Summary Of Exposure |
A) USES: Leflunomide is indicated to reduce signs and symptoms, improve physical function, and inhibit structural damage in adult patients with rheumatoid arthritis. Teriflunomide is the active metabolite of leflunomide and is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis.
B) PHARMACOLOGY: Leflunomide, an isoxazole immunomodulatory agent, inhibits dihydrooratate dehydrogenase (an enzyme in de novo pyrimidine synthesis), and has anti-inflammatory and immunomodulating activity. Teriflunomide, the primary active metabolite of leflunomide. Although the exact mechanism of action in multiple sclerosis is unknown, it may involve a reduction in activated lymphocytes in the CNS.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) Leflunomide and teriflunomide have similar adverse effects. COMMON: Hypertension, reversible alopecia, diarrhea, rashes, and elevated liver enzyme levels. OTHER EFFECTS: Chest pain, nausea, anorexia, abdominal pain, headache, dizziness, pancytopenia, agranulocytosis, thrombocytopenia, tenosynovitis, bronchitis, respiratory infection, Stevens-Johnson Syndrome (rare), Toxic Epidermal Necrolysis (rare). Based on postmarketing experience, rare cases of hepatotoxicity have been reported with therapeutic use. Individuals with multiple risk factors may be at greatest risk. Rare reports of severe infections, including sepsis have also occurred, but may be confounded by concomitant immunosuppressant therapy or comorbidity.
2) REPRODUCTIVE: Leflunomide and teriflunomide are US FDA pregnancy category X, due to the risk of severe teratogenicity or fetal death.
E) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. A woman developed no adverse effects after inadvertently taking leflunomide 120 mg daily for 28 days.
2) SEVERE TOXICITY: Chronic high doses of leflunomide (an average of 34 mg/daily for 26 months) produced interstitial nephritis in one adult.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) LEFLUNOMIDE: Fever, accompanied by photophobia, facial burning, thrombocytosis, and leukocytosis was associated with leflunomide therapy, in a single case report (Koenig & Abruzzo, 2002).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) LEFLUNOMIDE: CYSTOID MACULAR EDEMA: In a case report, a 57-year-old man developed cystoid macular edema after initiation of leflunomide treatment for severe rheumatoid arthritis. Blurred vision developed 2 weeks after leflunomide therapy started; an angiogram 2 weeks later confirmed the diagnosis of cystoid macular edema. Three months after the discontinuation of leflunomide, the blurred vision had cleared and there were no clinical signs of cystoid macular edema (Barak et al, 2004).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE 1) INCIDENCE: Hypertension was reported in 10% of patients (n=1339) involved in leflunomide clinical trials to treat rheumatoid arthritis (Prod Info ARAVA(R) oral tablets, 2010).
2) During phase II clinical trials conducted to determine the safety and efficacy of leflunomide in the treatment of rheumatoid arthritis, hypertension was reported as a frequent adverse effect (Mladenovic et al, 1995). Because of a pre-existing incidence of hypertension, it was difficult to assess whether the hypertension was causally related to leflunomide administration.
b) TERIFLUNOMIDE 1) During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, hypertension was reported in 4% and 4% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 2% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
B) CHEST PAIN 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: INCIDENCE: Chest pain was reported in 2% of patients (n=1339) involved in leflunomide clinical trials to treat rheumatoid arthritis (Prod Info ARAVA(R) oral tablets, 2010).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) BRONCHITIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: In clinical trials of leflunomide (n=1339), bronchitis was reported by 7% of patients receiving leflunomide and 2% receiving placebo (Prod Info ARAVA(R) oral tablets, 2010).
