Auberif 14mg Tablets

AUBERIF is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease to reduce the frequency of relapses and to delay the accumulation of physical disability.

Posology
The treatment should be initiated and supervised by a medical practitioner experienced in multiple sclerosis.
The recommended dose of AUBERIF is 14 mg orally once daily. AUBERIF can be taken with or without food.

Special populations
Elderly: AUBERIF has not been specifically studied in the elderly (over 65 years of age).
Renal impairment: No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment.
Hepatic impairment: No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. AUBERIF is contraindicated in patients with severe hepatic impairment.
Paediatric population: The safety and efficacy of AUBERIF in children aged 0 to 18 years have not yet been established. Use in this age group is not recommended.

Method of administration
For oral administration.

• Hypersensitivity to teriflunomide, leflunomide or to any of the excipients (see section 6.1).
• Patients with severe hepatic impairment.
• As leflunomide is the parent compound of teriflunomide, co-administration of AUBERIF with leflunomide is not recommended.
• AUBERIF is contraindicated in women during pregnancy or women of childbearing potential who are not on reliable contraception during treatment with AUBERIF and thereafter, as long as its plasma levels are above 0,02 u03bcg/mL (see section 4.6).

Hepatic effects: Elevations of liver enzymes have been observed in patients receiving AUBERIF. In placebo-controlled trials, alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN) occurred in 62/1 002 (6,2 %) of patients on AUBERIF and 38/997 (3,8 %) of patients on placebo, during the treatment period. These elevations occurred mostly within the first 6 months of treatment. Half of the cases returned to normal without medicine discontinuation. In clinical trials, teriflunomide was discontinued if the ALT elevation exceeded 3 times the ULN twice. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of AUBERIF. One additional clinically significant case of u201ctoxic hepatitisu201d was reported in a 35-year-old female patient. Although the aetiology of the hepatic event remained unclear, a causal role of AUBERIF in this case is possible. Cases of drug-induced liver injury (DILI) have been observed in the post-marketing setting, sometimes life-threatening, often in combination with other hepatotoxic medicines. Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBERIF therapy. Monitor ALT levels at least monthly for six months after starting AUBERIF. Consider monitoring when AUBERIF is given with other potentially hepatotoxic medicines. Consider discontinuing AUBERIF if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBERIF therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBERIF-induced, discontinue AUBERIF and start an accelerated elimination procedure (see section 4.9) and monitor liver tests weekly until normalised. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBERIF therapy may be considered.

Usage in women of childbearing potential / during pregnancy: Animal data suggest risks to the fetus. Women of childbearing potential must use effective contraception to avoid pregnancy while taking AUBERIF. If AUBERIF is stopped, women should continue contraception until teriflunomide plasma concentrations have been checked to be equal to 0,02 u03bcg/mL or lower. Women who are pregnant or planning to become pregnant, should be advised that an accelerated elimination procedure can be used to quickly decrease the plasma concentration of teriflunomide. Without the accelerated elimination procedure, on average it takes 8 months to reach plasma concentrations less than or equal to 0,02 u03bcg/mL. However, due to individual variation in clearance it may take up to 2 years. The accelerated elimination could be used at any time after discontinuation of AUBERIF (see section 4.9).

Blood pressure effects: In placebo-controlled studies, mean change from baseline to endpoint value in systolic blood pressure was 2,7 mm Hg for AUBERIF and 0,6 mm Hg for the placebo. The change from baseline in diastolic blood pressure was 1,9 mm Hg for AUBERIF and - 0,3 mm Hg for the placebo. Hypertension was reported as an adverse reaction in 4,3 % of patients treated with AUBERIF, compared with 1,8 % on the placebo. Check blood pressure before the start of AUBERIF treatment and periodically thereafter. Blood pressure elevation should be appropriately managed during treatment with AUBERIF.

