS – Drug Interactions – Hepatotoxic Drugs).
Rifampin
Following concomitant administration of a single dose of Arava to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when Arava was given alone. Because of the potential for Arava levels to continue to increase with multiple dosing, caution should be used if patients are to receive both Arava and rifampin.
Clinical Studies
A. ADULTS
The efficacy of Arava in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function.
1. Reduction of signs and symptoms
Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR)20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study.
2. Inhibition of structural damage
Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233–241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.
3. Improvement in physical function
Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).
In all Arava monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter.
US301 Clinical Trial in Adults
Study US301, 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. 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.
The rate and reason for withdrawal is summarized in Table 3.
| n(%) patients | |||
|---|---|---|---|
| Leflunomide 190 | Placebo 128 | Methotrexate 190 | |
| |||
| Withdrawals in Year-1 | |||
| Lack of efficacy | 33 (17.4) | 70 (54.7) | 50 (26.3) |
| Safety | 44 (23.2) | 12 (9.4) | 22 (11.6) |
| Other* | 15 (7.9) | 10 (7.8) | 17 (9.0) |
| Total | 92 (48.4) | 92 (71.9) | 89 (46.8) |
| Patients entering Year 2 | 98 | 36 | 101 |
| Withdrawals in Year-2 | |||
| Lack of efficacy | 4 (4.1) | 1 (2.8) | 4 (4.0) |
| Safety | 8 (8.2) | 0 (0.0) | 10 (9.9) |
| Other* | 3 (3.1) | 8 (22.2) | 7 (6.9) |
| Total | 15 (15.3) | 9 (25.0) | 21 (20.8) |
Study MN301 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 MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303).
Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 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 MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Patient withdrawal data in MN301/303/305 is summarized in Table 4.
| n(%) patients | |||
|---|---|---|---|
| Leflunomide 133 | Placebo 92 | Sulfasalazine 133 | |
| |||
| Withdrawals in MN301 (Mo 0–6) | |||
| Lack of efficacy | 10 (7.5) | 29 (31.5) | 14 (10.5) |
| Safety | 19 (14.3) | 6 (6.5) | 25 (18.8) |
| Other* | 8 (6.0) | 6 (6.5) | 11 (8.3) |
| Total | 37 (27.8) | 41 (44.6) | 50 (37.6) |
| Patients entering MN303 | 80 | 76 | |
| Withdrawals in MN303 (Mo 7–12) | |||
| Lack of efficacy | 4 (5.0) | 2 (2.6) | |
| Safety | 2 (2.5) | 5 (6.6) | |
| Other* | 3 (3.8) | 1 (1.3) | |
| Total | 9 (11.3) | 8 (10.5) | |
| Patients entering MN305 | 60 | 60 | |
| Withdrawals in MN305 (Mo 13–24) | |||
| Lack of efficacy | 0 (0.0) | 3 (5.0) | |
| Safety | 6 (10.0) | 8 (13.3) | |
| Other* | 1 (1.7) | 2 (3.3) | |
| Total | 7 (11.7) | 13 (21.7) | |
Study MN302 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 MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.
Patient withdrawal data in MN302/304 is summarized in Table 5.
| n(%) patients | ||
|---|---|---|
| Leflunomide 501 | Methotrexate 498 | |
| ||
| Withdrawals in MN302 (Year-1) | ||
| Lack of efficacy | 37 (7.4) | 15 (3.0) |
| Safety | 98 (19.6) | 79 (15.9) |
| Other* | 17 (3.4) | 17 (3.4) |
| Total | 152 (30.3) | 111 (22.3) |
| Patients entering MN304 | 292 | 320 |
| Withdrawals in MN304 (Year-2) | ||
| Lack of efficacy | 13 (4.5) | 9 (2.8) |
| Safety | 11 (3.8) | 22 (6.9) |
| Other* | 12 (4.1) | 12 (3.8) |
| Total | 36 (12.3) | 43 (13.4) |
1. Signs and symptoms Rheumatoid Arthritis
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 US301 (at the primary 12 months endpoint) and MN301 (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 2.
