Toxicity leflunomide

The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity a complete blood cell count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter. It is teratogenic and should be avoided during pregnancy. 

Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide. 

Leflunomide is a potent noncyto toxic inhibitor of the proliferation of stimulated B and T-lymphocytes, which depend on de novo pyrimidine synthesis to fulfill their metabolic needs (Breedveld and Dayer, 2000 Herrmann et al., 2000). This antiproliferative effect can be antagonized in vitro by the addition of uridine or cytidine to the cell culture medium, underscoring the significance of this mechanism of action (Cao et al., 1995 Williamson et al., 1995 Zielinski et al.,... 

Leflunomide can cause abnormal liver function tests, but the risk of serious and non-serious hepatic adverse events is not higher than with methotrexate (71). In the MN301, US301, and MN302 trials, there were abnormal liver enzymes in 6-10% (9,10,12). The co-administration of methotrexate is a risk factor (18,72-74). According to the National Cancer Institute Common Toxicity Criteria, 8.9% of patients developed grade 2 or 3 hepato-toxicity within the first year, mainly within 6 months and in combination with methotrexate, after the start of leflunomide therapy based on liver enzyme determinations (72). The use of folate was also associated with less... 

Leflunomide is taken orally. In most regimens it is begun with a loading dose of 100 mg/day over 3 days followed by a maintenance dosage of 10-20 mg/day. Leflunomide 100 mg/week had similar effectiveness and less toxicity in open trials compared with daily dosing (21,93). 

Leflunomide has efficacy similar to that of methotrexate for treating rheumatoid arthritis. The drug may cause liver toxicity and is contraindicated in patients with pre-existing liver disease. Patients taking the drug should have ALT monitored monthly initially, and periodically thereafter as long as they continue treatment. 

Leflunomide is administered orally as a single daily dose without regard to meals. Therapy may be initiated with a loading dosage given for 3 days, followed by the usual maintenance dose. It undergoes primarily enterohepatic circulation, extending its duration of action. Cholestyramine can be used to enhance its elimination in cases of toxicity. 

JNK activation may be a mechanism that is associated with the initiation of mitochondrial permeability transition (MPT) (Hanawa et al. 2008 Latchoumycan-dane et al. 2006, 2007). As discussed above, both JNK activation (Matsumaru et al. 2003) and MPT (Lemasters 1998) are known to occur as a result of increased oxidative stress. MPT leads to additional oxidative stress with loss of mitochondrial membrane potential and loss of the ability of the hepatocyte to synthesize ATP. Latchoumycandane et al. (2006, 2007) found that leflunomide protected mice from mitochondrial permeabilization. Direct evidence for a role of JNK activation in acetaminophen-induced MPT was recently reported by Hanawa et al. (2008). A time course of events indicated GSH depletion by 1-2 h, JNK activation in liver homogenate by 2-4- h, JNK translocation to mitochondria by 4 h, and increased toxicity (serum ALT by 6 h). The JNK inhibitor did not alter GSH depletion but blocked JNK activation in homogenate, JNK translocation to mitochondria, and toxicity. Mitochondria from liver of acetaminophen-treated mice showed decreased State III respiration and decreased respiratory control ratios, whereas mice treated with acetaminophen plus JNK inhibitor were partially protected from these losses. Addition of activated JNKl or JNK2 to mitochondria from acetaminophen-treated mice plus JNK inhibitor showed a decrease in State 111 respiration and decreased respiratory control ratio. Addition of the MPT inhibitor cyclosporine A prevented these decreases. It was hypothesized that activated JNK is an important mediator of acetaminophen-induced MPT (Hanawa et al. 2008). 

The manufacturers advise caution if leflunomide is given with phenytoin or tolbutamide. The reason is that the active metabolite of leflunomide (A771726) has been shown by in vitro studies to be an inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is concerned with the metabolism of these two drugs. If this inhibition were to occur in vivo it could possibly lead to a decrease in their metabolism and an increase in their toxicity. Although so far there appear to be no clinical reports of an interaction, the manufacturers made a similar prediction with warfarin, another CYP2C9 substrate, which has, in isolated cases, been borne out in practice. See Coumarins + Leflunomide , p.423. 

Skin Toxic epidermal necrolysis has been attributed to leflunomide in a patient with rheumatoid arthritis [43 ]. 

Hassikou H, El Haouri M, Tabache F, Baaj M, Safi S, Hadri L. Leflunomide-induced toxic epidermal necrolysis in a patient with rheumatoid arthritis. Joint Bone Spine 2008 75(5) 597-9. 

Bohanec Grabar P, Rozman B, Tomsic M, Suput D, Logar D, Dolzan V. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Chn Pharmacol 2008 64(9) 871-6. 

For ILDs, the reported use of leflunomide (Arava) has been limited to sarcoidosis (97,128). In most cases, LEF has been used as an alternative when MTX toxicity has been encountered or used in combination with MTX. 

Systemic corticosteroids are required for cases of anterior uveits that are refractory to eyedrops and for cases of intermediate and posterior uveitis because eyedrops cannot adequately penetrate deep into the eye. The initial corticosteroid dose is 40 mg/day of prednisone equivalent, which is adjusted according to the response to therapy. Corticosteroid-sparing alternatives are often considered for sarcoid uveitis because of the toxicity of systemic corticosteroids. Methotrexate (21), azathioprine (22), leflunomide (23), and infliximab (24) have been used for this purpose. 

A review summarises the effect of leflunomide on psoriasis and other cutaneous conditions [77 ]. The most common dermatologic complication associated with leflunomide administration is reversible alopecia. However, also more specific conditions have been reported, such as drug-induced subacute cutaneous lupus erythemasosus, erythema multiforme and toxic epidermal necrolysis. 

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