Zurampic
Generic Name: lesinurad
Dosage Form: tablet, film coated
WARNING: RISK OF ACUTE RENAL FAILURE, MORE COMMON WHEN USED
WITHOUT A XANTHINE OXIDASE INHIBITOR
· Acute
renal failure has occurred with Zurampic and was more common when Zurampic was
given alone.
· Zurampic
should be used in combination with a xanthine oxidase inhibitor [see Limitations of Use
(1.1), Warnings
and Precautions (5.1), Adverse Reactions
(6.1)].
Indications and Usage for Zurampic
Zurampic
is indicated in combination with a xanthine oxidase inhibitor for the treatment
of hyperuricemia associated with gout in patients who have not achieved target
serum uric acid levels with a xanthine oxidase inhibitor alone [see Clinical Studies (14)].
Limitations of Use
Zurampic
is not recommended for the treatment of asymptomatic hyperuricemia.
Zurampic
should not be used as monotherapy [see Warnings and Precautions (5.1)].
Zurampic Dosage and Administration
Recommended Dosing
Zurampic
tablets are for oral use and should be co-administered with a xanthine oxidase
inhibitor, including allopurinol or febuxostat.
Zurampic
is recommended at 200 mg once daily. This is also the maximum daily dose.
Zurampic should be taken by mouth, in the morning with food and water.
Zurampic
may be added when target serum uric acid levels are not achieved on the
medically appropriate dose of the xanthine oxidase inhibitor alone.
Use of
Zurampic is not recommended for patients taking daily doses of allopurinol less
than 300 mg (or less than 200 mg in patients with estimated creatinine
clearance (eCLcr) less than 60 mL/min). Take Zurampic at the same time as the
morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase
inhibitor is interrupted, Zurampic should also be interrupted. Failure to
follow these instructions may increase the risk of renal events [see Warnings and Precautions (5.1)].
Patients
should be instructed to stay well hydrated (eg, 2 liters [68 oz] of liquid per
day).
Patients with Renal Impairment
No dose
adjustment is needed in patients with mild or moderate renal impairment (eCLcr
of 45 mL/min or greater). Zurampic should not be initiated in patients with an
eCLcr less than 45 mL/min. Assessment of renal function is recommended prior to
initiation of Zurampic therapy and periodically thereafter [see Warnings and Precautions (5.1)]. More frequent renal function monitoring is
recommended in patients with an eCLcr below 60 mL/min. Zurampic should be
discontinued when eCLcr is persistently less than 45 mL/min [see Warnings and Precautions (5.1) and Use
in Specific Populations (8.6)].
Gout Flares
Gout
flares may occur after initiation of urate lowering therapy, including
Zurampic, due to changing serum uric acid levels resulting in mobilization of
urate from tissue deposits. Gout flare prophylaxis is recommended when starting
Zurampic, according to practice guidelines.
If a gout
flare occurs during Zurampic treatment, Zurampic need not be discontinued. The
gout flare should be managed concurrently, as appropriate for the individual
patient.
Dosage Forms and Strengths
Zurampic
200 mg tablets are blue, oval shaped, film-coated tablets debossed with
"LES200".
Contraindications
The use
of Zurampic is contraindicated in the following conditions:
· Severe renal impairment (eCLcr less than 30 mL/min),
end stage renal disease, kidney transplant recipients, or patients on dialysis
[see Use
in Specific Populations (8.6)]
· Tumor lysis syndrome or Lesch-Nyhan syndrome [see Use in Specific Populations (8.8)].
Warnings and Precautions
Renal Events
Treatment
with Zurampic 200 mg in combination with a xanthine oxidase inhibitor was
associated with an increased incidence of serum creatinine elevations, most of
which were reversible [see Adverse Reactions (6)]. Adverse reactions related to renal function have occurred
after initiating Zurampic. A higher incidence of serum creatinine elevations
and renal-related adverse reactions, including serious adverse reactions of
acute renal failure, was observed with Zurampic 400 mg, with the highest
incidence as monotherapy. Zurampic should not be used as monotherapy [see Limitation of Use (1.1)].
Zurampic
should not be initiated in patients with an eCLcr less than 45 mL/min. Renal
function should be evaluated prior to initiation of Zurampic and periodically
thereafter, as clinically indicated. More frequent renal function monitoring is
recommended in patients with an eCLcr less than 60 mL/min [see Renal Impairment (8.6)] or with serum creatinine elevations 1.5 to 2 times the
pre-treatment value. Zurampic treatment should be interrupted if serum
creatinine is elevated to greater than 2 times the pre-treatment value. In
patients who report symptoms that may indicate acute uric acid nephropathy
including flank pain, nausea or vomiting, interrupt treatment and measure serum
creatinine promptly. Zurampic should not be restarted without another
explanation for the serum creatinine abnormalities.
Cardiovascular Events
In
clinical trials, major adverse cardiovascular events (defined as cardiovascular
deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed
with Zurampic [see Adverse Reactions (6.1)]. A causal relationship with Zurampic has not been established.
Adverse Reactions
The
following adverse reactions are also discussed in other sections:
· Renal Events [see Warnings and Precautions (5.1)]
· Cardiovascular Events [see Warnings and Precautions (5.2)]
Clinical Trials Experience
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in clinical practice.
