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PRODUCT MONOGRAPH PrOTEZLA®
10 mg, 20 mg, and 30 mg tablets Selective Immunosuppressant Date of Preparation: 6755 Mississauga Road November 12, 2014 Submission Control No: 169862 2014 Celgene Corporation. ® OTEZLA is a registered trademark of Celgene Corporation. Page 1 of 28 TABLE OF CONTENTS
Page 2 of 28 OTEZLA®
apremilast tablets PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form /
Clinically Relevant Nonmedicinal Ingredients
Strength
For a complete listing see Dosage Forms, Composition and Packaging section. INDICATIONS AND CLINICAL USE
OTEZLA® (apremilast) is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Limitations of Use:
OTEZLA® has not been studied and is therefore not indicated in combination with other
systemic (conventional or biologic) therapies or phototherapy for psoriasis.
Geriatrics (≥ 65 years of age):
No overall differences were observed in the safety or efficacy profile of elderly patients
≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Due
to limited data available in very elderly patients (≥75 years of age), OTEZLA® should be
used with caution in this patient population.
Pediatrics (< 18 years of age):
The safety and effectiveness of OTEZLA® in pediatric patients have not been established.
OTEZLA® should not be used in this patient population.
OTEZLA® (apremilast) is contraindicated in:
 Patients with known hypersensitivity to the active substance or to any of the excipients. For a complete listing, see DOSAGE FORMS, COMPOSITION
AND PACKAGING
 Pregnancy  Women who are breastfeeding. Page 3 of 28 WARNINGS AND PRECAUTIONS
Cardiovascular
Tachyarrhythmia: There have been uncommon reports of tachyarrhythmia, including
atrial fibrillation, in Phase 2/3 studies. The incidence of tachyarrhythmia events was
0.2% for placebo and 0.6% for OTEZLA® 30 mg BID patients. Of these, atrial
fibrillation had an incidence of 0.1% for placebo and 0.3% for OTEZLA® patients. Use
with caution in patients with a history of tachyarrhythmia or conditions that can be
worsened by increases in heart rate (e.g. ischemic heart disease or congestive heart
failure) (see ACTION AND CLINICAL PHARMACOLOGY, Cardiac
Electrophysiology).

Endocrine and Metabolic
Weight loss: Weight decreases of greater than 5% of baseline body weight during the
placebo-controlled period (16 weeks) were reported in 5.0% of patients treated with
placebo compared to 13.3% of patients treated with OTEZLA® 30 mg BID. Weight
decreases of greater than 5% of baseline body weight following 52 weeks of treatment
were reported in 19.2% of patients treated with OTEZLA® 30 mg BID, including
decreases of greater than 10% reported in 5.7% of patients. Weight decreases of greater
than 5% of baseline body weight were observed more frequently in women than in men.
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.

Gastrointestinal
Diarrhea and Nausea: OTEZLA® was associated with an increased incidence of
diarrhea and nausea during the placebo-controlled period (see ADVERSE
REACTIONS).
Physicians should discuss the potential for diarrhea and nausea with OTEZLA® with their
patients and/or caregivers (see ADVERSE REACTIONS).

Immune
OTEZLA® has not been studied in patients with severe immunological diseases, severe
acute infectious diseases, or psoriasis patients treated with immunosuppressive medicinal
products. Experience in patients with latent infections such as tuberculosis, viral
hepatitis, herpes viral infection and herpes zoster is limited. OTEZLA® should be used
with caution in these patient populations.
Page 4 of 28 Neurologic
In Phase 3 psoriasis studies, OTEZLA® was associated with an increased incidence of
headache and migraine during the placebo-controlled period (see ADVERSE
REACTIONS).
Physicians should discuss the potential for headache/migraine with OTEZLA® with their
patients and/or caregivers (see ADVERSE REACTIONS).

Psychiatric
Depression: In Phase 3 psoriasis studies, treatment with OTEZLA® was associated with
an increase in adverse reactions of depression during the placebo-controlled period. The
incidence of depression or depressed mood was 1.44% for OTEZLA® 30 mg BID and
0.48% for placebo. In Phase 2/3 studies with OTEZLA®, the incidence of serious events
of depression or of suicidal ideation was uncommon in patients treated with OTEZLA®
30 mg BID.
