Download A Guide to the Accelerated Elimination Procedure for AUBAGIO(R

A GUIDE TO THE
ACCELERATED ELIMINATION
PROCEDURE FOR
AUBAGIO® (teriflunomide)
WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
AUBAGIO is available in 14 mg and 7 mg tablets.
Hepatotoxicity
Severe liver injury including fatal liver failure has been reported in patients treated with
leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be
expected for teriflunomide because recommended doses of teriflunomide and
leflunomide result in a similar range of plasma concentrations of teriflunomide.
Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase
the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months
before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six
months after starting AUBAGIO. If drug induced liver injury is suspected, discontinue
AUBAGIO and start an accelerated elimination procedure with cholestyramine or
charcoal. AUBAGIO is contraindicated in patients with severe hepatic impairment.
Patients with pre-existing liver disease may be at increased risk of developing elevated
serum transaminases when taking AUBAGIO.
Risk of Teratogenicity
Based on animal data, AUBAGIO may cause major birth defects if used during
pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is
contraindicated in pregnant women or women of childbearing potential who are not
using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment
or prior to the completion of an accelerated elimination procedure after
AUBAGIO treatment.
References:
1. AUBAGIO (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation;
September 2012.
2. Data on file, Sanofi/Genzyme.
www.genzyme.com
© 2013 Genzyme Corporation, a Sanofi company.
All rights reserved. MS.US.PO1245.0113
AUBAGIO is available in 14 mg and 7 mg tablets.
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING.
AUBAGIO is available in 14 mg and 7 mg tablets.
The safety and effectiveness of AUBAGIO have not been
established in pediatric patients and in patients aged >65 years.
The most frequent adverse reactions (≥10% and ≥2% greater
than placebo) with AUBAGIO 7 mg and 14 mg and placebo,
respectively, were ALT increased (12% and 14% vs 7%), alopecia
(10% and 13% vs 3%), diarrhea (15% and 18% vs 9%), influenza
(9% and 12% vs 10%), nausea (9% and 14% vs 7%), and
paresthesia (9% and 10% vs 8%).
The type or dose of oral contraceptives used in combination
with teriflunomide should be considered because of increased
ethinylestradiol and levonorgestrel levels following repeated
doses of teriflunomide.
A 25% decrease in peak international normalized ratio (INR) was
observed when teriflunomide was coadministered with warfarin
vs warfarin alone. Close INR follow-up and monitoring are
recommended.
Teriflunomide is an inhibitor of CYP2C8 and may be a weak
inducer of CYP1A2. Monitor patients when teriflunomide is
coadministered with drugs metabolized by these pathways.
Interstitial lung disease and worsened preexisting interstitial
lung disease have been reported with leflunomide, with a similar
risk expected with teriflunomide.
Increased blood pressure has occurred with AUBAGIO.
Hypertension was reported in 4% of patients taking AUBAGIO
vs 2% on placebo. Measure blood pressure at treatment
initiation and manage appropriately during treatment.
11
What is the accelerated elimination procedure?
Drug elimination processes can be used in certain
situations to reduce plasma concentrations of some drugs.
A reliable accelerated elimination procedure is available for
AUBAGIO® (teriflunomide), indicated for the treatment of
relapsing forms of multiple sclerosis.
When is the accelerated elimination
procedure required?
The accelerated elimination procedure should be used after
discontinuation of AUBAGIO when1:
•P
regnancy occurs during AUBAGIO therapy (use of this
procedure may decrease risk to the fetus)
•A
patient taking AUBAGIO wants to become pregnant
or father a child
•D
rug-induced liver injury is suspected
•A
ccelerated removal of drug is clinically desired
(eg, overdose or serious skin reactions)
The procedure is also recommended after discontinuation of
therapy in women of childbearing potential or in the event
of clinically significant toxicity.1
2
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING regarding
hepatotoxicity and use in pregnancy.
Why is accelerated elimination required in
these cases?