Infections: In placebo-controlled studies of AUBERIF, no overall increase in the risk of serious infections was observed with teriflunomide (2,7 %) compared to placebo (2,2 %). However, one fatal case of Klebsiella pneumoniae sepsis occurred in a patient taking AUBERIF for 1,7 years. In clinical studies with AUBERIF, cytomegalovirus, hepatitis reactivation and tuberculosis have been observed. However, based on the immunomodulatory effect of AUBERIF, if a patient develops a serious infection, consider suspending treatment with AUBERIF and reassess the benefits and risks prior to re-initiation of therapy. Due to the prolonged half-life, accelerated elimination with colestyramine or charcoal may be considered. Instruct patients receiving AUBERIF to report symptoms of infections to a medical practitioner. Patients with active acute or chronic infections should not start treatment with AUBERIF until the infection(s) is resolved. AUBERIF is not recommended with severe immunodeficiency, bone marrow disease, or severe uncontrolled infections. The safety of AUBERIF in individuals with latent tuberculosis infection is unknown, as tuberculosis screening was not systematically performed in clinical studies. Patients testing positive in tuberculosis screening, should be treated according to standard medical practice prior to therapy with AUBERIF.

Respiratory effects: Interstitial lung disease, including acute interstitial pneumonitis, has been reported with AUBERIF in the post-marketing setting. Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease may occur acutely at any time during therapy, with a variable clinical presentation. Interstitial lung disease may be fatal. New onset or worsening pulmonary symptoms, such as cough and dyspnoea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of AUBERIF therapy is necessary, consider initiation of an accelerated elimination procedure (see section 4.9).

Haematological effects: A mean decrease in white blood cell (WBC) count of approximately 15 % (mainly neutrophils and lymphocytes) and in platelet counts of approximately 10 % was observed in placebo-controlled trials with AUBERIF as compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1,5 x 10 9 /L was observed in 16 % of patients on AUBERIF, compared with 7 % of patients on placebo; lymphocyte count < 0,8 x 10 9 /L was observed in 12 % of patients on AUBERIF compared with 6 % of patients on placebo. At baseline, a recent blood cell count should be available before the initiation of treatment with AUBERIF and assessed during AUBERIF therapy. Further monitoring should be based on signs and symptoms suggestive of infection.

Vaccination: Two clinical studies have shown that vaccinations with inactivated neoantigen (first vaccination) or recall antigen (re-exposure) were safe and effective during AUBERIF treatment. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided.

Skin reactions: Severe cutaneous adverse reactions (SCARs) Cases of serious skin reactions, sometimes fatal, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with teriflunomide. If skin and/or mucosal reactions (ulcerative stomatitis) are observed which raise the suspicion of severe generalised major skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis u2013 Lyellu2019s syndrome, or drug reaction with eosinophilia and systemic symptoms), AUBERIF and any other possibly associated treatment must be discontinued, and an accelerated elimination procedure initiated immediately. In such cases patients should not be re-exposed to teriflunomide (see section 4.9).

Peripheral neuropathy: Cases of peripheral neuropathy have been reported in patients receiving AUBERIF. Most patients improved after discontinuation of AUBERIF. However, there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved, and some patients had persistent symptoms. If a patient taking AUBERIF develops a confirmed peripheral neuropathy, consider discontinuing AUBERIF therapy and performing the accelerated elimination procedure.

Concomitant use of immunosuppressive or immunomodulating therapies: As leflunomide is the parent compound of teriflunomide, co-administration of AUBERIF with leflunomide is contraindicated. Co-administration with antineoplastic or immunosuppressive therapies used for treatment of MS has not been evaluated. Safety studies, in which AUBERIF was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long-term safety of these combinations in the treatment of multiple sclerosis has not been established.

Elimination procedure: Teriflunomide is slowly eliminated from the plasma. When desired, an accelerated elimination procedure can be used (see section 4.9).

Lactose: Since AUBERIF tablets contain lactose, patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take AUBERIF.

The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor pathway, with limited involvement of cytochrome P450 (CYP) or flavin monoamine oxidase enzymes.