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. Physicians should discuss psychiatric adverse events with
their patients and/or caregivers. Patients and/or caregivers should be instructed to notify
the physician if these events do occur.
In Phase 3 psoriasis studies, the safety profile observed in patients with mild renal
impairment was comparable to patients with normal renal function. The safety and
efficacy of OTEZLA® have not been evaluated in psoriasis patients with moderate or
severe renal impairment. There are limited pharmacokinetic data available in mild or
moderate renal impairment. Use with caution in patients with mild, moderate, or severe
renal impairment
The maximal recommended dose of OTEZLA® is 30 mg once daily in patients with
severe renal impairment (creatinine clearance [CLcr] of less than 30 mL per minute
estimated by the Cockroft–Gault equation), based on Phase 1 study data. Assessment of
renal function is recommended prior to initiation of OTEZLA® (see DOSAGE AND
ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).
Page 5 of 28 Special Populations
Pregnant Women:
There are no adequate and well controlled studies of OTEZLA® in pregnant women.
OTEZLA® is contraindicated during pregnancy and should not be used in women
attempting to conceive (see CONTRAINDICATIONS).
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.
Nursing Women:
It is not known whether apremilast, or its metabolites, are excreted in human milk.
Therefore, OTEZLA® is contraindicated in nursing women (see
CONTRAINDICATIONS).
Apremilast was detected in milk of lactating mice. An increased incidence of peri- and
post-natal pup mortality was observed at doses ≥ 80 mg/kg/day (≥4.0-fold clinical
exposure) (see TOXICOLOGY).
Pediatrics (< 18 years of age):
The safety and effectiveness of OTEZLA® in pediatric patients have not been established.
Therefore, OTEZLA® should not be used in this patient population.
Geriatrics (≥ 65 years of age):
No overall differences were observed in the safety or efficacy profile of elderly patients
≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Due
to limited data available in very elderly patients (≥75 years of age), OTEZLA® should be
used with caution in this patient population.
Monitoring and Laboratory Tests
Weight: 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.
Renal Function: Assessment of renal function is recommended prior to initiation of
OTEZLA®.
Page 6 of 28 ADVERSE REACTIONS
Adverse Drug Reaction Overview

The most common adverse reactions (≥ 5%) were diarrhea, nausea, upper respiratory
tract infection, tension headache, and headache (Table 1). The incidences of these events
were higher in females than males. In particular, during the placebo-controlled period,
nausea was experienced by 29.7% of women (compared to 9.9% of males), diarrhea by
24.0% of women (compared to 14.6% of men), vomiting by 7.9% of women (compared
to 1.6% of men), and tension headache by 11.5% of women (compared to 5.2% of men).
The majority of the adverse reactions of diarrhea, nausea, tension headache, and
headache began within the first two weeks of treatment, and nearly half of these adverse
reactions resolved within 2 weeks of onset. These events were mostly mild in intensity
with the incidence of severe events ranging from 0.1 % - 0.6 %.
In the period of exposure to OTEZLA® in the pivotal trials, the most common serious
adverse event for patients exposed to OTEZLA® was nephrolithiasis (0.3%). The most
common adverse reactions leading to discontinuation for patients taking OTEZLA® were
nausea, diarrhea, psoriasis, headache, and vomiting.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice, and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. In two 52-week Phase 3 pivotal trials (Studies ESTEEM 1 and ESTEEM 2) (see
CLINICAL TRIALS), 418 subjects were randomized to receive placebo, and
832 subjects to receive at least one dose of OTEZLA® 30 mg BID. Including placebo
subjects switched to receive OTEZLA® 30 mg BID at Week 16, a total of 1184 subjects
were exposed to OTEZLA® 30 mg BID. A total of 564 subjects received OTEZLA®
30 mg BID for at least 52 weeks. Patients ranged in age from 18 to 83 years, with an
overall median age of 46 years.