AUBAGIO is eliminated slowly from the plasma. Without accelerated
elimination, it takes an average of 8 months, or up to 2 years in
some patients, to reach plasma concentrations <0.02 mcg/mL
(<0.02 mg/L).1 With the accelerated elimination procedure, these
low plasma drug levels can be reached within 11 days.
What is the accelerated elimination regimen
for AUBAGIO?
The recommended procedure is administration of oral
cholestyramine 8 g three times daily for 11 days. In patients
who do not tolerate this regimen, the dosage may be reduced
to 4 g. If tolerability is an issue, cholestyramine administration
does not need to occur on consecutive days unless there is
a need to lower teriflunomide plasma concentrations rapidly.
Oral activated charcoal (50 g twice daily for 11 days) may be
substituted for cholestyramine.1
Accelerated elimination regimens for AUBAGIO
Agent
Dosage
Duration of treatment
Cholestyramine
8 g tid
11 days
Cholestyramine
4 g tid
11 days
50 g bid
11 days
Activated charcoal
AUBAGIO is available in 14 mg and 7 mg tablets.
3
After 11 days of cholestyramine or activated charcoal
administration, plasma concentrations of teriflunomide are
reduced by >98%.1,2 Accelerated elimination using cholestyramine
appears to be more efficient than charcoal.2 In patients who are
pregnant or wish to become pregnant, or in males who wish to
father a child, a blood sample should be taken to confirm that
blood levels are <0.02 mcg/mL, a level expected to have minimal
risk to the fetus.1
Teriflunomide plasma concentration (mcg/mL)
Plasma concentrations of teriflunomide
after accelerated elimination2
40
Activated charcoal 50 g bid (n≤30)
Cholestyramine 4 g tid (n≤16)
Cholestyramine 8 g tid (n≤14)
30
20
10
0
0 13
14
16
Day
20
24
First administration of accelerated elimination procedure
Teriflunomide was administered from days 1–12.
•A
t the end of 11 days, both regimens successfully accelerated
teriflunomide elimination
4
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING regarding
hepatotoxicity and use in pregnancy.
How does accelerated elimination of
AUBAGIO® (teriflunomide) work?
AUBAGIO normally undergoes enterohepatic recycling,2 a process
in which bile acids and other substances excreted by the liver are
absorbed by the intestinal mucosa and returned to the liver via
the portal vein.
Cholestyramine and activated charcoal bind and sequester
teriflunomide in the small intestine and prevent it from being
reabsorbed, thus accelerating its elimination.2
Liver
Plasma
Reabsorption
Excretion
Teriflunomide
Gut
Bile
Feces
Cholestyramine and activated charcoal sequester
teriflunomide in the small intestine,
preventing reabsorption and enterohepatic recirculation2
AUBAGIO is available in 14 mg and 7 mg tablets.
5
Are there any adverse events associated with
the accelerated elimination procedure?
The accelerated elimination procedure is generally well
tolerated.2 In some cases, patients may experience transient,
mild to moderate gastrointestinal side effects such as upset
stomach or nausea.2 Consult the product information for
cholestyramine or activated charcoal for more information.
Use of the accelerated elimination procedure may potentially
result in return of disease activity if the patient had been
responding to AUBAGIO® (teriflunomide) treatment.1
Do I need to confirm that the drug has been
successfully eliminated?
When the accelerated elimination procedure is used for women
who are or wish to become pregnant, or men who wish to
father a child, a blood test is used to confirm that plasma drug
concentrations are reduced to <0.02 mcg/mL, a level expected
to have minimal risk to the fetus. Eleven days of treatment
with cholestyramine or activated charcoal is usually effective in
accelerating AUBAGIO elimination, leading to a >98% decrease
in teriflunomide plasma concentrations. However, if drug levels
remain above this level, a second course of cholestyramine or
charcoal is recommended.
When the procedure is used in situations unrelated to
current or potential pregnancy, confirmation of plasma
levels is NOT necessary.
6
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING regarding
hepatotoxicity and use in pregnancy.
