US20160030427A1 - Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients - Google Patents
Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients Download PDFInfo
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- US20160030427A1 US20160030427A1 US14/880,777 US201514880777A US2016030427A1 US 20160030427 A1 US20160030427 A1 US 20160030427A1 US 201514880777 A US201514880777 A US 201514880777A US 2016030427 A1 US2016030427 A1 US 2016030427A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- This invention relates to a method for managing the risk of an adverse interaction between teriflunomide and a substrate of breast cancer resistance protein (BCRP) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3).
- BCRP breast cancer resistance protein
- OATP1B1/B3 organic anion transporting polypeptide B1 and B3
- Teriflunomide is a novel oral disease-modifying therapy (DMT) for the treatment of relapsing forms of multiple sclerosis (RMS).
- DMT oral disease-modifying therapy
- RMS multiple sclerosis
- Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated (but not resting) lymphocytes.
- teriflunomide for treating multiple sclerosis is described in U.S. Pat. No. 6,794,410.
- teriflunomide inhibits of human OATP1B1 with a half maximal inhibitory concentration (IC 50 ) of 7.1 ⁇ M, OATP1B3 with an IC 50 of 7.04 ⁇ M, OAT3 with an IC 50 of 1.3 ⁇ M and BCRP with an IC 50 of 0.15 ⁇ M.
- Rosuvastatin a hypocholesterolemiant drug
- HMG-CoA 3-hydroxy-3-methylglutarylcoenzyme A reductase
- Rosuvastatin is a substrate for NTCP, OATP1B1, OATPB1B3, organic anion transporter 3 (OAT3) and BCRP transporters.
- this invention relates to a method for managing the risk of teriflunomide and rosuvastatin interaction in a patient having multiple sclerosis, particularly relapsing forms of multiple sclerosis, wherein rosuvastatin is co-administered with teriflunomide, comprising administering to the patient about 7 or 14 mg of teriflunomide daily, and administering to the patient rosuvastatin which is at the amount of about 50% of the normal dose of rosuvastatin.
- FIG. 1 shows plasma concentration of rosuvastatin following administration of rosuvastatin alone (Day 1) or with teriflunomide (Day 12) (n ⁇ 15).
- administering a combination of teriflunomide and rosuvastatin means administering both teriflunomide and rosuvastatin at the same time, in the same day or within a period of 24 hours, particularly within a period of 12 hours.
- Co-administered and “co-administering” means being administered or administering at the same time, in the same day or within a period of 24 hours, particularly within a period of 12 hours.
- Normal dose of rosuvastatin means a dose of rosuvastatin that would be recommended for a patient to take or a doctor would prescribe the patient to take if the patient is not taking teriflunomide concurrently.
- the normal dose of rosuvastatin is the dose approved by U.S. Food and Drug Administration, which is 5-40 mg daily.
- the normal dose of rosuvastatin is a dose that a patient has been taking prior to the initiation of the treatment with teriflunomide. The dose of rosuvastatin is calculated based on its free acid form. It should be understood that rosuvastatin can be administered as a pharmaceutically acceptable salt, particularly as rosuvastatin calcium, and the amount of salt administered should be adjusted accordingly.
- “Patient” means a human.
- “Pharmaceutically acceptable salts” as used herein means that the salts of the compound of the present invention can be used in medicinal preparations.
- the present invention also relates to a method of providing teriflunomide wherein the teriflunomide is provided along with information indicating that it is useful for treating patients with multiple sclerosis, particularly relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- the present invention also relates to a method of promoting the use of teriflunomide comprising conveying to a recipient at least one message comprising teriflunomide is useful for treating multiple sclerosis, particularly relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- the present invention also relates to an article of manufacture comprising
- the present invention also relates to a package comprising teriflunomide and a label, said label comprising a printed statement which informs a prospective user that:
- the present invention also relates to a method for administering a combination of teriflunomide and rosuvastatin to a patient having multiple sclerosis, particularly relapsing forms of multiple sclerosis, comprising administering to the patient about 7 or 14 mg of teriflunomide daily, and co-administering to the patient rosuvastatin which is at the amount of about 50% of the normal dose of rosuvastatin.