Potential for other medicines to affect AUBERIF: Based on in vitro studies, teriflunomide is a substrate of the efflux transporter BCRP. BCRP inhibitors (such as ciclosporin, eltrombopag, gefitinib) may increase exposure of teriflunomide.

Potent cytochrome P450 (CYP) and transporter inducers: Co-administration of repeated doses (600 mg once daily for 22 days) of rifampicin (a CYP2B6, 2C8, 2C9, 2C19, 3A inducer), as well as an inducer of the efflux transporters P-glycoprotein [P-gp] and breast cancer resistant protein [BCRP] and AUBERIF (70 mg single dose) resulted in an approximately 40 % decrease in teriflunomide exposure. Rifampicin and other known potent CYP and transporter inducers such as carbamazepine, phenobarbital (phenobarbitone), phenytoin and St Johnu2019s wort should be used with caution during the treatment with AUBERIF.

Potential for AUBERIF to affect other medicines: Effect of AUBERIF on CYP2C8 substrates: There was an increase in mean repaglinide C max and AUC (1,7- and 2,4-fold, respectively) following repeated doses of AUBERIF, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose. Therefore, monitoring patients with concomitant use of medicines metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone is recommended as they may have higher exposure.

Effect of AUBERIF on oral contraceptives: There was an increase in mean ethinylestradiol C max and AUC 0-24 (1,58- and 1,54-fold, respectively) and levonorgestrel Cmax and AUC 0-24 (1,33- and 1,41-fold, respectively) following repeated doses of AUBERIF. While this interaction of AUBERIF is not expected to adversely impact the efficacy of oral contraceptives, consideration should be given to the type or dose of oral contraceptives used in combination with AUBERIF.

Effect of AUBERIF on CYP1A2 substrates: Repeated doses of AUBERIF decreased mean C max and AUC of caffeine (CYP1A2 substrate) by 18 % and 55 %, respectively, suggesting that AUBERIF may be a weak inducer of CYP1A2 in vivo. Therefore, medicines metabolised by CYP1A2 (such as duloxetine, theophylline and tizanidine) should be used with caution during treatment with AUBERIF, as it could lead to the reduction of efficacy of these medicines.

Effect of AUBERIF on warfarin: A 25 % decrease in peak international normalised ratio (INR) was observed when AUBERIF was co-administered with warfarin as compared with warfarin alone. Therefore, when warfarin is co-administered with AUBERIF, close INR follow-up and monitoring is recommended.

Effect of AUBERIF on organic anion transporter 3 (OAT3) substrates: There was an increase in mean cefaclor C max and AUC (1,43- and 1,54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of OAT3 in vivo. Therefore, when AUBERIF is co-administered with substrates of OAT3, such as cefaclor, penicillin G, ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, methotrexate or zidovudine, caution should be observed.

Effect of AUBERIF on BCRP and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates: There was an increase in mean rosuvastatin C max and AUC (2,65- and 2,51-fold, respectively) following repeated doses of AUBERIF. However, there was no apparent impact of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. If used together, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g. methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitant administration of AUBERIF should also be undertaken with caution. Monitor patients closely for signs and symptoms of excessive exposure to these medicines and consider reduction of the dose of these medicines.

Effect of AUBERIF on CYP2B6, CYP3A, CYP2C9, CYP2C19 and CYP2D6 substrates: AUBERIF did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate) and metoprolol (a CYP2D6 substrate).

Pregnancy
There are no adequate and well-controlled studies of AUBERIF in pregnant women. However, based on animal studies, AUBERIF may increase the risk of fetal death or teratogenic effects when administered to pregnant women. AUBERIF is contraindicated during pregnancy and in women of childbearing potential not using reliable contraception (see section 4.3).

Use in males
The risk of male-mediated embryo-fetal toxicity through AUBERIF treatment is considered low, however patients should be advised to use barrier contraception.

Breastfeeding
Mothers must not breastfeed their infants while taking AUBERIF. Animal studies have shown excretion of AUBERIF in breast milk.