Although
other doses have been studied, the recommended dose of Zurampic is 200 mg once
daily in combination with a xanthine oxidase inhibitor.
In 3
randomized, placebo-controlled studies of Zurampic in combination with a
xanthine oxidase inhibitor (Studies 1 and 2 were with allopurinol and Study 3
was with febuxostat) for up to 12 months, a total of 511, 510, and 516 patients
were treated with Zurampic 200 mg, Zurampic 400 mg, and placebo, respectively.
The mean duration of treatment with Zurampic was 11.2 months. The mean age of
the population was 52 years (18-82), and 95% were males. At baseline, 62% of
the patient population showed mild or moderate renal impairment (eCLcr less
than 90 mL/min) and 79% of patients had at least one co-morbid condition including
hypertension (65%), hyperlipidemia (45%), diabetes (17%), and kidney stones
(12%).
Renal Events
Zurampic
causes an increase in renal uric acid excretion, which may lead to renal events
including transient increases in serum creatinine, renal-related adverse
reactions, and kidney stones. These renal events occurred more frequently in
patients receiving Zurampic 400 mg, when used as monotherapy or in combination
with a xanthine oxidase inhibitor [see Warnings and Precautions (5.1)].
The
number of patients with serum creatinine elevations in the 12-month
placebo-controlled trials in combination with a xanthine oxidase inhibitor are
shown in Table 1. Most of these elevations on Zurampic 200 mg and Zurampic 400
mg resolved without treatment interruption (Table 1).
Table 1: Patients with Elevated Serum Creatinine Values in the
Placebo-Controlled Clinical Studies with Zurampic in Combination with a
Xanthine Oxidase Inhibitor (XOI)
|
|
[n (%)]
|
Placebo+XOI
(N=516)
|
Zurampic 200 mg + XOI
(N=511)
|
Zurampic 400 mg + XOI
(N=510)
|
|
Serum creatinine
elevation 1.5 × to < 2.0 × baseline
|
12 (2.3%)
|
20 (3.9%)
|
51 (10.0%)
|
|
Resolution
of serum creatinine elevations by end of study
|
9/12 (75.0%)
|
18/20 (90.0%)
|
42/51 (82.4%)
|
|
Serum creatinine
elevation ≥ 2.0 × baseline
|
0
|
9 (1.8%)
|
34 (6.7%)
|
|
Resolution
of serum creatinine elevations by end of study
|
N/A
|
8/9 (88.9%)
|
26/34 (76.5%)
|
Renal-related
adverse reactions, including blood creatinine increases and renal failure, and
nephrolithiasis reported in patients receiving Zurampic 200 mg, Zurampic 400 mg
and placebo in combination with a xanthine oxidase inhibitor are shown in Table
2 [see Warnings
and Precautions (5.1)].
The incidence of reports of "blood creatinine increased" was higher
with Zurampic and was highest with Zurampic 400 mg. Renal-related adverse
reactions by baseline renal function category are shown in Table 3 [see Warnings and Precautions (5.1)]. Blood creatinine increased occurred more
frequently in patients treated with Zurampic in combination with a xanthine
oxidase inhibitor across baseline renal function categories (Table 3).
Table 2: Incidence of Renal-Related Adverse Reactions and
Nephrolithiasis in Placebo-Controlled Clinical Studies with Zurampic in
Combination with a Xanthine Oxidase Inhibitor (XOI)
|
|
[n (%)]
|
Placebo + XOI
(N=516)
|
Zurampic 200 mg + XOI
(N=511)
|
Zurampic 400 mg + XOI
(N=510)
|
|
*
Renal failure includes the following adverse
reactions: renal failure, renal impairment, renal failure chronic, renal
failure acute, acute prerenal failure.
|
|
Blood creatinine
increased
|
12 (2.3%)
|
22 (4.3%)
|
40 (7.8%)
|
|
Renal failure*
|
11 (2.1%)
|
6 (1.2%)
|
18 (3.5%)
|
|
Nephrolithiasis
|
9 (1.7%)
|
3 (0.6%)
|
13 (2.5%)
|
Table 3: Incidence of Renal-Related Adverse Reactions by Baseline
Renal Function Category in Placebo-Controlled Clinical Studies with Zurampic
in Combination with a Xanthine Oxidase Inhibitor (XOI)
|
|
n (%)
|
Placebo + XOI
|
Zurampic 200 mg + XOI
|
Zurampic 400 mg + XOI
|
|
*
Renal failure includes the following adverse
reactions: renal failure, renal impairment, renal failure chronic, renal
failure acute, acute prerenal failure.