B) RESPIRATORY TRACT INFECTION 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: In clinical trials (n=1339), respiratory infection was reported by 15% of patients receiving leflunomide (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, upper respiratory tract infection was reported in 9% and 9% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 7% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
C) INTERSTITIAL LUNG DISEASE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, was reported rarely during postmarketing surveillance. In some cases, the outcome was fatal (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: Interstitial lung disease and worsening of preexisting interstitial lung disease have been reported with leflunomide use and has been associated with fatal outcomes. Similar reactions can be expected with teriflunomide therapy (Prod Info AUBAGIO(R) oral tablets, 2012).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Two case reports suggest that leflunomide is associated with reversible peripheral neuropathy. The temporal relationship between the initial dose of leflunomide and the development of peripheral neuropathy, and the resolution of symptoms when the drug was discontinued, suggests a causative link (Carulli & Davies, 2002).
b) TERIFLUNOMIDE: Peripheral neuropathy has been reported in patients receiving teriflunomide. Most cases resolved after discontinuation of therapy; however, some patients experienced persistent symptoms. Age greater than 60 years old, concomitant neurotoxic agents, and diabetes may be risk factors for peripheral neuropathy (Prod Info AUBAGIO(R) oral tablets, 2012).
B) DIZZINESS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Dizziness was reported by 4% of patients in clinical trials of leflunomide (n=1339) (Prod Info ARAVA(R) oral tablets, 2010).
C) HEADACHE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Headache was experienced by 7% of patients in clinical trials of leflunomide (n=1339) (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, headache was reported in 22% and 19% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 18% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
D) PARESTHESIA 1) WITH THERAPEUTIC USE a) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, paresthesia was reported in 9% and 10% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 8% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: INCIDENCE: Nausea has been reported in 9% of all patients (n=1339) involved in rheumatoid arthritis studies of leflunomide (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, nausea was reported in 9% and 14% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 7% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: INCIDENCE: Diarrhea occurred in 17% of all patients (n=1339) involved in rheumatoid arthritis studies of leflunomide (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, diarrhea was reported in 15% and 18% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 9% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
C) LOSS OF APPETITE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: During placebo-controlled clinical trials of leflunomide, weight loss was reported in 4% of patients treated with 10 mg and 25 mg leflunomide versus 2% in the placebo and 5 mg group. This indicates that anorexia may be a dose-related adverse effect of leflunomide administration (Furst, 1995).
D) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Abdominal pain has been reported as a frequent adverse effect following therapeutic administration of leflunomide (Merkel et al, 1995). 1) INCIDENCE: Abdominal pain was reported in 5% of all patients (n=1339) involved in rheumatoid arthritis studies of leflunomide (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, upper abdominal pain was reported in 5% and 6% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 4% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012). |
Hepatic |
3.9.2) CLINICAL EFFECTS
A) INCREASED LIVER ENZYMES 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE 1) In all controlled and uncontrolled clinical trials, abnormal liver enzymes were reported in 5% of rheumatoid arthritis patients who received leflunomide (n=1339) for up to 12 months (Prod Info ARAVA(R) oral tablets, 2010).
2) In a 6-month study of 263 patients with persistent RA symptoms treated with methotrexate and having normal liver enzymes, leflunomide was added to the drug regimen for 133 patients at 10 mg per day and increased to 20 mg as indicated. In the leflunomide group, an increase in ALT greater than or equal to 3 times the upper limit of normal was observed in 3.8% of patients as compared with 0.8% in the methotrexate and placebo group (n=130) (FDA, 2003).
3) Elevated SGPT levels were reported in 6% of patients taking 25 mg of leflunomide versus 1% of patients taking lower doses of leflunomide (Furst, 1995).
4) One study reported the occurrence of elevated liver enzyme levels in 10 mg and 25 mg leflunomide-treated patients involved in placebo- controlled clinical trials (Mladenovic et al, 1995).
b) TERIFLUNOMIDE 1) Cases of severe liver injury, including fatal hepatic failure, have been reported leflunomide therapy. A similar risk is expected with teriflunomide (Prod Info AUBAGIO(R) oral tablets, 2012).