- a single-center, open-label, 1-sequence, 2-period, 2-treatment crossover study with a 5-day washout between periods was conducted in 15 healthy male subjects aged 18 to 45 to evaluate the effect of repeated doses of teriflunomide on the pharmacokinetics (PK) of a single dose of rosuvastatin 10 mg. All subjects received the following treatments during each period:
- cholestyramine was administered for at least 11 days in order to accelerate the elimination of teriflunomide and until teriflunomide concentration was ⁇ 0.25 ⁇ g/mL.
- the total duration of study participation for each subject was up to 3 months, including the screening period and the cholestyramine washout procedure up to the end-of-study (EOS) visit.
- EOS end-of-study
- PK parameters were calculated using noncompartmental methods from plasma rosuvastatin concentration obtained after single dose administration:
- Rosuvastatin Area under the plasma concentration versus time curve (AUC) from time zero to the real time corresponding to the last concentration above the lower limit of quantitation, t last , (AUC last ) and area under the plasma concentration versus time curve extrapolated to infinity (AUC).
- Rosuvastatin Maximum plasma concentration (C max ) observed, time to reach maximum concentration (T max ), t last , and terminal half-life (t 1/2z ).
- Teriflunomide Plasma concentration before treatment administration on Days 10 to 13 during repeated dosing and plasma concentration during cholestyramine treatment on Days 14, 15, 16, 20 and 25.
- Rosuvastatin Blood samples were collected at predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours postdose on Day 1 of Period 1 and Day 12 of Period 2.
- Bioanalytical methods Rosuvastatin plasma concentrations were determined by a validated liquid chromatography couples with tandem mass spectrometry (LC-MS/MS) method, with a LLOQ (lower limit of quantification) of 50.1 pg/mL. Teriflunomide plasma concentrations were determined with a validated LC-MS/MS method with an LLOQ of 0.01 ⁇ g/mL.
- LC-MS/MS tandem mass spectrometry
- Rosuvastatin PK parameters and teriflunomide C trough were summarized with descriptive statistics for each treatment.
- C max , AUC last and AUC of rosuvastatin the effect of repeated oral doses of teriflunomide on single-dose rosuvastatin PK parameters was analyzed using a linear mixed-effect model to obtain estimates and 90% confidence intervals (CIs) for the ratio of geometric means of rosuvastatin co-administered with teriflunomide versus rosuvastatin alone.
- Teriflunomide is an inhibitor of BCRP and an OATP1B1/B3 substrate. Therefore, a 50% dose reduction of rosuvastatin is recommended when co-administering with teriflunomide.
- BCRP e.g. methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin
- HMG-Co reductase inhibitors e.g. simvastatin, atorvastatin pravastatin, methotrexate, nateglinide, repaglinide, rifampin
- concomitant administration of teriflunomide should also be undertaken with caution. Patients should be monitored closely for signs and symptoms of excessive exposure to the drugs and reduction of the dose of these drugs should be considered.
Abstract
This invention relates to a method for managing the risk of an adverse interaction between teriflunomide and a substrate of breast cancer resistance protein (BCRP) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3).
Description
- This invention relates to a method for managing the risk of an adverse interaction between teriflunomide and a substrate of breast cancer resistance protein (BCRP) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3).
- Teriflunomide is a novel oral disease-modifying therapy (DMT) for the treatment of relapsing forms of multiple sclerosis (RMS). Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated (but not resting) lymphocytes.
- The compound of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide (also known as teriflunomide, Formula I) is described in U.S. Pat. No. 5,679,709.
- The use of teriflunomide for treating multiple sclerosis is described in U.S. Pat. No. 6,794,410. In vitro, teriflunomide inhibits of human OATP1B1 with a half maximal inhibitory concentration (IC50) of 7.1 μM, OATP1B3 with an IC50 of 7.04 μM, OAT3 with an IC50 of 1.3 μM and BCRP with an IC50 of 0.15 μM.
- Rosuvastatin, a hypocholesterolemiant drug, is a selective, reversible, competitive inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate early in the cholesterol pathway. Rosuvastatin is a substrate for NTCP, OATP1B1, OATPB1B3, organic anion transporter 3 (OAT3) and BCRP transporters.