|
|
≥ 90 mL/min
|
n=180
|
n=200
|
n=203
|
|
Blood
creatinine increased
|
1 (0.6%)
|
6 (3.0%)
|
12 (5.9%)
|
|
Renal
failure*
|
0
|
3 (1.5%)
|
7 (3.4%)
|
|
≥ 60 - < 90 mL/min
|
n=229
|
n=208
|
n=213
|
|
Blood
creatinine increased
|
4 (1.7%)
|
8 (3.8%)
|
21 (9.9%)
|
|
Renal
failure*
|
4 (1.7%)
|
1 (0.5%)
|
7 (3.3%)
|
|
≥ 30 - < 60 mL/min
|
n=101
|
n=101
|
n=92
|
|
Blood
creatinine increased
|
6 (5.9%)
|
7 (6.9%)
|
10 (10.9%)
|
|
Renal
failure*
|
5 (5.0%)
|
2 (2.0%)
|
4 (4.3%)
|
Renal-related
adverse reactions resulted in a similar discontinuation rate on Zurampic 200 mg
in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase
inhibitor alone (1%) and a higher rate on Zurampic 400 mg in combination with a
xanthine oxidase inhibitor (3.3%). Serious renal-related adverse reactions were
reported in patients on Zurampic 400 mg in combination with a xanthine oxidase
inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients
on Zurampic 200 mg in combination with a xanthine oxidase inhibitor during the
12-month controlled period of the studies. Serious renal-related adverse
reactions were reported with Zurampic 200 mg and Zurampic 400 mg in the
uncontrolled long-term extensions.
Monotherapy:
In a 6-month double-blind, placebo-controlled monotherapy study, renal failure
(9.3%), blood creatinine increased (8.4%), and nephrolithiasis (0.9%) were
reported in patients receiving Zurampic 400 mg alone and in no patients
receiving placebo [see Warnings and Precautions (5.1) and Dosage
and Administration (2.1)]. Serum creatinine elevations 1.5-fold or greater occurred in
24.3 % of patients receiving Zurampic 400 mg and in no patients receiving
placebo.
Cardiovascular Safety
Cardiovascular
events and deaths were adjudicated as Major Adverse Cardiovascular Events
(cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke)
in the Phase 3 randomized controlled studies of Zurampic. In the randomized
controlled studies, the numbers of patients with adjudicated MACE events
(incidences per 100 patient-years of exposure) were: 3 (0.71) for placebo, 4
(0.96) for Zurampic 200 mg, and 8 (1.94) for Zurampic 400 mg when used in
combination with a xanthine oxidase inhibitor. Incidence rate ratios for
Zurampic 200 mg and 400 mg compared with placebo were 1.36 (95% CI: 0.23, 9.25)
and 2.71 (95% CI: 0.66, 16.00), respectively.
Other Adverse Reactions
Adverse
reactions occurring in 2% or more of patients on Zurampic 200 mg in combination
with a xanthine oxidase inhibitor and at least 1% greater than that observed in
patients on placebo with a xanthine oxidase inhibitor are summarized in Table
4.
Table 4: Adverse Reactions Occurring in ≥ 2% of Zurampic 200 mg-Treated
Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in
Controlled Studies with Zurampic in Combination with a Xanthine Oxidase
Inhibitor (XOI)
|
|
Adverse Reaction
|
Placebo + XOI
(N=516)
|
Zurampic 200 mg + XOI
(N=511)
|
|
Headache
|
4.1%
|
5.3%
|
|
Influenza
|
2.7%
|
5.1%
|
|
Gastroesophageal
reflux disease
|
0.8%
|
2.7%
|
Drug Interactions
CYP2C9 Inhibitors, CYP2C9 Poor Metabolizers, and
CYP2C9 Inducers
Lesinurad
exposure is increased when Zurampic is co-administered with inhibitors of
CYP2C9, and in CYP2C9 poor metabolizers. Zurampic should be used with caution
in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone),
and in CYP2C9 poor metabolizers [see Clinical Pharmacology (12.3)].
Lesinurad
exposure is decreased when Zurampic is co-administered with moderate inducers
of CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic
effect of Zurampic [see Clinical Pharmacology (12.3)].
CYP3A Substrates
In
interaction studies conducted in healthy subjects with Zurampic and CYP3A
substrates, lesinurad reduced the plasma concentrations of sildenafil and
amlodipine [see Clinical Pharmacology (12.3)]. Although there was not a clinically significant
interaction with atorvastatin, HMG-CoA reductase inhibitors that are sensitive
CYP3A substrates may be affected. The possibility of reduced efficacy of
concomitant drugs that are CYP3A substrates should be considered and their
efficacy (eg, blood pressure and cholesterol levels) should be monitored.
Epoxide Hydrolase Inhibitors
In vitro studies suggest that lesinurad is not an inhibitor of
epoxide hydrolase; however, inhibitors of epoxide hydrolase (ie, valproic acid)
may interfere with metabolism of lesinurad. Zurampic should not be administered
with inhibitors of epoxide hydrolase.
Hormonal Contraceptives
Hormonal
contraceptives, including oral, injectable, transdermal, and implantable forms,
may not be reliable when Zurampic is co-administered. Females should practice
additional methods of contraception and not rely on hormonal contraception
alone when taking Zurampic.