2) During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, increased ALT was reported in 12% and 14% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 7% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
B) HEPATIC FAILURE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Rare cases of severe liver injury, including fatal hepatic failure and acute hepatic necrosis, have been reported with leflunomide therapy during postmarketing surveillance (Prod Info ARAVA(R) oral tablets, 2010).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) NEPHRITIS 1) WITH POISONING/EXPOSURE a) LEFLUNOMIDE: CHRONIC OVERDOSAGE: A 70-year-old man with RA was taking leflunomide (LFM) daily, and developed interstitial nephritis 26 months after the start of therapy. In addition, to the 20 mg/daily (normal therapeutic dose), the patient was taking 100 mg once a week for an average daily dose of 34 mg. After drug cessation, the patient was started on oral steroids (mainly to control RA), and creatinine levels began to decline within one month and returned to baseline after 5 months. The authors attributed the interstitial nephritis to chronic overdose of LFM (Haydar et al, 2004).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) PANCYTOPENIA 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Postmarketing surveillance has identified rare cases of pancytopenia, agranulocytosis and thrombocytopenia in patients taking leflunomide alone. These effects are more frequent in patients taking concomitant methotrexate or other immunosuppressive drugs, patients who recently discontinued immunosuppressive therapy, and patients with a previous history of hematologic abnormalities (Prod Info ARAVA(R) oral tablets, 2010; FDA, 2003).
b) LEFLUNOMIDE: CASE REPORT: Pancytopenia was reported in a 62-year-old woman approximately 3 weeks after beginning leflunomide therapy, 20 mg daily, for treatment of rheumatoid arthritis. A bone marrow biopsy showed hypercellularity and trilinear maturation disorder consistent with a regeneratory state after bone marrow toxicity. The patient completely recovered, without sequelae, following discontinuation of leflunomide and filgrastim administration (Auer et al, 2000).
B) AGRANULOCYTOSIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Postmarketing surveillance has identified rare cases of pancytopenia, agranulocytosis and thrombocytopenia in patients taking leflunomide alone. These effects are more frequent in patients taking concomitant methotrexate or other immunosuppressive drugs, patients who recently discontinued immunosuppressive therapy, and patients with a previous history of hematologic abnormalities (Prod Info ARAVA(R) oral tablets, 2010; FDA, 2003).
C) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Postmarketing surveillance has identified rare cases of pancytopenia, agranulocytosis and thrombocytopenia in patients taking leflunomide alone. These effects are more frequent in patients taking concomitant methotrexate or other immunosuppressive drugs, patients who recently discontinued immunosuppressive therapy, and patients with a previous history of hematologic abnormalities (Prod Info ARAVA(R) oral tablets, 2010; FDA, 2003).
b) TERIFLUNOMIDE: During placebo-controlled clinical studies, mean platelet decreases of approximately 10% were reported in patients receiving teriflunomide 7 mg or 14 mg (Prod Info AUBAGIO(R) oral tablets, 2012).
D) THROMBOCYTOSIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: CASE REPORT: Thrombocytosis developed in a 50-year-old man after he received approximately 2 months of therapy with leflunomide (20 mg daily during month 1, increased to 30 mg daily during month 2) for treatment of polychondritis. The patient initially presented with daily fevers spiking up to 103 degrees F, accompanied by photophobia, facial burning, leukocytosis, and a platelet count of approximately 1.15 million units/L (graphic analysis). Bone marrow aspiration showed the bone marrow to be hypercellular, without other abnormality. Leflunomide was discontinued and cholestyramine was administered. The patient's WBC and platelet counts returned to within normal limits in the following month, without further recurrence of fever (Koenig & Abruzzo, 2002).
E) LEUKOCYTOSIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: CASE REPORT: Leukocytosis developed in a 50-year-old man after he received approximately 2 months of therapy with leflunomide (20 mg daily during month 1, increased to 30 mg daily during month 2) for treatment of polychondritis. The patient initially presented with daily fevers spiking up to 103 degrees Fahrenheit, accompanied by photophobia, facial burning, thrombocytosis, and a white blood cell (WBC) count of approximately 27000 cells/L (graphic analysis). Bone marrow aspiration showed the bone marrow to be hypercellular, without other abnormality. Leflunomide was discontinued and cholestyramine was administered. The patient's WBC and platelet counts returned to within normal limits in the following month, without further recurrence of fever (Koenig & Abruzzo, 2002).
