Lunava

Lunava is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Lunava was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.

Treatment of active rheumatoid arthritis (RA) in adults to reduce signs and symptoms, inhibit structural damage as evidence by X-ray erosions and joint space narrowing, and improve physical function.

Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with Lunava. The combined use of Lunava with antimalarials, IM or oral gold, D-penicillamine, azathioprine or methotrexate has not been adequately studied.

Lunava affects the immune system and reduces swelling and inflammation in the body.

Lunava is used to treat the symptoms of rheumatoid arthritis. Lunava also helps reduce joint damage and improves physical functioning.

Lunava may also be used for other purposes not listed in this medication guide.

Recommended Dosage

The recommended dosage of Lunava is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of Lunava-associated hepatotoxicity and Lunava-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly.

• For patients who are at low risk for Lunava-associated hepatotoxicity and Lunava-associated myelosuppression the recommended Lunava loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily.
• For patients at high risk for Lunava-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or Lunava-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended Lunava dosage is 20 mg once daily without a loading dose.

The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1).

Monitor patients carefully after dosage reduction and after stopping therapy with Lunava, since the active metabolite of Lunava, teriflunomide, is slowly eliminated from the plasma. After stopping Lunava treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping Lunava.

Evaluation and Testing Prior to Starting Lunava

Prior to starting Lunava treatment the following evaluations and tests are recommended:

• Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection
• Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts
• For females of reproductive potential, pregnancy testing
• Check blood pressure

See also:
What is the most important information I should know about Lunava?

Known hypersensitivity to Lunava or to any of the components of Lunava.

Use in pregnancy: Lunava can cause fetal harm when administered to pregnant women.

Women of Childbearing Potential: There are no adequate and well-controlled studies evaluating Lunava in pregnant women. However, based on animal studies, Lunava may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on Lunava until pregnancy is excluded and counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, notify the physician immediately for pregnancy testing, and if positive, the physician and the patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure as follows at the first delay of menses may decrease the risk to the fetus from Lunava. Upon discontinuing Lunava, it is recommended that all women of childbearing potential undergo the drug elimination procedure as described as follows. Women receiving Lunava treatment who wish to become pregnant must discontinue Lunava and undergo the drug elimination procedure which includes verification of M1 metabolite plasma levels <0.02 mg/mL (0.02 mcg/mL). Human plasma levels of the active metabolite (M1) <0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data.

Drug Elimination Procedure: The following drug elimination procedure is recommended to achieve nondetectable plasma levels (<0.02 mg/L or 0.02 mcg/mL) after stoping treatment with Lunava: Administer cholestyramine 8 g 3 times daily for 11 days. The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.

Verify plasma levels <0.02 mg/L (0.02 mcg/mL) by 2 separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels <0.02 mg/L due to individual variation in drug clearance.

Use Lunava as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Lunava by mouth with or without food.
• It may take 4 weeks or more to notice any improvement while taking Lunava.
• If you miss a dose of Lunava, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Lunava.

Use: Labeled Indications

Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis (RA).

Off Label Uses

BK virus (viremia or nephropathy; in kidney transplant recipients)

Data from a small retrospective study suggest Lunava may be of benefit as a replacement for mycophenolate in kidney transplant recipients with BK virus (viremia or nephropathy).

See also:
What other drugs will affect Lunava?

Following oral administration, Lunava is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Lunava's in vivo activity. Drug interaction studies have been conducted with both Lunava (Lunava) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

Effect of Potent CYP and Transporter Inducers

Lunava is metabolized by CYP450 metabolizing enzymes. Concomitant use of Lunava 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 Lunava when coadministered with rifampin. Because of the potential for Lunava concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both Lunava and rifampin.

Effect on CYP2C8 Substrates

Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking Lunava, 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.

Effect on Warfarin

Coadministration of Lunava with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of Lunava, 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 Lunava.

Effect on CYP1A2 Substrates

Teriflunomide, the active metabolite of Lunava, may be a weak inducer of CYP1A2 in vivo. In patients taking Lunava, 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.

Effect on Organic Anion Transporter 3 (OAT3) Substrates

Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking Lunava, 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.

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 Lunava, 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 Lunava.

See also:
What are the possible side effects of Lunava?

The following serious adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity
• Immunosuppression
• Bone marrow suppression
• Stevens-Johnson syndrome and toxic epidermal necrolysis
• Peripheral neuropathy
• Interstitial lung disease

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with Lunava administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.

Elevation of Liver Enzymes

Treatment with Lunava 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.

Table 1: Liver Enzyme Elevations > 3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3**

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, Lunava 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 Lunava-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 Lunava treatment group).

Table 2: Percentage Of Patients With Adverse Events ≥ 5% In Any Lunava Treated Group in all RA Studies in Patients with RA

Adverse events during a second year of treatment with Lunava 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 Lunava 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;

Post Marketing Experience

The following additional adverse reactions have been identified during postapproval use of Lunava. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;

Infection: opportunistic infections, severe infections including sepsis;

Gastrointestinal: acute hepatic necrosis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure

Immune System: angioedema;

Nervous system: peripheral neuropathy;

Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;

Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.