Aspirin
Aspirin
at doses higher than 325 mg per day may decrease the efficacy of Zurampic in
combination with allopurinol. Aspirin at doses of 325 mg or less per day (ie,
for cardiovascular protection) does not decrease the efficacy of Zurampic and
can be coadministered with Zurampic.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
There are
no available human data on use of Zurampic in pregnant women to inform a
drug-associated risk. No teratogenicity or effects on fetal development were
observed in embryo-fetal development studies with oral administration of
lesinurad to pregnant rats and rabbits during organogenesis at doses that
produced maternal exposures up to approximately 45 and 10 times, respectively,
the exposure at the maximum recommended human dose (MRHD). No adverse
developmental effects were observed in a pre- and postnatal development study
with administration of lesinurad to pregnant rats from organogenesis through
lactation at a dose approximately 5 times the MRHD. [see Data]
In theU.S.general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In an
embryo-fetal development study in pregnant rats dosed during the period of
organogenesis from gestation days 6-17, lesinurad was not teratogenic and did
not affect fetal development or survival at exposures up to approximately 45
times the MRHD (on an AUC basis at maternal oral doses up to 300 mg/kg/day). In
an embryo-fetal development study in pregnant rabbits dosed during the period
of organogenesis from gestation days 7-20, lesinurad was not teratogenic and
did not affect fetal development at exposures up to approximately 10 times the
MRHD (on an AUC basis at maternal oral doses up to 75 mg/kg/day). Severe
maternal toxicity, including mortality, was observed in rats and rabbits at
exposures equal to or greater than approximately 45 and 4 times the MRHD (on an
AUC basis at maternal oral doses of 300 mg/kg/day in rats and 25 mg/kg/day and
higher in rabbits), respectively.
In a pre-
and postnatal development study in pregnant female rats dosed from gestation
day 7 through lactation day 20, lesinurad had no effects on delivery or growth
and development of offspring at a dose approximately 5 times the MRHD (on a
mg/m2 basis at a maternal oral dose of 100
mg/kg/day). In rats, plasma and milk concentrations of lesinurad were
approximately equal.
Lactation
Risk Summary
There is
no information regarding the presence of Zurampic in human milk, the effects on
the breastfed infant, or the effects on milk production. Lesinurad is present
in the milk of rats [see Use in Specific Populations (8.1)]. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for
Zurampic and any potential adverse effects on the breastfed infant from
Zurampic or from the underlying maternal condition.
Pediatric Use
Safety
and effectiveness in pediatric patients under 18 years of age have not been
established.
Geriatric Use
No dose
adjustment is necessary in elderly patients. In a pool of clinical safety and
efficacy studies of Zurampic in gout patients, 13% were 65 years and older and
2% were 75 years and older. No overall differences between lesinurad and
placebo in safety and effectiveness were observed between these subjects and
younger subjects but greater sensitivity of some older individuals cannot be
ruled out.
Renal Impairment
The
pharmacokinetics (PK) of Zurampic was evaluated in studies that included
patients with mild (eCLcr 60 to less than 90 mL/min), moderate (eCLcr 30 to
less than 60 mL/min), and severe renal impairment (eCLcr less than 30 mL/min).
Lesinurad exposure (AUC) increased by 30%, 50-73%, and 113%, respectively, in
subjects with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)].
The
efficacy and safety of Zurampic were evaluated in studies that included gout
patients with mild and moderate renal impairment [see Adverse Reactions (6) and Clinical
Studies (14)]. There
were no clear differences in safety and effectiveness of Zurampic in patients
with mild renal impairment compared to patients with normal renal function and
no dose adjustment is recommended [see Dosage and Administration (2.2) and Clinical
Studies (14)].
Across
all Zurampic and placebo treatment groups, patients with moderate renal
impairment had a higher occurrence of renal related adverse reactions compared
to patients with mild renal impairment or normal renal function [see Adverse Reactions (6.1)]. The experience with Zurampic in patients with an eCLcr less
than 45 mL/min is limited and there was a trend toward lesser efficacy [see Clinical Studies (14.5)]. Zurampic should not be initiated in patients with an eCLcr
less than 45 mL/min. No dose adjustment is recommended in patients with an
eCLcr 45 to less than 60 mL/min, however, more frequent renal function
monitoring is recommended. Zurampic should be discontinued when eCLcr is
persistently less than 45 mL/min [see Dosage
and Administration (2.2) and Warnings
and Precautions (5.1)].
The
efficacy and safety of Zurampic have not been evaluated in gout patients with
severe renal impairment (eCLcr less than 30 mL/min), with end-stage renal disease,
or receiving dialysis. Zurampic is not expected to be effective in these
patient populations [see Contraindications
(4)].
Hepatic Impairment
No dose
adjustment is necessary in patients with mild or moderate hepatic impairment
(Child-Pugh classes A and B) [see Clinical Pharmacology (12.3)]. Lesinurad has not been studied in patients with
severe hepatic impairment and is therefore not recommended.
Secondary Hyperuricemia
No
studies have been conducted in patients with secondary hyperuricemia (including
organ transplant recipients); Zurampic is contraindicated for use in tumor
lysis syndrome or Lesch-Nyhan syndrome, where the rate of uric acid formation
is greatly increased [see Contraindications (4)].
Overdosage
Zurampic
was studied in healthy subjects given single doses up to 1600 mg without
evidence of dose-limiting toxicities. In case of overdose patients should be
managed by symptomatic and supportive care including adequate hydration.
Zurampic Description
Zurampic
(lesinurad) is a URAT1 inhibitor. Lesinurad has the following chemical name:
2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic
acid. The molecular formula is C17H14BrN3O2S and the molecular weight is 404.28. The structural formula is:
Zurampic
is available as blue film-coated tablets for oral administration containing 200
mg lesinurad and the following inactive ingredients: lactose monohydrate,
microcrystalline cellulose, hypromellose 2910, crospovidone, and magnesium
stearate. Zurampic tablets are coated with Opadry blue.
