Otezla
Generic Name: apremilast
Dosage Form: tablet, film coated
Indications and Usage for Otezla
Psoriatic Arthritis
Otezla is
indicated for the treatment of adult patients with active psoriatic arthritis.
Psoriasis
Otezla is
indicated for the treatment of patients with moderate to severe plaque
psoriasis who are candidates for phototherapy or systemic therapy.
Otezla Dosage and Administration
Dosage in Psoriatic Arthritis and Psoriasis
The
recommended initial dosage titration of Otezla from Day 1 to Day 5 is shown
in Table
1. Following the 5-day
titration, the recommended maintenance dosage is 30 mg twice daily taken orally
starting on Day 6. This titration is intended to reduce the gastrointestinal
symptoms associated with initial therapy.
Otezla
can be administered without regard to meals. Do not crush, split, or chew the
tablets.
Table 1: Dosage Titration Schedule
|
|
Day 1
|
Day 2
|
Day 3
|
Day 4
|
Day 5
|
Day 6
&
thereafter
|
|
AM
|
AM
|
PM
|
AM
|
PM
|
AM
|
PM
|
AM
|
PM
|
AM
|
PM
|
|
10 mg
|
10 mg
|
10 mg
|
10 mg
|
20 mg
|
20 mg
|
20 mg
|
20 mg
|
30 mg
|
30 mg
|
30 mg
|
Dosage Adjustment in Patients with Severe Renal
Impairment
Otezla
dosage should be reduced to 30 mg once daily in patients with severe renal
impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated
by the Cockcroft–Gault equation) [see Use in
Specific Populations (8.6) and Clinical Pharmacology (12.3)].
For initial dosage titration in this group, it is recommended that Otezla be
titrated using only the AM schedule listed in Table
1 and the PM
doses be skipped.
Dosage Forms and Strengths
Otezla is
available as diamond shaped, film coated tablets in the following dosage
strengths:
10-mg pink tablet engraved with “APR” on one side and “10” on
the other side20-mg brown tablet engraved with “APR” on one side and “20” on
the other side30-mg beige tablet engraved with “APR” on one side and “30” on
the other side.
Contraindications
Otezla is
contraindicated in patients with a known hypersensitivity to apremilast or to
any of the excipients in the formulation [see Adverse
Reactions (6.1)].
Warnings and Precautions
Diarrhea, Nausea, and Vomiting
There
have been postmarketing reports of severe diarrhea, nausea, and vomiting
associated with the use of Otezla. Most events occurred within the first few
weeks of treatment. In some cases patients were hospitalized. Patients 65 years
of age or older and patients taking medications that can lead to volume
depletion or hypotension may be at a higher risk of complications from severe
diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to
complications of diarrhea or vomiting. Patients who reduced dosage or
discontinued Otezla generally improved quickly. Consider Otezla dose reduction
or suspension if patients develop severe diarrhea, nausea, or vomiting.
Depression
Treatment
with Otezla is associated with an increase in adverse reactions of depression.
Before using Otezla in patients with a history of depression and/or suicidal
thoughts or behavior prescribers should carefully weigh the risks and benefits
of treatment with Otezla in such patients. Patients, their caregivers, and
families should be advised of the need to be alert for the emergence or
worsening of depression, suicidal thoughts or other mood changes, and if such
changes occur to contact their healthcare provider. Prescribers should
carefully evaluate the risks and benefits of continuing treatment with Otezla
if such events occur.
Psoriatic arthritis: During the 0 to 16 week placebo-controlled period of the 3
controlled clinical trials, 1.0% (10/998) of subjects treated with Otezla
reported depression or depressed mood compared to 0.8% (4/495) treated with
placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with
Otezla discontinued treatment due to depression or depressed mood compared with
none in placebo treated subjects (0/495). Depression was reported as serious in
0.2% (3/1441) of subjects exposed to Otezla, compared to none in placebo-treated
subjects (0/495). Instances of suicidal ideation and behavior have been
observed in 0.2% (3/1441) of subjects while receiving Otezla, compared to none
in placebo treated subjects (0/495). In the clinical trials, 2 subjects who
received placebo committed suicide compared to none in Otezla-treated subjects.
Psoriasis:
During the 0 to 16 week placebo-controlled period of the 3 controlled clinical
trials, 1.3% (12/920) of subjects treated with Otezla reported depression
compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1%
(1/1308) of subjects treated with Otezla discontinued treatment due to
depression compared with none in placebo-treated subjects (0/506). Depression
was reported as serious in 0.1% (1/1308) of subjects exposed to Otezla,
compared to none in placebo-treated subjects (0/506). Instances of suicidal
behavior have been observed in 0.1% (1/1308) of subjects while receiving
Otezla, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical
trials, one subject treated with Otezla attempted suicide while one who
received placebo committed suicide.