F) LYMPHOCYTOPENIA 1) WITH THERAPEUTIC USE a) TERIFLUNOMIDE: During placebo-controlled clinical studies, lymphocyte counts less than 0.8 x 10(9)/L were reported in 7% and 10% of patients administered teriflunomide 7 mg and 14 mg, respectively, compared with 5% of patients administered placebo (Prod Info AUBAGIO(R) oral tablets, 2012)
G) NEUTROPENIA 1) WITH THERAPEUTIC USE a) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, neutropenia was reported in 2% and 4% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 0.3% of patients administered placebo (n=360) (Prod Info AUBAGIO(R) oral tablets, 2012).
b) TERIFLUNOMIDE: During placebo-controlled clinical studies, neutrophil counts less than 1.5 x 10(9)/L were reported in 10% and 15% of patients administered teriflunomide 7 mg and 14 mg, respectively, compared with 5% of patients administered placebo (Prod Info AUBAGIO(R) oral tablets, 2012)
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Rash was reported in 10% of patients (n=1339) involved in leflunomide clinical trials to treat rheumatoid arthritis (Prod Info ARAVA(R) oral tablets, 2010).
b) LEFLUNOMIDE: Exfoliative dermatitis was reported in 1 patient 7 days after starting leflunomide therapy for rheumatoid arthritis (Bandyopadhyay, 2003).
B) ALOPECIA 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Alopecia has been reported as a common occurrence following therapeutic administration of leflunomide and appears to be dose-related and reversible upon discontinuation of therapy (Mladenovic et al, 1995) Silva & Morris, 1997; (Merkel et al, 1995).
b) LEFLUNOMIDE: Alopecia was reported in 10% of patients (n=1339) involved in leflunomide clinical trials to treat rheumatoid arthritis (Prod Info ARAVA(R) oral tablets, 2010).
c) TERIFLUNOMIDE: During a long-term (108 week), placebo-controlled study in patients with relapsing multiple sclerosis, alopecia was reported in 10% and 13% of patients administered teriflunomide 7 mg (n=368) and 14 mg (n=358), respectively, compared with 3% of patients administered placebo (n=360). Alopecia was the most common cause of discontinuation of teriflunomide therapy (Prod Info AUBAGIO(R) oral tablets, 2012).
C) ERYTHEMA MULTIFORME 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Erythema Multiforme has been reported rarely in postmarketing experience with therapeutic leflunomide use (Prod Info ARAVA(R) oral tablets, 2010).
D) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Stevens-Johnson Syndrome has been reported rarely in postmarketing experience with therapeutic leflunomide use (Prod Info ARAVA(R) oral tablets, 2010).
b) TERIFLUNOMIDE: Stevens-Johnson syndrome has been reported rarely with leflunomide use. A similar reaction can be expected with teriflunomide use (Prod Info AUBAGIO(R) oral tablets, 2012).