Zurampic - Clinical Pharmacology
Mechanism of Action
Lesinurad
reduces serum uric acid levels by inhibiting the function of transporter
proteins involved in uric acid reabsorption in the kidney. Lesinurad inhibited
the function of two apical transporters responsible for uric acid reabsorption,
uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with
IC50 values of 7.3 and 3.7 µM, respectively. URAT1 is responsible for the
majority of the reabsorption of filtered uric acid from the renal tubular
lumen. OAT4 is a uric acid transporter associated with diuretic-induced
hyperuricemia. Lesinurad does not interact with the uric acid reabsorption
transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal
tubule cell.
Pharmacodynamics
Effects on Serum Uric Acid and Urinary Excretion of
Uric Acid
In gout
patients, Zurampic lowered serum uric acid levels and increased renal clearance
and fractional excretion of uric acid. Following single and multiple oral doses
of Zurampic to gout patients, dose-dependent decreases in serum uric acid
levels and increases in urinary uric acid excretion were observed.
Effect on Cardiac Repolarization
The
effect of Zurampic on cardiac repolarization as assessed by the QTc interval
was evaluated in normal healthy subjects and gout patients. Zurampic at doses
up to 1600 mg did not demonstrate an effect on the QTc interval.
Pharmacokinetics
Following
oral administration of Zurampic 200 mg in healthy subjects, the mean (% CV) Cmax and AUC for lesinurad were 6 µg/mL (31%) and 30
µg∙hr/mL (44%), respectively. Cmax and
AUC exposures of lesinurad increased proportionally with single doses of
Zurampic from 5 to 1200 mg. Following multiple once daily dosing of Zurampic,
there was no evidence of time dependent changes in pharmacokinetics and dose
proportionality was preserved.
Absorption
The
absolute bioavailability of lesinurad is approximately 100%. Lesinurad is
rapidly absorbed after oral administration. Following administration of a
single dose of a Zurampic tablet in either fed or fasted state, maximum plasma
concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of lesinurad increased
proportionally with single doses of Zurampic from 5 to 1200 mg.
Administration
with a high-fat meal (800 to 1000 calories with 50% of calories being derived
from fat content) decreases lesinurad Cmax by
up to 18% but does not alter AUC as compared with fasted state. In clinical
trials, Zurampic was administered with food.
Distribution
Lesinurad
is extensively bound to proteins in plasma (greater than 98%), mainly to
albumin. Plasma protein binding of lesinurad is not meaningfully altered in
patients with renal or hepatic impairment. The mean steady state volume of
distribution of lesinurad was approximately 20 L following intravenous dosing
of Zurampic.
Elimination
The elimination
half-life (t½) of lesinurad was approximately 5 hours. Zurampic does not
accumulate following multiple doses. The total body clearance is approximately
6 L/hr.
Metabolism
Lesinurad
undergoes oxidative metabolism mainly via the polymorphic cytochrome P450
CYP2C9 enzyme. Plasma exposure of metabolites is minimal (< 10% of unchanged
lesinurad). Metabolites are not known to contribute to the uric acid lowering
effects of Zurampic. A transient oxide metabolite is rapidly eliminated by
microsomal epoxide hydrolase in the liver and not detected in plasma.
Patients
who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A
cross-study pharmacogenomic analysis assessed the association between CYP2C9
polymorphism and lesinurad exposure in patients receiving single or multiple
doses of lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, Zurampic
exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e.,
subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared to CYP2C9
extensive metabolizers (i.e., CYP2C9 *1/*1 [N=41] genotype). Use with caution
in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of
CYP2C9 [see Drug
Interactions (7.1)].
Excretion
Within 7
days following single dosing of radiolabeled lesinurad, 63% of administered
radioactive dose was recovered in urine and 32% of administered radioactive
dose was recovered in feces. Most of the radioactivity recovered in urine (>
60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine
accounted for approximately 30% of the dose.
Special Populations
Renal Impairment
Two
dedicated studies were performed to assess PK in renal impairment (classified
using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects
compared to healthy subjects.
Study 1
was a single-dose, open-label study evaluating the pharmacokinetics of Zurampic
200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min) and moderate
renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy
subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90
mL/min), plasma AUC of lesinurad was increased by approximately 30% and 73% in
subjects with mild (N=8) and moderate (N=10) renal impairment, respectively.
Study 2
was a single-dose, open-label study evaluating the pharmacokinetics of Zurampic
400 mg in subjects with moderate and severe renal impairment (eCLcr less than
30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6),
plasma AUC of lesinurad was increased by approximately 50% and 113% in subjects
with moderate (N=6) and severe (N=6) renal impairment, respectively.
Hepatic Impairment
Following
administration of a single dose of Zurampic at 400 mg in patients with mild
(Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment,
lesinurad Cmax was comparable and lesinurad AUC was 7% and 33%
higher, respectively, compared to individuals with normal hepatic function.
There is no clinical experience in patients with severe (Child-Pugh class C)
hepatic impairment.
Effect of Age, Gender, Race and Ethnicity on
Pharmacokinetics
Based on
the population pharmacokinetic analysis, age, gender, race and ethnicity do not
have a clinically meaningful effect on the pharmacokinetics of lesinurad [see Use in Specific Populations (8.5)].