- During an interaction study with teriflunomide, it is now found that administration of this active principle together with rosuvastatin causes an increase in the plasma concentration of rosuvastatin.
- Accordingly, this invention relates to a method for managing the risk of teriflunomide and rosuvastatin interaction in a patient having multiple sclerosis, particularly relapsing forms of multiple sclerosis, wherein rosuvastatin is co-administered with teriflunomide, comprising administering to the patient about 7 or 14 mg of teriflunomide daily, and administering to the patient rosuvastatin which is at the amount of about 50% of the normal dose of rosuvastatin.
-
FIG. 1 shows plasma concentration of rosuvastatin following administration of rosuvastatin alone (Day 1) or with teriflunomide (Day 12) (n≦15). - As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
- “Administering a combination of teriflunomide and rosuvastatin” means administering both teriflunomide and rosuvastatin at the same time, in the same day or within a period of 24 hours, particularly within a period of 12 hours.
- “Co-administered” and “co-administering” means being administered or administering at the same time, in the same day or within a period of 24 hours, particularly within a period of 12 hours.
- “Normal dose of rosuvastatin” means a dose of rosuvastatin that would be recommended for a patient to take or a doctor would prescribe the patient to take if the patient is not taking teriflunomide concurrently. In one aspect, the normal dose of rosuvastatin is the dose approved by U.S. Food and Drug Administration, which is 5-40 mg daily. In another aspect, the normal dose of rosuvastatin is a dose that a patient has been taking prior to the initiation of the treatment with teriflunomide. The dose of rosuvastatin is calculated based on its free acid form. It should be understood that rosuvastatin can be administered as a pharmaceutically acceptable salt, particularly as rosuvastatin calcium, and the amount of salt administered should be adjusted accordingly.
- “Patient” means a human.
- “Pharmaceutically acceptable salts” as used herein means that the salts of the compound of the present invention can be used in medicinal preparations.
- The present invention also relates to a method of providing teriflunomide wherein the teriflunomide is provided along with information indicating that it is useful for treating patients with multiple sclerosis, particularly relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- The present invention also relates to a method of promoting the use of teriflunomide comprising conveying to a recipient at least one message comprising teriflunomide is useful for treating multiple sclerosis, particularly relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- The present invention also relates to an article of manufacture comprising
-
- a) a packaging material:
- b) teriflunomide, and
- c) a label or package insert contained within the packaging material indicating that teriflunomide is useful for treating multiple sclerosis, particularly relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- The present invention also relates to a package comprising teriflunomide and a label, said label comprising a printed statement which informs a prospective user that:
-
- a) teriflunomide is indicated in patients with relapsing forms of multiple sclerosis; and
- b) in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the normal dose of rosuvastatin by about 50% is recommended.
- The present invention also relates to a method for administering a combination of teriflunomide and rosuvastatin to a patient having multiple sclerosis, particularly relapsing forms of multiple sclerosis, comprising administering to the patient about 7 or 14 mg of teriflunomide daily, and co-administering to the patient rosuvastatin which is at the amount of about 50% of the normal dose of rosuvastatin.
- The present invention may be better understood by reference to the following non-limiting Example, which is exemplary of the invention. It should in no way be construed, however, as limiting the breath of the scope of the invention.
- A single-center, open-label, 1-sequence, 2-period, 2-treatment crossover study with a 5-day washout between periods was conducted in 15 healthy male subjects aged 18 to 45 to evaluate the effect of repeated doses of teriflunomide on the pharmacokinetics (PK) of a single dose of rosuvastatin 10 mg. All subjects received the following treatments during each period:
-
- 1. Period 1: A single 10 mg dose of rosuvastatin was administered in fasted state followed by a 5-day washout (from Days 1 to 6). Day 6 corresponded to Day 1 of Period 2.
- 2. Period 2: A loading dose of 70 mg teriflunomide was administered once a day for 4 days (Days 1 to 4), followed by 14 mg once a day for 8 days (Days 5 to 12) in fed conditions except for
Day 12. A single dose of 10 mg rosuvastatin was co-administered with teriflunomide onDay 12 in fasted conditions.