E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Toxic Epidermal Necrolysis has been reported rarely in postmarketing experience with therapeutic leflunomide use (Prod Info ARAVA(R) oral tablets, 2010). b) TERIFLUNOMIDE: Toxic epidermal necrolysis has been reported rarely with leflunomide use. A similar reaction can be expected with teriflunomide use (Prod Info AUBAGIO(R) oral tablets, 2012). 1) CASE REPORT: A 46-year-old woman who had been taking teriflunomide for 19 days for relapsing multiple sclerosis, presented with flu-like symptoms that resolved completely after taking acetaminophen for 5 days. She presented again with fever and asthenia on day 28. Despite the discontinuation of teriflunomide, she presented the next day with catarrh, vulvar pruritus, odynophagia and an erythematous macular eruption of the face and upper trunk. On day 30, she developed respiratory failure, necessitating mechanical ventilation. Physical examination revealed diffuse erythema, confluent flaccid blisters with positive Nikolsky's sign, 95% of detached-detachable skin leading to extensive areas of denuded skin and erosions of all mucosa. The diagnosis of toxic epidermal necrolysis (severity of illness score of 5; predictive mortality of 83%) was confirmed after ruling out other causes. Despite supportive treatment, including cholestyramine (to accelerate teriflunomide clearance), her condition deteriorated with multiple organ dysfunctions, resulting in death on day 39 (Gerschenfeld et al, 2015).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) TENOSYNOVITIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: During clinical trials of leflunomide involving a total of 1339 patients, tenosynovitis occurred in 3% of patients receiving leflunomide (Prod Info ARAVA(R) oral tablets, 2010).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: CASE REPORT: A case of skin eruption consistent with subacute cutaneous lupus erythematosus (SCLE) was described in a 64-year-old woman taking leflunomide for rheumatoid arthritis. The patient presented with a month-long history of a pruritic, photosensitive, nonscarring rash on her arms. At the time of the presentation, besides leflunomide 20 mg/day taken for 4 months, concurrent medications included etanercept 25 mg twice weekly taken for 6 weeks, and prednisone 5 to 7.5 mg/day taken for 1 year. Physical examination revealed numerous erythematosus scaling plaques located primarily on the dorsal aspect of patient's hands and forearms. Immunologic and histopathologic examinations of a biopsy specimen were consistent for SCLE. Treatment with moderate- to high-potency topical corticosteroids for 4 weeks yielded no improvement. Discontinuation of etanercept, which was initially suspected to be causing the rash, did not result in improvement, with the rash progressing to the upper back and chest. Four weeks after discontinuing etanercept, leflunomide was stopped and cholestyramine was administered to hasten elimination. In addition, prednisone dose was escalated to 60 mg and then tapered over 4 weeks to baseline dose. Within 2 weeks, the rash improved significantly and was completely resolved by 8 weeks. Subsequently, etanercept was resumed without recurrence of rash. It is proposed that the suppressive effect of leflunomide on tumor necrosis factor-related mechanisms may be partly responsible for causing SCLE (Elias et al, 2005).
B) ANAPHYLAXIS 1) WITH THERAPEUTIC USE a) LEFLUNOMIDE: Anaphylaxis was described in one rheumatoid arthritis patient after intermittent withdrawal of leflunomide (Lang, 1996).
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Reproductive |
3.20.1) SUMMARY
A) Leflunomide and teriflunomide are classified as FDA pregnancy category X. Embryofetal toxicity (ie, anophthalmia, microphthalmia, internal hydrocephalus, fused dysplastic sternebrae, increased embryolethality, decreases in postnatal survival, and a smaller fetal body weight in surviving fetuses) have been reported with animal studies. It is unknown if leflunomide or teriflunomide are excreted in human breast milk. TERIFLUNOMIDE: Should a pregnancy occur during therapy, discontinue teriflunomide and initiate an accelerated elimination procedure. Teriflunomide has been detected in human semen and men should avoid pregnancy in sexual partners. Men wishing to father a child should discontinue teriflunomide and undergo the drug elimination procedure.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALIES 1) There are no adequate or well controlled studies of leflunomide use during human pregnancy. An analysis of pregnancy exposures of 16 women with exposure to leflunomide during the first trimester and 29 women prior to conception resulted in liveborn infants in all but 2 cases. All women discontinued leflunomide use prior to conception or upon recognition of pregnancy and underwent a washout procedure with cholestyramine. A higher incidence of preterm delivery was reported in women exposed to leflunomide during the first trimester compared with preconception exposure (50% and 25.9%, respectively). The incidence of preterm delivery was higher when leflunomide was stopped within 15 weeks of conception compared with earlier termination (33.3% and 11.1%, respectively). Two of the liveborn infants from the during-pregnancy exposure group reportedly had major malformations including aplasia cutis congenita of the thighs in a female twin. The other twin was spontaneously aborted. Functional anomalies were also reported in one infant from each of the 2 study groups and included severe sensorineural hearing loss and cerebral palsy (Cassina et al, 2012).