Is there anything I should know about how to
prescribe cholestyramine?
It is recommended that patients take other medications at least
1 hour before or 4 to 6 hours after taking cholestyramine.
If I do need to confirm my patient’s plasma levels
of teriflunomide, how do I obtain the assay?
Confirmation of elimination via an assay is only recommended
for women who are or wish to become pregnant or men wishing
to father a child.
The assay is available through LabCorp and is paid for by
Genzyme. Forms to set up an account with LabCorp are
available from your Genzyme representative or by contacting
MS One to One™ at 1-855-MSOne2One (1-855-676-6326). Once
your account is set up, you will be provided with assay requisition
forms and can order the assay for your patients as needed.
AUBAGIO is available in 14 mg and 7 mg tablets.
7
INDICATION
AUBAGIO® (teriflunomide) is indicated for the treatment of
patients with relapsing forms of multiple sclerosis.
IMPORTANT SAFETY INFORMATION
Hepatotoxicity—AUBAGIO is contraindicated in patients
with severe hepatic impairment and in patients taking
leflunomide. Severe liver injury, including fatal liver failure,
has been reported in patients treated with leflunomide,
which is indicated for rheumatoid arthritis. Teriflunomide is
the principal active metabolite of leflunomide. A similar risk
would be expected for teriflunomide because recommended
doses of teriflunomide and leflunomide provide similar plasma
concentrations of teriflunomide. Obtain transaminase and
bilirubin levels within 6 months before starting AUBAGIO;
monitor ALT levels at least monthly for 6 months after starting
AUBAGIO. Patients with preexisting liver disease may be at
increased risk of elevated serum transaminases when taking
AUBAGIO. Patients with preexisting acute or chronic liver
disease, or those with serum alanine aminotransferase (ALT)
>2 times the upper limit of normal (ULN) before initiating
treatment, should not normally be treated with AUBAGIO.
In clinical trials, if ALT elevation was >3 times the ULN on 2
consecutive tests, AUBAGIO was discontinued and patients
underwent accelerated elimination.
Consider additional monitoring if coadministering AUBAGIO
with other potentially hepatotoxic drugs because of increased
risk of severe liver injury; monitor patients who develop
symptoms suggestive of hepatic dysfunction (e.g., unexplained
nausea, vomiting, abdominal pain, fatigue, anorexia, or
jaundice and/or dark urine). If drug-induced liver injury is
suspected, discontinue use of AUBAGIO, start accelerated
elimination, and monitor liver tests weekly until normalized.
8
Please see accompanying Full Prescribing Information, including
boxed WARNING regarding hepatotoxicity and use in pregnancy.
Risk of Teratogenicity—AUBAGIO is contraindicated in
pregnant women or women of childbearing potential who
are not using reliable contraception. Based on animal
data, AUBAGIO may cause major birth defects if used
during pregnancy. Before starting therapy, pregnancy must
be excluded, use of reliable contraception confirmed, and
the patient fully counseled. Patients having delayed onset
of menses or other reason to suspect pregnancy should
immediately notify their physician and be apprised of the
potential hazards to the fetus. If the patient is pregnant or
wishes to become pregnant, treatment should be discontinued
immediately, followed by accelerated elimination until plasma
concentrations of <0.02 mcg/mL are verified. It is not known
whether AUBAGIO passes into breast milk; patients should
be counseled on whether they should take AUBAGIO or
breastfeed—they should not do both at the same time.
Women who become pregnant while taking AUBAGIO should
enroll in the AUBAGIO Pregnancy Registry to monitor fetal
outcomes, by calling 1-800-745-4447, option 2.
AUBAGIO is eliminated slowly from the plasma. Without
accelerated elimination, reaching plasma concentrations of
<0.02 mcg/mL takes an average of 8 months or, in some
patients, up to 2 years. Accelerated elimination may cause
disease activity to return in patients who were responding to
AUBAGIO treatment.