AUBERIF has no or negligible influence on the ability to drive and use machines.

a. Summary of the safety profile
A total of 2 047 patients on AUBERIF and 997 on placebo constituted the safety population in the pooled analysis of placebo-controlled studies in patients with relapsing forms of MS (RMS). In clinical trials, the most frequent adverse reactions for AUBERIF (incidence u2265 10 %) in the placebo-controlled studies were headache, diarrhoea, nausea, alopecia and increased ALT.

b. Tabulated list of adverse reactions
Adverse reactions reported with AUBERIF 14 mg in placebo-controlled studies are shown below. Frequencies were defined using the following convention when applicable: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

System organ class

• Very common (u2265 1/10)
• Infections and infestations: Upper respiratory tract infection, influenza, urinary tract infection, bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral herpes, tooth infection, laryngitis, tinea pedis
• Blood and lymphatic system disorders: Neutropenia
• Immune system disorders: Mild allergic reactions, seasonal allergy
• Psychiatric disorders: Anxiety
• Nervous system disorders: Headache, paraesthesia, sciatica, carpal tunnel syndrome, hyperaesthesia, neuralgia
• Cardiac disorders: Palpitations
• Vascular disorders: Hypertension
• Gastrointestinal disorders: Diarrhoea, nausea, upper abdominal pain, vomiting, toothache
• Skin and subcutaneous tissue disorders: Alopecia*, rash, acne
• Musculoskeletal and connective tissue disorders: Arthralgia, musculoskeletal pain, myalgia
• Renal and urinary disorders: Pollakiuria
• Reproductive system and breast disorders: Menorrhagia
• General disorders and administration site conditions: Pain
• Investigations: Increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyltransferase (GGT), decreased weight, decreased neutrophil count, increased blood creatine phosphokinase, decreased white blood cell count
• Injury, poisoning and procedural complications: Post-traumatic pain

c. Description of selected adverse reactions
*Alopecia: Alopecia was reported as hair thinning, decreased hair density, hair loss, associated or not with hair texture change, in 15,2 % of patients treated with 14 mg AUBERIF versus 4,3 % in patients treated with placebo. Most cases were described as diffuse or generalised over the scalp and were more likely to occur during the first 6 months. Polyneuropathy: In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g. carpal tunnel syndrome), was reported more frequently in patients taking AUBERIF than in patients taking placebo. In the pivotal, placebo-controlled studies, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1,9 % (17 patients) on doses of 14 mg of AUBERIF, compared with 0,4 % on placebo (4 patients). Treatment was discontinued in 5 patients with confirmed neuropathy. Recovery following treatment discontinuation was reported in 4 of these patients. In post-marketing experience (spontaneous reports) In post-marketing experience with AUBERIF, the following adverse reactions have been identified: Immune system disorders: Hypersensitivity reactions (immediate or delayed), some of which were severe, such as anaphylaxis and angioedema. Skin and subcutaneous tissue disorders: Severe skin reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS); psoriasis (including pustular psoriasis and nail psoriasis); nail disorders. Respiratory, thoracic and mediastinal disorders: Interstitial lung disease (ILD). Gastrointestinal disorders: Stomatitis (such as aphthous or ulcerative), pancreatitis and colitis. Hepatobiliary disorders: Drug-induced liver injury (DILI).

There is no experience regarding AUBERIF overdose or intoxication in humans. In the event of relevant overdose or toxicity, colestyramine or activated charcoal is recommended to accelerate elimination. Accelerated elimination procedure: colestyramine and activated charcoal: Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 6 months to reach plasma concentrations less than 0,25 u03bcg/mL. Due to individual variations in medicine clearance, it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBERIF. Elimination can be accelerated by either of the following procedures:

• Administration of colestyramine 8 g every 8 hours for 11 days. If colestyramine 8 g three times a day is not well tolerated, colestyramine 4 g three times a day can be used.
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days. If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.