B) ANIMAL STUDIES 1) LEFLUNOMIDE a) Teratogenicity (ie, anophthalmia, microphthalmia, internal hydrocephalus) occurred in animals at oral leflunomide doses approximately one-tenth the human exposure based on the AUC (Prod Info ARAVA(R) oral tablets, 2015).
b) In studies where female animals were treated with leflunomide approximately one-one hundredth the human exposure level initiated 14 days prior to mating and continuing until the end of lactation, fused dysplastic sternebrae and decreases in postnatal survival of greater than 90% were observed in offspring (Prod Info ARAVA(R) oral tablets, 2015).
c) Teratogenicity was not observed in animals at a 1-mg/kg leflunomide dose (Prod Info ARAVA(R) oral tablets, 2015).
2) TERIFLUNOMIDE a) RATS, RABBITS: There are no adequate or well-controlled studies of teriflunomide use during human pregnancy. Teriflunomide was selectively teratogenic and embryolethal in multiple animal species when administered during pregnancy at lower doses than those used clinically. Administration of teriflunomide up to 12 mg/kg/day during organogenesis resulted in high incidences of fetal malformation and embryofetal death. Administration of teriflunomide up to 1 mg/kg/day during gestation and lactation resulted in decreased growth, abnormalities of the skin and eyes, limb defects, and postnatal death. During animal reproduction studies with leflunomide, embryolethal and teratogenic effects were observed at or below clinically relevant teriflunomide plasma levels. At recommended human doses, both teriflunomide and leflunomide resulted in similar teriflunomide plasma concentrations (Prod Info AUBAGIO(R) oral tablets, 2014).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturers have classified teriflunomide as FDA pregnancy category X (Prod Info AUBAGIO(R) oral tablets, 2014; Prod Info ARAVA(R) oral tablets, 2007). 2) TERIFLUNOMIDE: There are no adequate or well-controlled studies of teriflunomide use during human pregnancy. Teriflunomide use is contraindicated in women who are pregnant or women of childbearing potential not using reliable contraception. Avoid pregnancy during teriflunomide therapy and until completion of the drug elimination procedure after discontinuation. Should a pregnancy occur during therapy, discontinue teriflunomide and initiate an accelerated elimination procedure. Teriflunomide has been detected in human semen and men should avoid pregnancy in sexual partners. Men wishing to father a child should discontinue teriflunomide and undergo the drug elimination procedure (Prod Info AUBAGIO(R) oral tablets, 2014). a) ACCELERATED ELIMINATION: In the event of a pregnancy during teriflunomide therapy, rapidly lowering the plasma concentration may decrease the risk to the fetus. There are 2 recommended drug procedures for accelerated elimination. Cholestyramine 8 g is administered orally every 8 hours (or 4 g orally every 8 hours if not well tolerated) for 11 days OR activated charcoal powder 50 g is administered orally every 12 hours for 11 days. Unless there is a need to lower the plasma level rapidly, the 11 days may be nonconsecutive. Following discontinuation of teriflunomide, women of childbearing potential should undergo the drug elimination procedure to achieve nondetectable teriflunomide plasma levels of less than 0.02 mcg/mL (Prod Info AUBAGIO(R) oral tablets, 2014).
B) RISK SUMMARY 1) LEFLUNOMIDE a) Use during pregnancy is contraindicated. Do not give this drug to a pregnant woman. If pregnancy occurs, discontinue use immediately, apprise patient of potential for fetal harm, and initiate accelerated drug elimination procedures to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) (Prod Info ARAVA(R) oral tablets, 2015).