AUBAGIO is detected in human semen. Men not wishing to
father a child should use reliable contraception to minimize
possible risk. Men wishing to father a child should discontinue
AUBAGIO and undergo accelerated elimination until plasma
concentrations of <0.02 mcg/mL are verified.
(cont.)
AUBAGIO is available in 14 mg and 7 mg tablets.
9
ADDITIONAL SAFETY INFORMATION
Decreases in white blood cell counts, mainly of neutrophils
and lymphocytes, and platelets have been reported in clinical
studies of AUBAGIO. Obtain a complete blood cell count within
6 months before starting treatment. Further monitoring should
be based on symptoms suggestive of bone marrow suppression.
AUBAGIO is not recommended for patients with severe
immunodeficiency, bone marrow disease, or severe uncontrolled
infections. Treatment in patients with infection(s), acute or
chronic, should not be started until the infection(s) is resolved.
Medications such as teriflunomide have immunosuppressive
potential; patients may therefore be more susceptible to infections.
The risk of malignancy, particularly lymphoproliferative disorders,
is increased with some immunosuppressive medications.
Vaccination with live vaccines is not recommended.
Tuberculosis has been observed in clinical studies of AUBAGIO.
Before starting treatment, screen patients for latent tuberculosis
infection with a tuberculin skin test.
Peripheral neuropathy, including polyneuropathy and
mononeuropathy, has been reported with AUBAGIO. Age >60
years, concomitant neurotoxic medications, and diabetes may
increase the risk. If peripheral neuropathy is suspected, consider
discontinuing treatment and performing accelerated elimination.
Transient acute renal failure and treatment-emergent hyperkalemia,
as well as increased renal uric acid clearance, have been reported
with AUBAGIO. Monitor renal function and potassium if symptoms
of acute renal failure or hyperkalemia appear.
Stevens-Johnson syndrome and toxic epidermal necrolysis have
been reported rarely in rheumatoid arthritis patients receiving
leflunomide, with a similar risk expected for teriflunomide;
therefore, stop treatment and use accelerated elimination if a
severe skin reaction develops.
10
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING regarding
hepatotoxicity and use in pregnancy.
AUBAGIO is available in 14 mg and 7 mg tablets.
A GUIDE TO THE
ACCELERATED ELIMINATION
PROCEDURE FOR
AUBAGIO® (teriflunomide)
WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
Hepatotoxicity
Severe liver injury including fatal liver failure has been reported in patients treated with
leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be
expected for teriflunomide because recommended doses of teriflunomide and
leflunomide result in a similar range of plasma concentrations of teriflunomide.
Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase
the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months
before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six
months after starting AUBAGIO. If drug induced liver injury is suspected, discontinue
AUBAGIO and start an accelerated elimination procedure with cholestyramine or
charcoal. AUBAGIO is contraindicated in patients with severe hepatic impairment.
Patients with pre-existing liver disease may be at increased risk of developing elevated
serum transaminases when taking AUBAGIO.
Risk of Teratogenicity
Based on animal data, AUBAGIO may cause major birth defects if used during
pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is
contraindicated in pregnant women or women of childbearing potential who are not
using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment
or prior to the completion of an accelerated elimination procedure after
AUBAGIO treatment.
References:
1. AUBAGIO (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation;
September 2012.
2. Data on file, Sanofi/Genzyme.
www.genzyme.com
11
© 2013 Genzyme Corporation, a Sanofi company.
All rights reserved. MS.US.PO1245.0113
AUBAGIO is available in 14 mg and 7 mg tablets.
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING.
AUBAGIO is available in 14 mg and 7 mg tablets.
The safety and effectiveness of AUBAGIO have not been
established in pediatric patients and in patients aged >65 years.
The most frequent adverse reactions (≥10% and ≥2% greater
than placebo) with AUBAGIO 7 mg and 14 mg and placebo,
respectively, were ALT increased (12% and 14% vs 7%), alopecia
(10% and 13% vs 3%), diarrhea (15% and 18% vs 9%), influenza
(9% and 12% vs 10%), nausea (9% and 14% vs 7%), and
paresthesia (9% and 10% vs 8%).