Weight Decrease
During
the controlled period of the studies in psoriatic arthritis (PsA), weight
decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects
treated with Otezla 30 mg twice daily compared to 3.3% (16/495) treated with
placebo [see Adverse Reactions (6.1)].
During
the controlled period of the trials in psoriasis, weight decrease between
5%-10% of body weight occurred in 12% (96/784) of subjects treated with Otezla
compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body
weight occurred in 2% (16/784) of subjects treated with Otezla 30 mg twice daily
compared to 1% (3/382) subjects treated with placebo.
Patients
treated with Otezla should have their weight monitored regularly. If
unexplained or clinically significant weight loss occurs, weight loss should be
evaluated, and discontinuation of Otezla should be considered.
Drug Interactions
Co-administration
of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of
systemic exposure of apremilast, which may result in a loss of efficacy of
Otezla. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin,
phenobarbital, carbamazepine, phenytoin) with Otezla is not recommended [see
Drug Interactions (7.1) and Clinical
Pharmacology (12.3)].
Adverse Reactions
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.
Psoriatic Arthritis Clinical Trials
Otezla was evaluated in 3 multicenter, randomized, double-blind,
placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design
in adult patients with active psoriatic arthritis [see Clinical
Studies (14.1)]. Across the 3 studies, there were 1493 patients
randomized equally to placebo, Otezla 20 mg twice daily or Otezla 30 mg twice
daily. Titration was used over the first 5 days [see Dosage and
Administration (2.1)]. Placebo patients whose tender and swollen joint
counts had not improved by at least 20% were re-randomized 1:1 in a blinded
fashion to either Otezla 20 mg twice daily or 30 mg twice daily at week 16
while Otezla patients remained on their initial treatment. Patients ranged in
age from 18 to 83 years, with an overall median age of 51 years.
The
majority of the most common adverse reactions presented in Table 2 occurred
within the first 2 weeks of treatment and tended to resolve over time with
continued dosing. Diarrhea, headache, and nausea were the most commonly
reported adverse reactions. The most common adverse reactions leading to
discontinuation for patients taking Otezla were nausea (1.8%), diarrhea (1.8%),
and headache (1.2%). The proportion of patients with psoriatic arthritis who
discontinued treatment due to any adverse reaction was 4.6% for patients taking
Otezla 30 mg twice daily and 1.2% for placebo-treated patients.
Table 2: Adverse Reactions Reported in ≥2%
of Patients on Otezla 30 mg Twice Daily and ≥1% Than That Observed in
Patients on Placebo for up to Day 112 (Week 16)
|
|
a Of
the reported gastrointestinal adverse reactions, 1 subject experienced a
serious adverse reaction of nausea and vomiting in Otezla 30 mg twice daily;
1 subject treated with Otezla 20 mg twice daily experienced a serious adverse
reaction of diarrhea; 1 patient treated with Otezla 30 mg twice daily
experienced a serious adverse reaction of headache.
|
|
b Of
the reported adverse drug reactions none were serious.
|
|
|
|
c n
(%) indicates number of patients and percent.
|
|
|
|
|
|
Placebo
|
Otezla 30 mg BID
|
|
Preferred Term
|
Day 1 to 5
(N=495)
n (%)c
|
Day 6 to Day 112
(N=490)
n (%)
|
Day 1 to 5
(N=497)
n (%)
|
Day 6 to Day 112
(N=493)
n (%)
|
|
Diarrheaa
|
6 (1.2)
|
8 (1.6)
|
46 (9.3)
|
38 (7.7)
|
|
Nauseaa
|
7 (1.4)
|
15 (3.1)
|
37 (7.4)
|
44 (8.9)
|
|
Headachea
|
9 (1.8)
|
11 (2.2)
|
24 (4.8)
|
29 (5.9)
|
|
Upper
respiratory tract
infectionb
|
3 (0.6)
|
9 (1.8)
|
3 (0.6)
|
19 (3.9)
|
|
Vomitinga
|
2 (0.4)
|
2 (0.4)
|
4 (0.8)
|
16 (3.2)
|
|
Nasopharyngitisb
|
1 (0.2)
|
8 (1.6)
|
1 (0.2)
|
13 (2.6)
|
|
Abdominal pain
upperb
|
0 (0.0)
|
1 (0.2)
|
3 (0.6)
|
10 (2.0)
|
Other
adverse reactions reported in patients on Otezla in clinical studies including
extension studies:
Immune system disorders: Hypersensitivity
Investigations: Weight decrease
Gastrointestinal Disorders: Frequent bowel
movement, gastroesophageal reflux disease, dyspepsia
Metabolism and Nutrition Disorders: Decreased
appetite*
Nervous System Disorders: Migraine
Respiratory, Thoracic, and Mediastinal Disorders: Cough
Skin and Subcutaneous Tissue Disorders: Rash
*1 patient treated with Otezla 30 mg twice daily experienced a serious adverse
reaction.