- After last PK sample for rosuvastatin in Period 2 and discharge, cholestyramine was administered for at least 11 days in order to accelerate the elimination of teriflunomide and until teriflunomide concentration was ≦0.25 μg/mL.
- The total duration of study participation for each subject was up to 3 months, including the screening period and the cholestyramine washout procedure up to the end-of-study (EOS) visit.
-
- 1. Screening: −21 to −1 days before inclusion
- 2. Period 1: 5 days (from Days 1 to 6)
- 3. Period 2: 13 days+11 days of cholestyramine treatment (24 days)
The EOS visit (Day 35 to 42) was not complete until the subject's teriflunomide concentration was 0.25 μg/mL or lower.
- Criteria for Evaluation:
- The following PK parameters were calculated using noncompartmental methods from plasma rosuvastatin concentration obtained after single dose administration:
- Primary:
- Rosuvastatin: Area under the plasma concentration versus time curve (AUC) from time zero to the real time corresponding to the last concentration above the lower limit of quantitation, tlast, (AUClast) and area under the plasma concentration versus time curve extrapolated to infinity (AUC).
- Secondary:
- Rosuvastatin: Maximum plasma concentration (Cmax) observed, time to reach maximum concentration (Tmax), tlast, and terminal half-life (t1/2z).
- Teriflunomide: Plasma concentration before treatment administration on Days 10 to 13 during repeated dosing and plasma concentration during cholestyramine treatment on
Days - Pharmacokinetic Sampling Times and Bioanalytical Methods:
- Sampling:
- Rosuvastatin: Blood samples were collected at predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours postdose on Day 1 of Period 1 and
Day 12 of Period 2. - Teriflunomide: Blood samples were collected at predose on
Days - Bioanalytical methods: Rosuvastatin plasma concentrations were determined by a validated liquid chromatography couples with tandem mass spectrometry (LC-MS/MS) method, with a LLOQ (lower limit of quantification) of 50.1 pg/mL. Teriflunomide plasma concentrations were determined with a validated LC-MS/MS method with an LLOQ of 0.01 μg/mL.
- Statistical Analysis:
- Rosuvastatin PK parameters and teriflunomide Ctrough (trough plasma concentration) were summarized with descriptive statistics for each treatment. For log transformed Cmax, AUClast and AUC of rosuvastatin, the effect of repeated oral doses of teriflunomide on single-dose rosuvastatin PK parameters was analyzed using a linear mixed-effect model to obtain estimates and 90% confidence intervals (CIs) for the ratio of geometric means of rosuvastatin co-administered with teriflunomide versus rosuvastatin alone.
- Results:
- It was found that there was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following teriflunomide 70 mg QD for 4 days and 14 mg QD for 8 days. Mean±SD (CV %) [Geometric Mean] of the pharmacokinetic parameters of rosuvastatin with ratio estimates and 90% CIs are shown in Table I below and
FIG. 1 . -
Rosuvastatin Rosuvastatin + Treatment alone Teriflunomide Ratioa (90% CI) N 15 14 — Cmax (pg/mL) 3650 ± 1780 9340 ± 5110 2.65 (2.25, 3.12) tmax b (h) 3.00 (2.00-5.00) 3.00 (2.00-3.00) — t1/2z (h) 11.1 ± 2.99 12.3 ± 2.28 — AUClast 31500 ± 16400 75400 ± 38700 2.52 (2.17, 2.91) (pg · h/mL)c AUC 34800 ± 17300d 83000 ± 41400 2.51 (2.16, 2.91) (pg · h/mL) aTeriflunomide + rosuvastatin versus rosuvastatin alone; bMedian (min-Max); cMedian tlast was 36 h for both treatment; dn = 14 due to AUC extrapolation >20% - Teriflunomide is an inhibitor of BCRP and an OATP1B1/B3 substrate. Therefore, a 50% dose reduction of rosuvastatin is recommended when co-administering with teriflunomide. For other substrates of BCRP (e.g. methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family, especially HMG-Co reductase inhibitors (e.g. simvastatin, atorvastatin pravastatin, methotrexate, nateglinide, repaglinide, rifampin), concomitant administration of teriflunomide should also be undertaken with caution. Patients should be monitored closely for signs and symptoms of excessive exposure to the drugs and reduction of the dose of these drugs should be considered.