Pediatric Use
Studies
characterizing the pharmacokinetics of lesinurad in pediatric patients have not
been conducted.
Drug-Drug Interactions
Effects of Other Drugs on Lesinurad
Based on
in vitro data, lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no
clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg,
probenecid).
Figure 1
shows the effect of co-administered drugs on the pharmacokinetics of lesinurad.
Figure 1: Effect of Co-administered Drugs on the
Pharmacokinetics of Lesinurad
Effects of Lesinurad on Other Drugs
Lesinurad
is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme
for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition
(CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4).
Based on
in vitro studies, lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3;
however, lesinurad is not an in vivo inhibitor of these transporters. In vivo
drug interaction studies indicate that lesinurad does not decrease the renal
clearance of furosemide (substrate of OAT1/3), or affect the exposure of
atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on
in vitro studies, lesinurad has no relevant effect on P-glycoprotein.
Figure 2
shows the effect of lesinurad on co-administered drugs.
Figure 2: Effect of Lesinurad on the Pharmacokinetics of
Co-administered Drugs
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
The
carcinogenic potential of lesinurad was evaluated in Sprague-Dawley rats and
TgRasH2 mice. No evidence of tumorigenicity was observed in male or female rats
that received lesinurad for 91 to 100 weeks at oral doses up to 200 mg/kg/day
(approximately 35 times the MRHD on an AUC basis). No evidence of
tumorigenicity was observed in TgRasH2 mice that received lesinurad for 26
weeks at oral doses up to 125 and 250 mg/kg/day in male and female mice,
respectively.
Lesinurad
tested negative in the following genotoxicity assays: the in vitroAmesassay, in vitro
chromosomal aberration assay in Chinese hamster ovary cells, and in vivo rat
bone marrow micronucleus assay.
Fertility
and reproductive performance were unaffected in male or female rats that received
lesinurad at oral doses up to 300 mg/kg/day (approximately 15 times the MRHD on
a mg/m2 basis).
Clinical Studies
Overview of Clinical Studies of Zurampic
The
efficacy of Zurampic 200 mg and 400 mg once daily was studied in 3 multicenter,
randomized, double-blind, placebo-controlled clinical studies in adult patients
with hyperuricemia and gout in combination with a xanthine oxidase inhibitor,
allopurinol or febuxostat. All studies were of 12 months duration and patients
received prophylaxis for gout flares with colchicine or non-steroidal
anti-inflammatory drugs (NSAIDs) during the first 5 months of Zurampic
treatment.
Although
other doses have been studied, the recommended dose of Zurampic is 200 mg once
daily in combination with a xanthine oxidase inhibitor.
Add-on to Allopurinol in Inadequate Responders
Study 1
and Study 2 enrolled patients with gout who were on a stable dose of
allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that
had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the
prior 12 months. Mean years since gout diagnosis were 12 years. More than half
of the patients (61%) had mild or moderate renal impairment and 19% of the patients
had tophi. Patients continued their allopurinol dose and were randomized 1:1:1
to receive Zurampic 200 mg, Zurampic 400 mg, or placebo once daily. The average
dose of allopurinol in the studies was 310 mg (range: 200-900 mg).
As shown
in Table 5, Zurampic 200 mg in combination with allopurinol was superior to
allopurinol alone in lowering serum uric acid to less than 6 mg/dL at Month 6.
Table 5: Proportion of Patients Achieving Target Serum Uric Acid
Levels (< 6 mg/dL) in Two Studies of Zurampic in Combination with
Allopurinol
|
|
|
Study
|
Timepoint
|
Patients Achieving Serum Uric Acid
Target
|
Difference of Proportion
(95% C.I.)
|
|
|
Placebo + Allopurinol
|
Zurampic 200 mg + Allopurinol
|
Zurampic 200 mg vs Placebo
|
|
|
Study 1 (N=603)
|
Month 6
|
28%
|
54%
|
0.26
( 0.17, 0.36)
|
|
|
Study 2 (N=610)
|
Month 6
|
23%
|
55%
|
0.32
(0.23, 0.41)
|
|
The
estimated effect of Zurampic 200 mg on serum uric acid in the subgroup of
patients taking thiazide diuretics at baseline was similar to the estimated
effect in the overall population. The estimated effect was also similar in the
subgroup of patients taking low dose aspirin at baseline.
As shown
in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was
noted for Zurampic 200 mg in combination with allopurinol at the Month 1 visit
and was maintained throughout the 12-month study.
Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled
Clinical Studies with Zurampic in Combination with Allopurinol (Study 1 and
Study 2)
Combination with Febuxostat in Tophaceous Gout
Study 3
enrolled gout patients with measurable tophi. Patients received febuxostat 80
mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of
Zurampic 200 mg, Zurampic 400 mg, or placebo in combination with febuxostat. A
total of 66% of patients had mild or moderate renal impairment. Fifty percent
of patients did not reach target serum uric acid < 5.0 mg/dL at Baseline
after 3 weeks of febuxostat treatment.
As shown
in Table 6, there was not statistical evidence of a difference in the
proportion of patients treated with Zurampic 200 mg in combination with
febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with
patients receiving febuxostat alone. However, the average decrease in serum
uric acid with Zurampic 200 mg in Study 3 was similar to that seen in Study 1
and Study 2 (see Figure
3 and Figure 4).