Psoriasis Clinical Trials
The safety of Otezla® was assessed in 1426 subjects in 3 randomized,
double-blind, placebo-controlled trials in adult subjects with moderate to
severe plaque psoriasis who were candidates for phototherapy or systemic
therapy. Subjects were randomized to receive Otezla 30 mg twice daily or
placebo twice daily. Titration was used over the first 5 days [see
Dosage and Administration (2.1)]. Subjects ranged in age from 18 to 83 years, with
an overall median age of 46 years.
Diarrhea,
nausea, and upper respiratory tract infection were the most commonly reported
adverse reactions. The most common adverse reactions leading to discontinuation
for subjects taking Otezla were nausea (1.6%), diarrhea (1.0%), and headache
(0.8%). The proportion of subjects with psoriasis who discontinued treatment
due to any adverse reaction was 6.1% for subjects treated with Otezla 30 mg
twice daily and 4.1% for placebo-treated subjects.
Table 3: Adverse Reactions Reported in ≥1%
of Subjects on Otezla and With Greater Frequency Than in Subjects on Placebo;
up to Day 112 (Week 16)
|
|
*Two
subjects treated with Otezla experienced serious adverse reaction of
abdominal pain.
|
|
Preferred
Term
|
Placebo (N=506)
n (%)
|
Otezla 30 mg BID (N=920)
n (%)
|
|
Diarrhea
|
32 (6)
|
160 (17)
|
|
Nausea
|
35 (7)
|
155 (17)
|
|
Upper
respiratory tract infection
|
31 (6)
|
84 (9)
|
|
Tension headache
|
21 (4)
|
75 (8)
|
|
Headache
|
19 (4)
|
55 (6)
|
|
Abdominal pain*
|
11 (2)
|
39 (4)
|
|
Vomiting
|
8 (2)
|
35 (4)
|
|
Fatigue
|
9 (2)
|
29 (3)
|
|
Dyspepsia
|
6 (1)
|
29 (3)
|
|
Decreased
appetite
|
5 (1)
|
26 (3)
|
|
Insomnia
|
4 (1)
|
21 (2)
|
|
Back pain
|
4 (1)
|
20 (2)
|
|
Migraine
|
5 (1)
|
19 (2)
|
|
Frequent bowel
movements
|
1 (0)
|
17 (2)
|
|
Depression
|
2 (0)
|
12 (1)
|
|
Bronchitis
|
2 (0)
|
12 (1)
|
|
Tooth abscess
|
0 (0)
|
10 (1)
|
|
Folliculitis
|
0 (0)
|
9 (1)
|
|
Sinus headache
|
0 (0)
|
9 (1)
|
Severe
worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following
discontinuation of treatment with Otezla.
Drug Interactions
Strong CYP450 Inducers
Apremilast
exposure is decreased when Otezla is co-administered with strong CYP450
inducers (such as rifampin) and may result in loss of efficacy [see
Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy
Category C:
Pregnancy
Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in
women exposed to Otezla during pregnancy. Information about the registry can be
obtained by calling 1-877-311-8972.
Risk Summary
Adequate
and well-controlled studies with Otezla have not been conducted in pregnant
women. In animal embryo-fetal development studies, the administration of
apremilast to cynomolgus monkeys during organogenesis resulted in dose-related
increases in abortion/embryo-fetal death at dose exposures 2.1-times the
maximum recommended human therapeutic dose (MRHD) and no adverse effect at an
exposure of 1.4-times the MRHD. In mice, there were no apremilast induced
malformations up to exposures 4.0-times the MRHD. The incidences of
malformations and pregnancy loss in human pregnancies have not been established
for Otezla. However, all pregnancies, regardless of drug exposure, have a
background rate of 2% to 4% for major malformations, and 15% to 20% for
pregnancy loss. Otezla should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Clinical Considerations
Labor or
delivery
The effects of Otezla on labor and delivery in pregnant women are unknown. In
mice, dystocia was noted at doses corresponding to ≥4.0-times the MRHD (on an
AUC basis at doses ≥80 mg/kg/day) of apremilast.
Animal
Data
Monkey embryo-fetal development: In an
embryo-fetal developmental study, cynomolgus monkeys were administered
apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of
organogenesis (gestation Days 20 through 50). There was a dose-related increase
in spontaneous abortions, with most abortions occurring during weeks 3 to 4 of
dosing in the first trimester, at doses approximately 2.1-times the MRHD and
greater (on an AUC basis at doses ≥50 mg/kg/day). No abortifacient effects were
observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose
of 20 mg/kg/day). Although, there was no evidence for a teratogenic effect at
doses of 20 mg/kg/day and greater when examined at day 100, aborted fetuses
were not examined.