Page 7 of 28 Treatment-Emergent Adverse Events With Subject Incidence ≥ 2% in
Any Treatment Group and the Incidence in OTEZLA® Exceeded
Placebo During Weeks 0-16 (PSOR Phase 3 Data Pool)
Subjects as Initially Treated at Week 0
OTEZLA® 30 BID
System organ class
Preferred Term
Gastrointestinal disorders Abdominal discomfort Frequent bowel movements Abdominal pain upper Infections and infestations Upper respiratory tract infection Nervous system disorders Tension headache General disorders and administration site conditions Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Psychiatric disorders Page 8 of 28 Less Common Clinical Trial Adverse Drug Reactions
Adverse reactions reported in less than 2% of patients on OTEZLA® in clinical studies
(including extension phases) in psoriasis and other patient populations:
 Gastrointestinal Disorders: Abdominal distension, Gastroesophageal reflux
 Immune System Disorders: Hypersensitivity
 Infections and Infestations: Bronchitis, Influenza, Pharyngitis, Rhinitis
 Investigations: Weight decrease
 Musculoskeletal and Connective Tissue Disorders: Arthralgia, Muscle
 Nervous System Disorders: Paresthesia, Sinus headache
 Psychiatric Disorders: Depression
 Respiratory, Thoracic, and Mediastinal Disorders: Cough
 Skin and Subcutaneous Tissue Disorders: Rash
The long-term safety profile of OTEZLA®, for up to 52 weeks of treatment, was
comparable to that observed with OTEZLA® for up to 16 weeks of treatment.
DRUG INTERACTIONS
Overview
In vitro, 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, weak 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). Therefore, apremilast is unlikely to result in clinically relevant drug-drug interactions when co-administered with drugs that are substrates or inhibitors of these CYP enzymes or transporters. Drug-Drug Interactions
No significant interactions were observed when 30 mg oral apremilast was administered with ketoconazole (CYP3A4 inhibitor), methotrexate and oral contraceptives (CYP3A4 substrate) containing ethinyl estradiol and norgestimate. Page 9 of 28 Combination with:
Strong CYP3A4 Inducers: Apremilast exposure (AUC) and maximal concentrations
(Cmax) were decreased by 72% and 43% when co-administered with CYP3A4 inducer
rifampin, and may result in reduced clinical efficacy of apremilast. Hence co-
administration of rifampin or other CYP3A4 inducers (e.g. phenobarbital,
carbamazepine, phenytoin) along with OTEZLA® is not recommended (Table 2).
Cyclosporine: OTEZLA® has not been evaluated and is not indicated in combination
with potent immunosuppressive drugs (e.g. cyclosporine, tacrolimus). OTEZLA® is not
recommended in combination with potent immunosuppressive drugs (see
INDICATIONS AND CLINICAL USE, Limitations of Use; WARNINGS AND
PRECAUTIONS, Immune).
Biological Therapeutics: OTEZLA® has not been evaluated and is not indicated to be
used in combination with biological therapeutics for psoriasis such as TNF antagonists
and anti-IL-12/23 p40 antibodies. OTEZLA® is not recommended in combination with
these biological therapeutics (see INDICATIONS AND CLINICAL USE, Limitations
of Use).
Page 10 of 28 Table 2: Established or Potential Drug-Drug Interactions
Clinical
Co-administration of the strong OTEZLA® is NOT
CYP3A4 inducer rifampin (600 mg RECOMMENDED for co- once daily for 15 days), with a single administration along with oral dose of 30 mg apremilast, resulted rifampin or other potent in reduction of apremilast's AUC and CYP3A4 inducers. Cmax by approximately 72% and 43%, respectively and may result in reduced clinical response of apremilast. Co-administration of ketoconazole (a OTEZLA® can be co-
strong CYP3A4 inhibitor, 400 mg administered with a potent QD) with a single dose (20 mg) of CYP3A4 inhibitor like apremilast increased mean apremilast ketoconazole. No dosage AUC 0-∞ and Cmax by approximately adjustment of OTEZLA® is
36 % and by 5%, respectively, which required on co-administration. is not clinically meaningful. was no pharmacokinetic drug- Efficacy and safety of drug interaction between apremilast OTEZLA® in combination
(30 mg BID) and methotrexate with methotrexate has not (between 7.5 mg and 20 mg once a been established and is week) in psoriatic arthritis patients. therefore NOT INDICATED. oral contraceptives There was no pharmacokinetic drug- OTEZLA® can be taken with
drug interaction between apremilast oral contraceptives without (30 mg BID) and oral contraceptives clinically relevant drug-drug containing ethinyl estradiol interaction. No dosage (0.035 mg) and norgestimate adjustment of OTEZLA® is
(0.18 mg/0.215 mg/0.25 mg). required on co-administration. Legend: AUC = Area under curve; CT = Clinical Trial; CYP = Cytochrome P450. Drug-Food Interactions
Interactions with food have not been established. Drug-Herb Interactions
St John's Wort is a CYP3A4 inducer, and co-administration with OTEZLA® may result in loss of efficacy or reduced clinical response, and is not recommended. Page 11 of 28 Drug-Laboratory Interactions
Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions
Population pharmacokinetic studies demonstrated that apremilast pharmacokinetics were similar between smokers and non-smokers. DOSAGE AND ADMINISTRATION
Dosing Considerations
OTEZLA® has not been evaluated and is therefore not indicated in combination with
potent immunosuppressants or biological therapeutics for psoriasis such as tumor
necrosis factor (TNF) antagonists and anti-IL-12/23 p40 antibodies (see INDICATIONS
AND CLINICAL USE, Limitations of Use).