Figure 1
| Comparisons | 95%Confidence Interval | p Value | |
|---|---|---|---|
| US301 | Leflunomide vs. Placebo | (12, 32) | <0.0001 |
| Methotrexate vs. Placebo | (8, 30) | <0.0001 | |
| Leflunomide vs. Methotrexate | (-4, 16) | NS | |
| MN301 | Leflunomide vs. Placebo | (7, 33) | 0.0026 |
| Sulfasalazine vs. Placebo | (4, 29) | 0.0121 | |
| Leflunomide vs. Sulfasalazine | (-8, 16) | NS | |
| MN302 | Leflunomide vs. Methotrexate | (-19, -7) | <0.0001 |
Figure 2
*Last Observation Carried Forward.
ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7.
| Study and Treatment Group | ACR20 | ACR50 | ACR70 |
|---|---|---|---|
| |||
| Placebo-Controlled Studies | |||
| US301 (12 months) | |||
| Leflunomide (n=178)† | 52.2‡ | 34.3‡ | 20.2‡ |
| Placebo (n=118)† | 26.3 | 7.6 | 4.2 |
| Methotrexate (n=180)† | 45.6 | 22.8 | 9.4 |
| MN301(6 months) | |||
| Leflunomide (n=130)† | 54.6‡ | 33.1‡ | 10.0§ |
| Placebo (n=91)† | 28.6 | 14.3 | 2.2 |
| Sulfasalazine (n=132)† | 56.8 | 30.3 | 7.6 |
| Non-Placebo Active-Controlled Studies | |||
| MN302 (12 months) | |||
| Leflunomide (n=495)† | 51.1 | 31.1 | 9.9 |
| Methotrexate (n=489)† | 65.2 | 43.8 | 16.4 |
Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. Arava was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. 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 | ||||||
|---|---|---|---|---|---|---|---|---|
| US301 (12 months) | MN301 Non-US (6 months) | MN302 Non-US (12 months) | ||||||
| Leflunomide | Methotrexate | Placebo | Leflunomide | Sulfasalazine | Placebo | Leflunomide | Methotrexate | |
| ||||||||
| Tender 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‡ | -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 |
2. 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) in studies US301, MN305, and MN304. 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.
3. Inhibition of structural damage
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
L= Leflunomide; M=methotrexate; S=sulfasalazine; P=placebo
| Comparisons | 95% Confidence Interval | p Value | |
|---|---|---|---|
| US301 | Leflunomide vs. Placebo | (-4.0, -1.1) | 0.0007 |
| Methotrexate vs. Placebo | (-2.6, -0.2) | 0.0196 | |
| Leflunomide vs. Methotrexate | (-2.3, 0.0) | 0.0499 | |
| MN301 | Leflunomide vs. Placebo | (-6.2, -1.8) | 0.0004 |
| Sulfasalazine vs. Placebo | (-6.9, 0.0) | 0.0484 | |
| Leflunomide vs. Sulfasalazine | (-3.3, 1.2) | NS | |
| MN302 | Leflunomide vs. Methotrexate | (-2.2, 7.4) | NS |
4. Improvement in physical function
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 US301, at 12 months, Arava provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.
Figure 4
| Comparisons | 95% Confidence Interval | p Value | |
|---|---|---|---|
| US301 | Leflunomide vs. Placebo | (-0.58, -0.29) | 0.0001 |
| Leflunomide vs. Methotrexate | (-0.34, -0.07) | 0.0026 | |
| MN301 | Leflunomide vs. Placebo | (-0.67, -0.36) | <0.0001 |
| Leflunomide vs. Sulfasalazine | (-0.33, -0.03) | 0.0163 | |
| MN302 | Leflunomide 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.
B. PEDIATRICS
Clinical Trials in Pediatrics
Arava was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving Arava, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ≥ 30 % responder endpoint. In this trial, the loading dose and maintenance dose of Arava was based on three weight categories: <20 kg, 20–40kg, and >40 kg. The response rate to Arava in pediatric patients ≤40 kg was less robust than in pediatric patients >40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious pla
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