Mouse embryo-fetal development: In an embryo-fetal development study,
apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams
during organogenesis (gestation Day 6 through 15). In a combined fertility and
embryo-fetal development study, apremilast was administered at doses of 10, 20,
40 or 80 mg/kg/day starting 15 days before cohabitation and continuing through
gestation Day 15. No teratogenic findings attributed to apremilast were
observed in either study; however, there was an increase in postimplantation
loss at doses corresponding to a systemic exposure of 2.3-times the MRHD and
greater (≥20 mg/kg/day). At doses of ≥20 mg/kg/day skeletal variations included
incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No
effects were observed at a dose approximately 1.3-times the MRHD (10
mg/kg/day).
Mouse pre- and postnatal development: In a pre- and postnatal study in mice,
apremilast was administered to pregnant female mice at doses of 10, 80, or 300
mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on
day 21. Dystocia, reduced viability, and reduced birth weights occurred at
doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80
mg/kg/day). No adverse effects occurred at a dose 1.3-times the MRHD (10
mg/kg/day). There was no evidence for functional impairment of physical
development, behavior, learning ability, immune competence, or fertility in the
offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300
mg/kg/day).
Nursing Mothers
It is not
known whether Otezla or its metabolites are present in human milk; however
apremilast was detected in milk of lactating mice. Because many drugs are
present in human milk, caution should be exercised when Otezla is administered
to a nursing woman.
Pediatric Use
The safety
and effectiveness of Otezla in pediatric patients less than 18 years of age
have not been established.
Geriatric Use
Of the
1493 subjects who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146
psoriatic arthritis subjects were 65 years of age and older, including 19
subjects 75 years and older. No overall differences were observed in the safety
profile of elderly subjects ≥65 years of age and younger adult subjects <65
years of age in the clinical studies.
Of the
1257 subjects who enrolled in two placebo-controlled psoriasis trials (PSOR 1
and PSOR 2), a total of 108 psoriasis subjects were 65 years of age and older,
including 9 subjects who were 75 years of age and older. No overall differences
were observed in the efficacy and safety in elderly subjects ≥65 years of age
and younger adult subjects <65 years of age in the clinical trials.
Renal Impairment
Apremilast
pharmacokinetics were characterized in subjects with mild, moderate, and severe
renal impairment as defined by a creatinine clearance of 60-89, 30-59, and less
than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no
dose adjustment is needed in patients with mild or moderate renal impairment,
the dose of Otezla should be reduced to 30 mg once daily in patients with
severe renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Hepatic Impairment
Apremilast
pharmacokinetics were characterized in subjects with moderate (Child Pugh B)
and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary
in these patients.
Overdosage
In case
of overdose, patients should seek immediate medical help. Patients should be
managed by symptomatic and supportive care should there be an overdose.
Otezla Description
The
active ingredient in Otezla tablets is apremilast. Apremilast is a
phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide.
Its empirical formula is C22H24N2O7S and the molecular weight is 460.5.
The
chemical structure is:
Otezla
tablets are supplied in 10-, 20-, and 30-mg strengths for oral administration.
Each tablet contains apremilast as the active ingredient and the following
inactive ingredients: lactose monohydrate, microcrystalline cellulose,
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide,
polyethylene glycol, talc, iron oxide red, iron oxide yellow (20 and 30 mg
only) and iron oxide black (30 mg only).
Otezla - Clinical Pharmacology
Mechanism of Action
Apremilast
is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for
cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased
intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts
its therapeutic action in psoriatic arthritis patients and psoriasis patients
is not well defined.
Pharmacokinetics
Absorption
Apremilast when taken orally is absorbed with an absolute bioavailability of
~73%, with peak plasma concentrations (Cmax)
occurring at a median time (tmax) of ~2.5
hours. Co-administration with food does not alter the extent of absorption of
apremilast.
Distribution
Human plasma protein binding of apremilast is approximately 68%. Mean apparent
volume of distribution (Vd) is 87 L.
Metabolism
Following oral administration in humans, apremilast is a major circulating
component (45%) followed by inactive metabolite M12 (39%), a glucuronide
conjugate of O-demethylated apremilast. It is extensively metabolized in
humans with up to 23 metabolites identified in plasma, urine and feces.
Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism
with subsequent glucuronidation and non-CYP mediated hydrolysis. In
vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor
contributions from CYP1A2 and CYP2A6.
Elimination
The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a
terminal elimination half-life of approximately 6-9 hours. Following oral
administration of radio-labeled apremilast, about 58% and 39% of the
radioactivity is recovered in urine and feces, respectively, with about 3% and
7% of the radioactive dose recovered as apremilast in urine and feces, respectively.
Specific Populations
Hepatic Impairment: The pharmacokinetics of apremilast is not affected by
moderate or severe hepatic impairment.
Renal Impairment: The pharmacokinetics of apremilast is not affected by mild
or moderate renal impairment. In 8 subjects with severe renal impairment
administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88%
and 42%, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Age: A
single oral dose of 30-mg apremilast was studied in young adults and elderly
healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years
of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age).