Recommended Dose and Dosage Adjustment
Recommended adult dose ( ≥ 18 years of age and older): The recommended dose of OTEZLA® is 30 mg twice daily. OTEZLA® tablets can be
taken with or without food. An initial titration schedule is required, as shown below in
Table 3, to reduce the risk of gastrointestinal symptoms. No re-titration is required after
initial dose titration.
Dose Titration Schedule
Special Populations:
Pediatrics ( < 18 years of age):
The safety and effectiveness of OTEZLA® in pediatric patients have not been established.
Therefore, OTEZLA® should not be used in this patient population.
Geriatrics ( ≥ 65 years of age):
No dosage adjustment is necessary for elderly patients (≥ 65 years of age). Due to
limited data available in very elderly patients (≥ 75 years of age), OTEZLA® should be
used with caution in this patient population.
Hepatic Impairment:
No dosage adjustment is necessary in patients with moderate and severe hepatic impairment. Page 12 of 28 Renal Impairment:
Use with caution in patients with mild or moderate renal impairment. The safety and efficacy of OTEZLA® have not been evaluated in psoriasis patients with
severe renal impairment. The maximal recommended dose of OTEZLA® is 30 mg once
daily in patients with severe renal impairment (creatinine clearance [CLcr] of less than
30 mL per minute estimated by the Cockroft–Gault equation). For initial dosage titration,
titrate using only the morning dose (AM dose) in Table 3 and skip the afternoon dose
(PM dose). Continue thereafter at 30 mg once daily (see WARNINGS AND
PRECAUTIONS, Renal).
Missed Dose
Patients should be advised that if they miss a dose of OTEZLA®, they should continue
with the next tablet at the usual time. Patients should not take a double dose to make up
for a missed dose.
OTEZLA® tablets should be swallowed whole. The tablets should not be crushed, split
or chewed.
OVERDOSAGE
In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care. For management of a suspected drug overdose, contact your regional Poison Control Centre. ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Apremilast, a small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. Phosphodiesterase 4 inhibition elevates intracellular cAMP levels, thereby reducing the inflammatory response by modulating the expression of tumor necrosis factor-α (TNF-α), interleukin-23 (IL-23), IL-17 and IL-10. In clinical trials in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-23p19, IL-17A, IL-22 and IL-8. Page 13 of 28 Cardiac Electrophysiology
A double-blind, placebo- and positive-controlled, randomized, multiple-dose, four period
crossover study was performed to investigate the effects of apremilast on ECG interval
parameters in healthy male volunteers (N=60). Apremilast was tested at a therapeutic
dose (30 mg BID on days 1-4 and 30 mg QD on day 5) and a supratherapeutic dose
(50 mg BID on days 1-4 and 50 mg QD on day 5). Apremilast 30 mg and 50 mg did not
have noteworthy effects on the QTc, QRS, or PR intervals on day 5 of treatment. For the
therapeutic 30 mg treatment arm, heart rate was increased from 0.5 h- 4 h post-dosing on
day 5, with a maximum mean difference from placebo of 3.4 bpm (90% CI: 1.1, 5.6) at
2 h. For the supratherapeutic 50 mg BID treatment arm, heart rate was increased from
0.5 h-4 h and at 23 h post-dosing on day 5, with a maximum mean difference from
placebo of 4.9 bpm (90% CI: 3.3, 6.6) at 3 h (see WARNINGS AND PRECAUTIONS,
Cardiovascular).