C) PREGNANCY REGISTRY 1) LEFLUNOMIDE a) Patients exposed to leflunomide during pregnancy may register with the pregnancy registry by calling 1-877-311-8972 or by visiting http://www.pregnancystudies.org/participate-in-a-study/ (Prod Info ARAVA(R) oral tablets, 2015).
2) TERIFLUNOMIDE a) Physicians may register patients exposed to teriflunomide during pregnancy in the AUBAGIO pregnancy registry by calling 1-800-745-4447 option 2 (Prod Info AUBAGIO(R) oral tablets, 2014).
D) PREGNANCY TESTING 1) LEFLUNOMIDE a) Exclude pregnancy in female patients of childbearing potential prior to initiation of treatment (Prod Info ARAVA(R) oral tablets, 2015).
E) CONTRACEPTION 1) LEFLUNOMIDE a) Advise female patients of childbearing potential to use adequate contraception during treatment and during the drug elimination procedure. Contraception should be used until it is verified that plasma teriflunomide concentrations are less than 0.02 mg/L (Prod Info ARAVA(R) oral tablets, 2015).
F) LACK OF EFFECT 1) LEFLUNOMIDE a) Leflunomide and its active metabolite are detectable in plasma up to 2 years after discontinuation of the drug. Therefore, a fetus may be exposed to leflunomide in utero for up to 2 years unless an oral cholestyramine regimen, 8 grams three times daily for 11 days is administered to obtain undetectable plasma levels (drug elimination procedure or washout procedure). In a case series, 5 pregnant women who conceived within 2 years of discontinuation of, or during, leflunomide treatment (4 exposed in the first trimester and one conceived 6.5 months after discontinuation) were referred to a teratogen information service between July 2002 and January 2004. One additional case of pregnancy during paternal exposure was reported with leflunomide taken from 6 months before conception and during the whole pregnancy. None of the women underwent the washout procedure. Three women had voluntary abortions; the other 3 delivered healthy infants (between 36 and 39 weeks gestation; one paternal and two maternal exposures) (De Santis et al, 2005).
b) Of 168 pregnant women evaluated as of January 2004 in a controlled, cohort study (Organization of Teratology Information Services (OTIS) Rheumatoid Arthritis in Pregnancy), women with rheumatoid arthritis (RA) exposed to leflunomide early in pregnancy (n=43) and those with RA not exposed to leflunomide during pregnancy (n=78) were a significant 12 times (95% confidence interval (CI) 2.5, 59.2) and a significant 10.1 times (95% CI 2.2, 47.3), respectively, more likely to deliver preterm infants compared with those in the non-diseased control group (n=47). The adjusted mean birth weight of full term infants was also significantly lower in the RA leflunomide group (3158 g, 95% CI 2979, 3336) and the RA control group (3250 g, 95% CI 3124, 3375) compared with the non-diseased control group (3618 g, 95% CI 3487, 3748; p < 0.001). Overall, all groups had the same proportion of infants born with major and/or minor malformations (Chambers et al, 2004).
c) Results from a survey of 175 rheumatologists identified 10 pregnancies among patients using leflunomide for autoimmune diseases. Outcomes included one pre-term delivery and 2 full-term deliveries, with no congenital abnormalities noted. Three patients aborted, 2 of which were elective abortions, 2 patients had not yet delivered, and 2 patients had not reported outcomes or status. Among 30 previously reported pregnancies, 27 elected to terminate the pregnancy rather than risk fetal malformation (Chakravarty et al, 2003).