[see Use in Specific Populations (8.5)].
Gender: In
pharmacokinetic studies in healthy volunteers, the extent of exposure in
females was about 31% higher and Cmax was
about 8% higher than that in male subjects.
Race and Ethnicity: The pharmacokinetics of apremilast in Chinese and Japanese
healthy male subjects is comparable to that in Caucasian healthy male subjects.
In addition, apremilast exposure is similar among Hispanic Caucasians,
non-Hispanic Caucasians, and African Americans.
Drug Interactions
In vitro data: Apremilast is not an
inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,
or CYP3A4 and not an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.
Apremilast is a substrate, but not an inhibitor of P-glycoprotein (P-gp)
and is not a substrate or an inhibitor of organic anion transporter (OAT)1 and
OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide
(OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP).
Drug
interaction studies were performed with apremilast and CYP3A4 substrates (oral
contraceptive containing ethinyl estradiol and norgestimate), CYP3A and P-gp
inhibitor (ketoconazole), CYP450 inducer (rifampin) and frequently
co-administered drug in this patient population (methotrexate).
No
significant pharmacokinetic interactions were observed when 30-mg oral
apremilast was administered with either oral contraceptive, ketoconazole, or
methotrexate. Co-administration of the CYP450 inducer rifampin (600 mg
once daily for 15 days) with a single oral dose of 30-mg apremilast resulted in
reduction of apremilast AUC and Cmax by
72% and 43%, respectively [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term
studies were conducted in mice and rats with apremilast to evaluate its carcinogenic
potential. No evidence of apremilast-induced tumors was observed in mice
at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an
AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08-
and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females,
respectively).
Apremilast
tested negative in theAmesassay, in vitro chromosome aberration assay of human peripheral blood
lymphocytes, and the in vivo mouse micronucleus assay.
In a
fertility study of male mice, apremilast at oral doses up to approximately
3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male
fertility. In a fertility study of female mice, apremilast was administered at
oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD (≥20
mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which
resulted in a longer interval until mating. Mice that became pregnant at doses
of 20 mg/kg/day and greater also had increased incidences of early
postimplantation losses. There was no effect of apremilast approximately
1.0-times the MRHD (10 mg/kg/day).
Clinical Studies
Psoriatic Arthritis
The
safety and efficacy of Otezla was evaluated in 3 multi-center, randomized,
double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of
similar design. A total of 1493 adult patients with active PsA (≥3 swollen
joints and ≥3 tender joints) despite prior or current treatment with
disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients
enrolled in these studies had a diagnosis of PsA for at least 6 months. One
qualifying psoriatic skin lesion of at least 2 cm in diameter was required in
Study PsA- 3. Previous treatment with a biologic, including TNF-blockers was allowed
(up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies,
patients were randomly assigned to placebo (n=496), Otezla 20 mg (n=500), or
Otezla 30 mg (n=497) given orally twice daily. Titration was used over the
first 5 days [see Dosage and Administration (2.1)]. Patients were allowed to receive stable doses of
concomitant methotrexate [MTX (≤25 mg/week)], sulfasalazine [SSZ (≤2 g/day)],
leflunomide [LEF (≤20 mg/day)], low dose oral corticosteroids (equivalent to ≤10
mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs)
during the trial. Treatment assignments were stratified based on small-molecule
DMARD use at baseline in Studies PsA-1, PsA-2 and PsA-3. There was an
additional stratification of BSA >3% with psoriasis in study PsA-3. The
patients who were therapeutic failures of >3 agents for PsA (small molecules
or biologics), or >1 biologic TNF blocker were excluded.
The
primary endpoint was the percentage of patients achievingAmericanCollegeof Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data
were collected and analyzed through Week 24. Patients whose tender and swollen
joint counts had not improved by at least 20% were considered non-responders at
Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to
either Otezla 20 mg twice daily or 30 mg twice daily following the titration
schema [see Dosage and Administration (2.1)].
Otezla patients remained on their initial treatment. At Week 24, all remaining
placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice
daily.
Patients
with subtypes of PsA were enrolled across the 3 studies, including symmetric
polyarthritis (62.0%), asymmetric oligoarthritis (27.0%), distal
interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and
predominant spondylitis (2.1%). The median duration of PsA disease was 5 years.
Patients received concomitant therapy with at least one DMARD (65.0%), MTX
(55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and
NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in
76.0% of patients and prior treatment with biologic DMARDs was reported in
22.0% of patients, which includes 9.0% who had failed prior biologic DMARD
treatment.
Clinical Response in Patients with Psoriatic Arthritis
The
percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1,
PsA-2, and PsA-3 are presented in Table
4 below. Otezla ±
DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in
signs and symptoms of psoriatic arthritis as demonstrated by the proportion of
patients with an ACR 20 response at Week 16.