Summary of Apremilast Pharmacokinetic Parameters after 30 mg
BID in Psoriasis Subjects
Dose Cmax
(ng•h/mL)
Legend: AUC= Area under curve; BID = Twice daily; Cmax = Maximum concentration *Geometric Mean (CV%) Absorption: Apremilast is well absorbed, with an absolute oral bioavailability of
approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time
(tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-
proportional increase in systemic exposure and less than dose proportional increase in
Cmax between the dose range of 10 to 100 mg daily in healthy volunteers. Co-
administration with food does not alter the extent of absorption (AUC and Cmax), but
slightly delays time to maximum concentration (tmax) of apremilast by 0.75 hour;
therefore, apremilast can be administered with or without food.
Distribution: Human plasma protein binding of apremilast is approximately 68%.
Mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular
distribution.
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.
Page 14 of 28 Excretion: The plasma clearance of apremilast is on average about 10 L/hr in healthy
subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral
administration of radiolabeled 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.
Special Populations and Conditions
Pediatrics: The safety and effectiveness of OTEZLA® in pediatric patients have not
been established and should not be used in this patient population (see INDICATIONS
AND CLINICAL USE, WARNINGS AND PRECAUTIONS, Special Populations).
Geriatrics: 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 younger
subjects (18 to 55 years of age). Age did not have a clinically meaningful effect on the
pharmacokinetics of apremilast (see INDICATIONS AND CLINICAL USE,
WARNINGS AND PRECAUTIONS, Special Populations).
Sex: In a pharmacokinetic study of apremilast in healthy volunteers, the exposure
(AUC0-∞ ) and maximal concentrations (Cmax) in females were 31% and 8% higher than
in male subjects. Sex did not have a clinically meaningful effect on the pharmacokinetics
of apremilast.
Race: The pharmacokinetics of apremilast in Chinese and Japanese healthy male
subjects is comparable to that in Caucasian healthy male subjects. Pharmacokinetic
analyses based on the pooled data from Phase 1 studies showed that apremilast exposure
is also similar among Hispanic Caucasians, non-Hispanic Caucasians, and African
Americans. The exposure (AUC0-∞ or AUC0- τ ) and maximal concentrations (Cmax) were
5% and 4% lower in Asian, and 11% and 1% higher in African American than in
Caucasian White. Race and ethnicity did not have a clinically meaningful effect on the
pharmacokinetics of apremilast.
Hepatic Insufficiency: Apremilast pharmacokinetics were characterized in subjects with
moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. The AUC0-inf
and Cmax decreased by 5.4% and 15.9% in moderate hepatic impaired subjects and by
1.6% and 35% in severely hepatic impaired patients with wider confidence intervals in
the geometric mean ratios, and are not considered clinically meaningful (see DOSAGE
AND ADMINISTRATION).
Renal Insufficiency: Limited pharmacokinetic data are available in subjects with mild
and moderate renal impairment (see DOSAGE AND ADMINISTRATION).
In 8 subjects with severe renal impairment administered a single dose of 30 mg
apremilast, the AUC0-inf and Cmax of apremilast increased by approximately 88% and
42%, respectively. These changes in AUC0-inf and Cmax are considered clinically
meaningful (see WARNINGS AND PRECAUTIONS, DOSAGE and
ADMINISTRATION).