Claims (6)
1. A method of providing teriflunomide wherein the teriflunomide is provided along with information indicating that it is useful for treating patients with relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the dose of rosuvastatin to not exceeding 10 mg once daily is recommended.
2. A method of promoting the use of teriflunomide comprising conveying to a recipient at least one message comprising teriflunomide is useful for treating relapsing forms of multiple sclerosis, and in cases said patients also receive treatment of rosuvastatin wherein rosuvastatin is co-administered with teriflunomide, reducing the dose of rosuvastatin to not exceeding 10 mg once daily is recommended.
3. A method for administering a combination of teriflunomide and rosuvastatin to a patient having multiple sclerosis, comprising administering to the patient about 7 or 14 mg of teriflunomide daily, and co-administering to the patient rosuvastatin at a dose that does not exceed 10 mg once daily.
4. The method according to claim 3 , wherein the patient has relapsing forms of multiple sclerosis.
5. The method according to claim 3 , wherein rosuvastatin is co-administered with teriflunomide at the same time.
6. The method according to claim 4 , wherein rosuvastatin is co-administered with teriflunomide at the same time.
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US15/846,553 US20180344732A1 (en) | 2013-02-04 | 2017-12-19 | Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients |
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US201361777361P | 2013-03-12 | 2013-03-12 | |
US14/172,082 US9186346B2 (en) | 2013-02-04 | 2014-02-04 | Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients |
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DE3121152A1 (en) * | 1981-05-22 | 1982-12-09 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | "USE OF THE COMBINATION OF AN AROMATASE INHIBITOR WITH AN ANTIANDROGEN FOR PROPHYLAXIS AND THERAPY OF PROSTATE HYPERPLASIA" |
US4658957A (en) * | 1985-01-28 | 1987-04-21 | Abbott Laboratories | Utility tray |
US5268382A (en) | 1985-09-27 | 1993-12-07 | Hoechst Aktiengesellschaft | Medicaments to combat autoimmune diseases, in particular systemic lupus erythematosus |
US20040013643A1 (en) * | 2000-09-19 | 2004-01-22 | Novlmmune S.A. | Methods for treatment of multiple sclerosis with statins |
ATE396719T1 (en) * | 2001-04-05 | 2008-06-15 | Aventis Pharma Inc | USE OF (Z)-2-CYANO-3-HYDROXY-BUT-2-ENEIC ACID (4'-TRIFLUOROMETHYLPHENYL)-AMIDE FOR THE TREATMENT OF MULTIPLATE SCLEROSIS |
GB0123571D0 (en) | 2001-04-05 | 2001-11-21 | Aventis Pharm Prod Inc | Use of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide for treating multiple sclerosis |
WO2012018704A1 (en) * | 2010-08-02 | 2012-02-09 | Sanofi-Aventis U.S. Llc | Use of teriflunomide for treating multiple sclerosis |
WO2012162339A1 (en) * | 2011-05-24 | 2012-11-29 | Sanofi-Aventis U.S. Llc | Use of teriflunomide for reducing occurrence of relapses requiring healthcare resources |
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2013
- 2013-02-04 EP EP13305130.0A patent/EP2762135A1/en not_active Ceased
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2014
- 2014-02-04 US US14/172,082 patent/US9186346B2/en active Active
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2015
- 2015-10-12 US US14/880,777 patent/US20160030427A1/en not_active Abandoned
-
2017
- 2017-12-19 US US15/846,553 patent/US20180344732A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9186346B2 (en) * | 2013-02-04 | 2015-11-17 | Sanofi | Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients |
Also Published As
Publication number | Publication date |
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US20140256758A1 (en) | 2014-09-11 |
US9186346B2 (en) | 2015-11-17 |
US20180344732A1 (en) | 2018-12-06 |
EP2762135A1 (en) | 2014-08-06 |
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Owner name: SANOFI, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MENGUY-VACHERON, FRANCOISE;CLOT, PIERRE-FRANCOIS;WEITZ, DIETMAR;AND OTHERS;SIGNING DATES FROM 20130522 TO 20140515;REEL/FRAME:037647/0030 |
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