Table 4: Proportion of Patients With ACR
Responses in Studies PsA-1, PsA-2 and PsA-3
|
|
a N
is number of randomized and treated patients.
b Statistically
significantly different from placebo (p<0.05).
|
|
|
PsA-1
|
PsA-2
|
PsA-3
|
|
Na
|
Placebo
±
DMARDs
N=168
|
Otezla
30 mg
twice
daily ±
DMARDs
N=168
|
Placebo
±
DMARDs
N=159
|
Otezla
30 mg
twice
daily ±
DMARDs
N=162
|
Placebo
±
DMARDs
N=169
|
Otezla
30 mg
twice
daily
±
DMARDs
N=167
|
|
ACR 20
Week
16
|
19%
|
38% b
|
19%
|
32% b
|
18%
|
41% b
|
|
ACR 50
Week
16
|
6%
|
16%
|
5%
|
11%
|
8%
|
15%
|
|
ACR 70
Week
16
|
1%
|
4%
|
1%
|
1%
|
2%
|
4%
|
Otezla 30
mg twice daily resulted in improvement for each ACR component, compared to
placebo at Week 16 in Study PsA-1 (Table
5). Consistent results
were observed in Studies PsA-2 and PsA-3.
Table 5: ACR Components Mean Change from
Baseline at Week 16 in Study PsA- 1
|
|
Mean changes
from baseline are least square means from analyses of covariance.
a Scale
0-78.
b Scale
0-76.
c VAS=Visual
Analog Scale; 0=best, 100=worst.
d HAQ-DI
= Health Assessment Questionnaire-Disability Index; 0=best, 3=worst; measures
the subject’s ability to perform the following: dress/groom, arise, eat,
walk, reach, grip, maintain hygiene, and maintain daily activity.
e CRP =
C-reactive protein; Reference range 0-0.5 mg/dL
* N reflects randomized patients; actual number of patients evaluable for
each endpoint may vary by timepoint.
|
|
|
Placebo
(N*=168)
|
Otezla 30 mg
twice daily
(N*=168)
|
|
Number of tender
jointsa
Sample Size
Baseline
Mean Change at Week 16
|
166
23
-2
|
164
23
-7
|
|
Number of
swollen jointsb
Sample Size
Baseline
Mean Change at Week 16
|
166
13
-2
|
164
13
-5
|
|
Patient’s
assessment of painc
Sample Size
Baseline
Mean Change at Week 16
|
165
61
-6
|
159
58
-14
|
|
Patient’s global
assessment of disease
activityc
Sample Size
Baseline
Mean Change at Week 16
|
165
59
-3
|
159
56
-10
|
|
Physician’s
global assessment of disease
activityc
Sample Size
Baseline
Mean Change at Week 16
|
158
55
-8
|
159
56
-19
|
|
HAQ-DId score
Sample Size
Baseline
Mean Change at Week 16
|
165
1.2
-0.09
|
159
1.2
-0.2
|
|
CRPe
Sample Size
Baseline
Mean Change at Week 16
|
166
1.1
0.1
|
167
0.8
-0.1
|
Treatment
with Otezla resulted in improvement in dactylitis and enthesitis in patients
with pre-existing dactylitis or enthesitis.
Physical Function Response
Otezla 30
mg twice daily demonstrated a greater improvement compared to placebo in mean
change from baseline for the Health Assessment Questionnaire Disability Index
(HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the
difference was (-0.26, -0.06)] in Study PsA-1. The proportions of HAQ-DI
responders (≥0.3 improvement from baseline) at Week 16 for the Otezla 30 mg
twice daily group were 38%, compared to 27%, for the placebo group in Study
PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3.
Psoriasis
Two
multicenter, randomized, double-blind, placebo-controlled trials (Studies
PSOR-1 and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older
with moderate to severe plaque psoriasis [body surface area (BSA) involvement
of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe
disease), Psoriasis Area and Severity Index (PASI) score ≥12, candidates for
phototherapy or systemic therapy]. Subjects were allowed to use low-potency
topical corticosteroids on the face, axilla and groin. Subjects with scalp
psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp
preparations on scalp lesions.
Study
PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both
studies, subjects were randomized 2:1 to Otezla 30 mg BID or placebo for 16
weeks. Both studies assessed the proportion of subjects who achieved PASI-75 at
Week 16 and the proportion of subjects who achieved a sPGA score of clear (0)
or almost clear (1) at Week 16. Across both studies, subjects ranged in age
from 18 to 83 years, with an overall median age of 46 years. The mean baseline
BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was
19.07 (median 16.80), and the proportion of subjects with sPGA score of 3
(moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively.
Approximately 30% of all subjects had received prior phototherapy and 54% had
received prior conventional systemic and/or biologic therapy for the treatment
of psoriasis with 37% receiving prior conventional systemic therapy and 30%
receiving prior biologic therapy. Approximately one-third of subjects had not
received prior phototherapy, conventional systemic nor biologic therapy. A
total of 18% of subjects had a history of psoriatic arthritis.