The type or dose of oral contraceptives used in combination
with teriflunomide should be considered because of increased
ethinylestradiol and levonorgestrel levels following repeated
doses of teriflunomide.
A 25% decrease in peak international normalized ratio (INR) was
observed when teriflunomide was coadministered with warfarin
vs warfarin alone. Close INR follow-up and monitoring are
recommended.
Teriflunomide is an inhibitor of CYP2C8 and may be a weak
inducer of CYP1A2. Monitor patients when teriflunomide is
coadministered with drugs metabolized by these pathways.
Interstitial lung disease and worsened preexisting interstitial
lung disease have been reported with leflunomide, with a similar
risk expected with teriflunomide.
Increased blood pressure has occurred with AUBAGIO.
Hypertension was reported in 4% of patients taking AUBAGIO
vs 2% on placebo. Measure blood pressure at treatment
initiation and manage appropriately during treatment.
A GUIDE TO THE
ACCELERATED ELIMINATION
PROCEDURE FOR
AUBAGIO® (teriflunomide)
WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
AUBAGIO is available in 14 mg and 7 mg tablets.
Hepatotoxicity
Severe liver injury including fatal liver failure has been reported in patients treated with
leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be
expected for teriflunomide because recommended doses of teriflunomide and
leflunomide result in a similar range of plasma concentrations of teriflunomide.
Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase
the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months
before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six
months after starting AUBAGIO. If drug induced liver injury is suspected, discontinue
AUBAGIO and start an accelerated elimination procedure with cholestyramine or
charcoal. AUBAGIO is contraindicated in patients with severe hepatic impairment.
Patients with pre-existing liver disease may be at increased risk of developing elevated
serum transaminases when taking AUBAGIO.
Risk of Teratogenicity
Based on animal data, AUBAGIO may cause major birth defects if used during
pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is
contraindicated in pregnant women or women of childbearing potential who are not
using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment
or prior to the completion of an accelerated elimination procedure after
AUBAGIO treatment.
References:
1. AUBAGIO (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation;
September 2012.
2. Data on file, Sanofi/Genzyme.
www.genzyme.com
© 2013 Genzyme Corporation, a Sanofi company.
All rights reserved. MS.US.PO1245.0113
AUBAGIO is available in 14 mg and 7 mg tablets.
Please see Important Safety Information on pages 8-11 and accompanying
Full Prescribing Information, including boxed WARNING.
AUBAGIO is available in 14 mg and 7 mg tablets.
The safety and effectiveness of AUBAGIO have not been
established in pediatric patients and in patients aged >65 years.
The most frequent adverse reactions (≥10% and ≥2% greater
than placebo) with AUBAGIO 7 mg and 14 mg and placebo,
respectively, were ALT increased (12% and 14% vs 7%), alopecia
(10% and 13% vs 3%), diarrhea (15% and 18% vs 9%), influenza
(9% and 12% vs 10%), nausea (9% and 14% vs 7%), and
paresthesia (9% and 10% vs 8%).
The type or dose of oral contraceptives used in combination
with teriflunomide should be considered because of increased
ethinylestradiol and levonorgestrel levels following repeated
doses of teriflunomide.
A 25% decrease in peak international normalized ratio (INR) was
observed when teriflunomide was coadministered with warfarin
vs warfarin alone. Close INR follow-up and monitoring are
recommended.
Teriflunomide is an inhibitor of CYP2C8 and may be a weak
inducer of CYP1A2. Monitor patients when teriflunomide is
coadministered with drugs metabolized by these pathways.
Interstitial lung disease and worsened preexisting interstitial
lung disease have been reported with leflunomide, with a similar
risk expected with teriflunomide.
Increased blood pressure has occurred with AUBAGIO.
Hypertension was reported in 4% of patients taking AUBAGIO
vs 2% on placebo. Measure blood pressure at treatment
initiation and manage appropriately during treatment.
11