Table 6: Proportion of Patients Achieving Target Serum Uric Acid
Levels (< 5 mg/dL) in a Study with Zurampic in Combination with
Febuxostat in Tophaceous Gout
|
|
|
Patients Achieving Serum Uric Acid
Target
|
Difference of Proportion
(95% C.I.)
|
|
Timepoint
|
Placebo + Febuxostat 80 mg
|
Zurampic 200 mg + Febuxostat 80 mg
|
Zurampic 200 mg vs Placebo
|
|
Month 6
|
47%
|
57%
|
0.10
(-0.03, 0.23)
|
As shown
in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was
noted for Zurampic 200 mg in combination with febuxostat at the Month 1 visit
and was maintained throughout the 12-month study.
Figure 4: Mean Serum Uric Acid Levels Over Time in a Study with
Zurampic in Combination with Febuxostat in Tophaceous Gout (Study 3)
Gout Flares and Tophus Outcomes
In each
of the three pivotal studies of Zurampic in combination with a xanthine oxidase
inhibitor, the rates of gout flare requiring treatment from the end of Month 6
to the end of Month 12 were not statistically different between Zurampic 200 mg
in combination with allopurinol or febuxostat compared with allopurinol or
febuxostat alone. In Study 3, the proportion of patients who experienced a
complete resolution of ≥ 1 target tophus was not statistically different
between Zurampic 200 mg in combination with febuxostat compared with febuxostat
alone.
Use in Patients with Renal Impairment
The
estimated differences between Zurampic and placebo in the proportions of
patients achieving target serum uric acid levels in the renal impairment
subgroups were largely consistent with the results in the overall population in
the three studies. However, there were limited data in patients with eCLcr less
than 45 mL/min and there was a trend toward decreasing magnitudes of effect
with decreasing renal function: in patients with eCLcr less than 45 mL/min, the
estimated difference between Zurampic 200 mg and placebo in the proportion
achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37),
as compared with 27% (95% CI: 9, 45) in the 45 to less than 60 mL/min subgroup
and 30% (95% CI: 23, 37) in the 60 mL/min or greater subgroup, based on
integrated data from Study 1 and Study 2.
How Supplied/Storage and Handling
How Supplied
Zurampic
Tablets, 200 mg are blue in color, oval shaped, debossed with
"LES200" and are supplied as follows:
|
NDC Number
|
Size
|
|
70785-011-05
|
Bottle of 5
tablets
|
|
70785-011-30
|
Bottle of 30
tablets
|
Storage and Handling
Protect
from light. Store at 20° to 25°C (68° to 77°F); excursions permitted from 15°
to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Patient Counseling Information
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
Administration
Advise
patients:
· To take Zurampic in the morning with food and water
at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat.
· Not to take Zurampic alone and to discontinue
Zurampic if treatment with the xanthine oxidase inhibitor medication is
discontinued.
· Not to take a missed dose of Zurampic later in the
day, to wait to take Zurampic on the next day, and not to double the dose.
· To stay well hydrated (eg, 2 liters [68 oz] of liquid
per day).
Renal Events
Inform
patients that renal events including transient increases in blood creatinine
level and acute renal failure have occurred in some patients who take Zurampic.
Advise patients that periodic monitoring of blood creatinine levels are
recommended [see Warnings and Precautions (5.1)].
Gout Flares
Inform
patients that gout flares may occur after initiation of Zurampic and of the
importance of taking gout flare prophylaxis medication to help prevent gout
flares. Advise patients not to discontinue Zurampic if a gout flare occurs
during treatment [see Dosage and Administration (2.3)].
Manufactured
for: Ironwood Pharmaceuticals, Inc.,Cambridge,MA02142
By:AstraZenecaAB, SE-151 85Södertälje,Sweden
Zurampic
is a trademark of the AstraZeneca group of companies.
©
AstraZeneca 2017
|
This Medication
Guide has been approved by the U.S. Food and Drug Administration
|
Revised:July 2017
|
|
MEDICATION GUIDE
Zurampic (zer-AM-pik)
(lesinurad)
tablets
|
|
What is the most important information I should
know about Zurampic?
Some patients taking Zurampic may have kidney problems such as a sudden
decrease in kidney function (acute kidney failure). This is more common when
you take Zurampic without a xanthine oxidase inhibitor. You should always
take Zurampic with a xanthine oxidase inhibitor.
|
|
What is Zurampic?
· Zurampic is a prescription medicine used
together with a xanthine oxidase inhibitor to lower uric acid levels in the
blood in adult patients with gout.
· Zurampic should not be taken without a
xanthine oxidase inhibitor such as allopurinol or febuxostat.
· Zurampic helps the kidneys remove uric
acid from the body and is added to a xanthine oxidase inhibitor, which
decreases the amount of uric acid your body makes.
· It is not known if Zurampic is safe and
effective in children under 18 years of age.
|
|
Who should not take Zurampic?
Do not take Zurampic if
you have:
· severe kidney problems, received a kidney
transplant or you are on dialysis
· a fast breakdown of cancer cells that can
lead to high uric acid (Tumor lysis syndrome)
· a rare inherited condition that causes
too much uric acid in the blood (Lesch Nyhan syndrome)
|
|
Before taking Zurampic, tell your healthcare
provider about all of your medical conditions, including if you:
· are pregnant or plan to become pregnant.