Clinical Response in Subjects with Plaque Psoriasis
The
proportion of subjects who achieved PASI -75 responses, and sPGA score of clear
(0) or almost clear (1), are presented in Table
6.
Table 6: Clinical Response at Week 16 in
Studies PSOR-1 and PSOR-2
|
|
a N
is number of randomized and treated patients.
b PASI=Psoriasis
Area and Severity Index.
c sPGA=Static
Physician Global Assessment.
|
|
|
Study PSOR-1
|
Study PSOR-2
|
|
|
Placebo
|
Otezla
30 mg BID
|
Placebo
|
Otezla
30 mg BID
|
|
Na
|
N=282
|
N=562
|
N=137
|
N=274
|
|
PASIb-75, n (%)
|
15 (5.3)
|
186 (33.1)
|
8 (5.8)
|
79 (28.8)
|
|
sPGAc of Clear or Almost
Clear,
n (%)
|
11 (3.9)
|
122 (21.7)
|
6 (4.4)
|
56 (20.4)
|
The
median time to loss of PASI-75 response among the subjects re-randomized to
placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1
weeks.
How Supplied/Storage and Handling
Otezla is
available as diamond-shaped, film-coated tablets in the following dosage
strengths: 10-mg pink tablet engraved with “APR” on one side and “10” on the
other side; 20-mg brown tablet engraved with “APR” on one side and “20” on the
other side; 30-mg beige tablet engraved with “APR” on one side and “30” on the
other side.
Tablets
are supplied in the following strengths and package configurations:
|
Package configuration
|
Tablet strength
|
NDC number
|
|
Bottles of 60
|
30 mg
|
59572-631-06
|
|
Two-week starter pack
|
13-tablet blister titration pack
containing: (4) 10-mg, (4) 20-mg,
and (5) 30-mg tablets with an
additional (14) 30-mg tablets
|
59572-630-27
|
|
28-count carton
|
Two 30-mg blister cards containing
(14) 30-mg tablets
|
59572-631-28
|
|
28-day starter pack
|
13-tablet blister titration pack
containing: (4) 10-mg, (4) 20-mg,
and (5) 30-mg tablets with an
additional (42) 30-mg tablets
|
59572-632-55
|
Storage and Handling
Store tablets below 30°C (86°F).
Patient Counseling Information
Diarrhea, Nausea, and Vomiting
Instruct patients to contact their healthcare provider if they experience
severe diarrhea, nausea, or vomiting. Prescribers should advise patients
of the potential complications of severe diarrhea, nausea, or vomiting.
Consider Otezla dose reduction or suspension if patients develop severe
diarrhea, nausea, or vomiting [
see
Warnings and Precautions (5.1)].
Depression
Before using Otezla in patients with a history of depression and/or
suicidal thoughts or behavior, prescribers should carefully weigh the
risks and benefits of treatment with Otezla in such patients. Patients,
their caregivers, and families should be advised of the need to be alert
for the emergence or worsening of depression, suicidal thoughts or other
mood changes, and if such changes occur to contact their healthcare
provider. Prescribers should carefully evaluate the risks and benefits of
continuing treatment with Otezla if such events occur [
see Warnings and Precautions (5.2)].
Weight Decrease
Patients treated with Otezla should have their weight monitored regularly.
If unexplained or clinically significant weight loss occurs, weight loss
should be evaluated, and discontinuation of Otezla should be considered [
see Warnings and Precautions (5.3)].
Drug Interactions
The use of strong cytochrome P450 enzyme inducers (e.g., rifampin,
phenobarbital, carbamazepine, phenytoin) with Otezla is not recommended [
see Warnings and Precautions (5.4), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].Instruct patients to take Otezla only as prescribed.Advise patients Otezla can be taken with or without food.Advise patients that the tablets should not be crushed, split,
or chewed.Advise patients about the side effects associated with Otezla
[
see Adverse Reactions (6.1)].
Manufactured
for: Celgene Corporation
Summit,NJ07901
Otezla® is
a registered trademark of Celgene Corporation.
Pat.
http://www.celgene.com/therapies
©
2014-2017 Celgene Corporation, All Rights Reserved.