G) ANIMAL STUDIES 1) LEFLUNOMIDE a) Increased embryolethality, decreased maternal body weight, and a smaller fetal body weight in surviving fetuses occurred in animals following oral leflunomide doses approximately one-tenth the human exposure based on the AUC (Prod Info ARAVA(R) oral tablets, 2015)
2) TERIFLUNOMIDE a) RATS, RABBITS: There are no adequate or well-controlled studies of teriflunomide use during human pregnancy. Teriflunomide was selectively teratogenic and embryolethal in multiple animal species when administered during pregnancy at lower doses than those used clinically. Administration of teriflunomide up to 12 mg/kg/day during organogenesis resulted in high incidences of fetal malformation and embryofetal death. Administration of teriflunomide up to 1 mg/kg/day during gestation and lactation resulted in decreased growth, abnormalities of the skin and eyes, limb defects, and postnatal death. During animal reproduction studies with leflunomide, embryolethal and teratogenic effects were observed at or below clinically relevant teriflunomide plasma levels. At recommended human doses, both teriflunomide and leflunomide resulted in similar teriflunomide plasma concentrations (Prod Info AUBAGIO(R) oral tablets, 2014).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) LEFLUNOMIDE a) There are no human studies to assess the effects of leflunomide on breast milk, breast milk production, or the breastfed infant. Due to the potential risk to the infant, women should be advised to discontinue nursing during treatment (Prod Info ARAVA(R) oral tablets, 2015).
2) TERIFLUNOMIDE a) Lactation studies with teriflunomide have not been conducted, but the drug was detected in the milk of lactating rats. It is not known whether teriflunomide is excreted into human breast milk; however, there is a potential for serious adverse effects in a nursing infant. A decision should be made to discontinue nursing or discontinue teriflunomide, taking into account the importance of the drug to the mother (Prod Info AUBAGIO(R) oral tablets, 2014).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) LEFLUNOMIDE a) LACK OF EFFECT: No impairment of fertility was demonstrated in reproduction studies in male and female animals receiving doses of leflunomide up to approximately one-thirtieth of the maximum human metabolite exposure (Prod Info ARAVA(R) oral tablets, 2015).
2) TERIFLUNOMIDE a) RATS: Oral administration of teriflunomide up to 10 mg/kg/day in male rats prior to and during mating resulted in no adverse effects on fertility, however, a reduced epididymal sperm count was observed. The no effect dose for reproductive toxicity in male rats was 1 mg/kg which is less than the maximum recommended human dose on a mg/m(2) basis. In female rats administered oral teriflunomide up to 8.6 mg/kg/day prior to mating through gestation day 6, embryolethality, reduced fetal body weight, and malformations were demonstrated at all doses tested (Prod Info AUBAGIO(R) oral tablets, 2014).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, no human data were available to assess the potential carcinogenic activity of leflunomide or teriflunomide.
3.21.4) ANIMAL STUDIES
A) LEFLUNOMIDE 1) MICE: Male mice exhibited an increased incidence in lymphomas at an oral leflunomide dose of 15 mg/kg (1.7 times the human leflunomide metabolite exposure based on AUC). Female mice have exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined at beginning leflunomide doses of 1.5 mg/kg (approximately 1/10 the human leflunomide metabolite exposure based on AUC) (Prod Info Arava(R), leflunomide, 1998).
B) LACK OF EFFECT 1) TERIFLUNOMIDE a) MICE AND RATS: There were no carcinogenic effects observed during lifetime carcinogenicity bioassays in mice and rats. Teriflunomide was administered in doses up to 12 mg/kg/day for up to 104 weeks (teriflunomide AUC approximately 3 times the maximum recommended human dose) (Prod Info AUBAGIO(R) oral tablets, 2012).
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Genotoxicity |
A) TERIFLUNOMIDE
1) There was no evidence of mutagenicity in Ames assays, in vitro HPRT assays, and in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive for mutagenicity in an in vitro chromosomal aberration assay in human lymphocytes. There was evidence of clastogenicity in the following tests: in vitro chromosomal aberration assay. The addition of uridine reduced the magnitude of the clastogenic effects (Prod Info AUBAGIO(R) oral tablets, 2012).
2) The minor metabolite 4-trifluoromethylaniline tested positive for mutagenicity in the following test: Ames assays, in vitro HPRT assay, and in vitro chromosomal aberration assay in mammalian cells. There was no evidence of mutagenicity in the following tests: in vivo micronucleus and chromosomal aberration assays (Prod Info AUBAGIO(R) oral tablets, 2012).
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