It is not known if Zurampic will harm your unborn baby.
· are breastfeeding or plan to breastfeed.
It is not known if Zurampic passes into your breast milk. You and your
healthcare provider should decide if you should take Zurampic while
breastfeeding.
Tell your healthcare provider about all the medicines you take,
including prescription and over-the-counter medicines, vitamins, and herbal
supplements.
Zurampic may affect the way other medicines work, and other medicines may
affect how Zurampic works.
Especially tell your
healthcare provider if you take:
· medicine for heart problems or high blood
pressure
· medicine for high blood cholesterol
· antifungals and antibiotics
· valproic acid
· aspirin
· other medicines for gout
· hormonal contraceptives. Women who use
birth control medicines containing hormones to prevent pregnancy (birth
control pills, skin patches, implants, and certain IUDs) should use a back-up
method of birth control during treatment with Zurampic.
Ask your
healthcare provider or pharmacist if you are not sure if you take any of
these medicines.
Know the medicines you take. Keep a list of them to show your healthcare
provider and pharmacist when you get a new medicine.
|
|
How should I take Zurampic?
· Take Zurampic exactly as your healthcare
provider tells you to take it.
· Take 1 Zurampic tablet in the morning
with your dose of xanthine oxidase inhibitor such as allopurinol or
febuxostat. Do not take more than 1 Zurampic tablet each day.
· Take Zurampic with food and water.
· Drink 2 liters (68 ounces) of fluid each
day to stay hydrated.
· If you miss taking the dose of Zurampic
in the morning, do not take Zurampic later in the day. Wait and take your
next dose of Zurampic in the morning with your dose of xanthine oxidase
inhibitor such as allopurinol or febuxostat. Do not double your dose of
Zurampic.
· Your gout may get worse (flare up) when
you first start taking Zurampic. Do not stop taking Zurampic even if you have
a flare. Your healthcare provider may give you other medicines to help
prevent your gout flares.
· Your healthcare provider may do blood
tests to check how well your kidneys are working before and during your
treatment with Zurampic.
|
|
What should I avoid while taking Zurampic?
· Avoid taking Zurampic alone. This could
increase your risk of kidney problems. Zurampic should always be taken
together with a xanthine oxidase inhibitor such as allopurinol or febuxostat.
· Avoid becoming dehydrated while taking
Zurampic.
|
|
What are the possible side effects of Zurampic?
Zurampic may cause serious
side effects, including:
· See "What is the most important information
I should know about Zurampic?"
· Heart
problems. People who
take Zurampic can have serious heart problems including heart attack and
stroke. It is not known that Zurampic causes these problems.
The most common side effects of Zurampic include:
· headache
· flu
· higher levels of blood creatinine (a
measure of kidney function)
· heart burn (acid reflux)
Tell your
healthcare provider if you have any side effect that bothers you or that does
not go away. These are not all of the possible side effects of Zurampic. For
more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
|
|
How should I store Zurampic?
· Store Zurampic at room temperature
between 68°F to 77°F (20°C to 25°C).
· Keep Zurampic away from light.
Keep Zurampic and all medicines out of the reach
of children.
|
|
General Information about the safe and effective
use of Zurampic.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use Zurampic for a condition for which it was not
prescribed. Do not give Zurampic to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about
Zurampic. If you would like more information about Zurampic, talk with your
healthcare provider. You can ask your pharmacist or healthcare provider for
information about Zurampic that is written for healthcare professionals.
|
|
What are the ingredients in Zurampic?
Active ingredient: lesinurad
Inactive ingredients: lactose
monohydrate, microcrystalline cellulose, hypromellose, crospovidone, and
magnesium stearate.
Manufactured for: Ironwood Pharmaceuticals, Inc.,Cambridge,MA02142;
Manufactured by:AstraZenecaAB,
SE-151 85 Södertälje,Sweden
Zurampic is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2017
For more information, go to www. Zurampic.com or call 1-844-374-4793.
|
PRINCIPAL DISPLAY PANEL - 200 mg Tablet Bottle Label
NDC 70785-011-30
30 Tablets
Zurampic®
lesinurad tablets
200 mg
Dispense the accompanying
Medication
Guide to each patient.
Rx only
Ironwood®
|
Zurampic lesinurad tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:70785-011
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
lesinurad (lesinurad)
|
lesinurad
|
200 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
HYPROMELLOSE 2910 (5 MPA.S)
|
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSPOVIDONE, UNSPECIFIED
|
|
|
MAGNESIUM STEARATE
|
|
|
TITANIUM DIOXIDE
|
|
|
TRIACETIN
|
|
|
FD&C BLUE NO. 2
|
|
|
FD&C BLUE NO. 1
|
|
|
|
Product
Characteristics
|
|
Color
|
BLUE
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
13mm
|
|
Flavor
|
|
Imprint Code
|
LES200
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:70785-011-05
|
5 TABLET, FILM
COATED in 1 BOTTLE
|
|
|
2
|
NDC:70785-011-30
|
30 TABLET, FILM
COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207988
|
09/18/2017
|
|
|
|
Labeler - Ironwood Pharmaceuticals, Inc.
(054451401)
|
Revised: 07/2017
Ironwood
Pharmaceuticals, Inc.