APRPI.006 06/17
RINCIPAL DISPLAY PANEL - NDC: 59572-630-27 - Two-Week Starter
Pack Wallet Label (Outside)
PRINCIPAL DISPLAY PANEL - NDC: 59572-630-27 - Two-Week Starter
Pack Wallet Label (Inside)
PRINCIPAL DISPLAY PANEL - NDC: 59572-630-99 - Sample Two-Week
Starter Pack Wallet Label (Outside)
PRINCIPAL DISPLAY PANEL - NDC: 59572-630-99 - Sample Two-Week
Starter Pack Wallet Label (Inside)
PRINCIPAL DISPLAY PANEL - NDC: 59572-630-98 - Sample Two-Week
Starter Pack Display Carton Label
PRINCIPAL DISPLAY PANEL - NDC: 59572-631-06 - 30mg 60-count Bottle Label
PRINCIPAL DISPLAY PANEL - NDC: 59572-631-28 - 30 mg 28-count
Blister Foil
PRINCIPAL DISPLAY PANEL - NDC: 59572-631-28 - 30 mg 28-count
Carton Label
PRINCIPAL DISPLAY PANEL - NDC: 59572-631-99 - Sample 30 mg
28-count Blister Foil
PRINCIPAL DISPLAY PANEL - NDC: 59572-631-99 - Sample 30 mg
28-count Carton Label
PRINCIPAL DISPLAY PANEL - NDC: 59572-632-55 - 28-day Starter
Pack Sleeve Label
PRINCIPAL DISPLAY PANEL - NDC: 59572-632-55 - 28-day Starter
Pack Wallet Label (Outside)
PRINCIPAL DISPLAY PANEL - NDC: 59572-632-55 - 28-day Starter
Pack Wallet Label (Inside)
|
Otezla apremilast kit
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59572-630
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59572-630-27
|
1 KIT in 1
BLISTER PACK
|
|
|
2
|
NDC:59572-630-99
|
1 KIT in 1
BLISTER PACK
|
|
|
|
Quantity of
Parts
|
|
Part #
|
Package
Quantity
|
Total
Product Quantity
|
|
|
|
Part 1
|
|
4
|
|
|
|
Part 2
|
|
4
|
|
|
|
Part 3
|
|
19
|
|
|
|
|
Part
1 of 3
|
|
Otezla apremilast tablet, film coated
|
|
|
Product
Information
|
|
|
|
|
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
10.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
PINK
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
APR;10
|
|
Contains
|
|
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
|
|
|
|
Part
2 of 3
|
|
Otezla apremilast tablet, film coated
|
|
|
Product
Information
|
|
|
|
|
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
20.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
BROWN
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
20;APR
|
|
Contains
|
|
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
|
|
|
|
Part
3 of 3
|
|
Otezla apremilast tablet, film coated
|
|
|
Product
Information
|
|
|
|
|
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
30.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE (Beige)
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
30;APR
|
|
Contains
|
|
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
03/25/2014
|
|
|
|
Otezla apremilast tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59572-631
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
30.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE (Beige)
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
30;APR
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59572-631-06
|
60 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:59572-631-28
|
28 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
1 TABLET, FILM
COATED in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
04/03/2014
|
|
|
|
Otezla apremilast kit
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59572-632
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59572-632-55
|
1 KIT in 1
BLISTER PACK
|
|
|
|
Quantity of
Parts
|
|
Part #
|
Package
Quantity
|
Total
Product Quantity
|
|
|
|
Part 1
|
|
4
|
|
|
|
Part 2
|
|
4
|
|
|
|
Part 3
|
|
47
|
|
|
|
|
Part
1 of 3
|
|
Otezla apremilast tablet, film coated
|
|
|
Product
Information
|
|
|
|
|
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
10.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
PINK
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
APR;10
|
|
Contains
|
|
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
|
|
|
|
Part
2 of 3
|
|
Otezla apremilast tablet, film coated
|
|
|
Product
Information
|
|
|
|
|
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
APREMILAST (APREMILAST)
|
APREMILAST
|
20.0 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
LACTOSE MONOHYDRATE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
|
Product
Characteristics
|
|
Color
|
BROWN
|
Score
|
no score
|
|
Shape
|
DIAMOND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
20;APR
|
|
Contains
|
|
|
|
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Marketing Information
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Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
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Marketing
End Date
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NDA
|
NDA205437
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Part
3 of 3
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Otezla apremilast tablet, film coated
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Product
Information
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Route of
Administration
|
ORAL
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DEA Schedule
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Active
Ingredient/Active Moiety
|
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Ingredient
Name
|
Basis of
Strength
|
Strength
|
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APREMILAST (APREMILAST)
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APREMILAST
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30.0 mg
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Inactive
Ingredients
|
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Ingredient
Name
|
Strength
|
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CELLULOSE, MICROCRYSTALLINE
|
|
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LACTOSE MONOHYDRATE
|
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CROSCARMELLOSE SODIUM
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MAGNESIUM STEARATE
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Product
Characteristics
|
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Color
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WHITE (Beige)
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Score
|
no score
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Shape
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DIAMOND
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Size
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12mm
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Flavor
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Imprint Code
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30;APR
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Contains
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Marketing Information
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|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
|
|
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|
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Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205437
|
02/01/2015
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|
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Labeler - Celgene Corporation (174201137)
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Revised: 06/2017
Celgene
Corporation