Page 15 of 28 Genetic polymorphism:
No studies have been conducted specifically to evaluate genetic polymorphisms. STORAGE AND STABILITY
Store at 15-30°C. DOSAGE FORMS, COMPOSITION AND PACKAGING
Each diamond-shaped, film-coated tablet contains apremilast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 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). Tablets are supplied in the following strengths and package configurations: Package configuration
Tablet strength
Description
Bottles of 60 (HDPE bottles The 30 mg tablet is beige with with an induction seal and "APR" engraved on one side and child-resistant cap) "30" on the opposite side. 28-Count Blister Pack 2 – 30 mg blister cards The 30 mg tablet is beige with containing (14) 30 mg "APR" engraved on one side and (PVC/aluminum foil blisters) "30" on the opposite side. 56-Count Blister Pack 4 - 30 mg blister cards The 30 mg tablet is beige with containing (14) 30 mg "APR" engraved on one side and (PVC/aluminum foil blisters) "30" on the opposite side. 27-Count Starter Pack Titration portion contains The 10 mg tablet is pink with "APR" engraved on one side and (PVC/aluminum foil blisters) "10" on the opposite side. (4) 10 mg tablets, The 20 mg tablet is brown with (4) 20 mg tablets, "APR" engraved on one side and (5) 30 mg tablets for "20" on the opposite side. upward dose titration, with an additional The 30 mg tablet is beige with (14) 30 mg tablets for one "APR" engraved on one side and week of dosing with 30 "30" on the opposite side. Legend: APR = Apremilast; HDPE = High density polyethylene; PVC = Polyvinyl Chloride Page 16 of 28 PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance

Molecular formula and molecular mass: C22H24N2O7S 460.5g/mL Physicochemical Apremilast is a white to pale yellow non-hygroscopic powder with a melting point of approximately 156.1°C. It is practically insoluble in water, slightly soluble in ethanol, and soluble in acetone. CLINICAL TRIALS
Study demographics and trial design
Two multicenter, randomized, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) enrolled a total of 1257 patients 18 years of age and older, with a diagnosis of plaque psoriasis for at least 12 months, moderate to severe plaque psoriasis at screening [i.e. had a body surface area (BSA) involvement of ≥ 10%, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe disease), and a Psoriasis Area and Severity Index (PASI) score ≥ 12], and who were candidates for phototherapy or systemic therapy. Concomitant anti-psoriatic medications were prohibited during the study up to Week 32, with the exception of low potency topical corticosteroids on the face, axillae and groin, coal tar shampoo and/or salicylic acid scalp preparations. Page 17 of 28 Efficacy on a background of other medications or phototherapy has not been adequately
studied with OTEZLA®.
Study ESTEEM 1 and Study ESTEEM 2 had a similar design through Week 32. In both
studies, patients were randomized 2:1 to OTEZLA® 30 mg BID or placebo for 16 weeks
(Placebo-Controlled Phase). All patients were initiated on study drug with dose-titration
over 5 days. From Weeks 16-32, all patients received OTEZLA® 30 mg BID
(Maintenance Phase). From Weeks 32-52, a selected subgroup of patients underwent a
Randomized Treatment Withdrawal Phase.

In both studies, the primary endpoint was the proportion of patients who achieved PASI-
75 at Week 16. The major secondary endpoint was the proportion of patients who
achieved a sPGA score of clear (0) or almost clear (1) at Week 16.
Baseline demographics were generally similar across the treatment groups in each study
and comparable between the studies. Across both studies, patients ranged in age from 18
to 83 years, with an overall median age of 46 years. A total of 108 patients (8.6%) were
aged ≥65 years old, including 9 patients (0.7%) aged ≥75 years old. Most of the patients
(68%) were male. Race was predominantly White (90%). Baseline demographics for
patients in each trial are presented in Table 5.
Table 5: Summary of Patient Demographics for Studies ESTEEM 1 and ESTEEM 2

Trial design
Dosage, route of
Subjects
(n = number)
Double Blind, Placebo-controlled study PO; placebo Double Blind, Placebo-controlled study Baseline disease characteristics were generally similar across the treatment groups in each study and comparable between the studies. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportions of patients with sPGA scores of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. The mean duration since diagnosis of plaque psoriasis was 19 (median 16.6) years. A total of 18% of patients had a history of psoriatic arthritis. Page 18 of 28 Approximately 35% of patients had not received prior phototherapy, conventional systemic or biologic therapy for the treatment of psoriasis. Approximately 30% of all patients had received prior phototherapy, 38% had received prior conventional systemic therapy, and 30% had received prior biologic therapy for the treatment of psoriasis. Study results
Clinical Response in Patients with Plaque Psoriasis

The proportion of patients achieving PASI -75 and -50 responses, and a sPGA score of
clear (0) or almost clear (1), are presented in Table 6 below. OTEZLA® resulted in a
significant improvement in moderate to severe plaque psoriasis, as demonstrated by the
proportion of patients who achieved PASI-75 response at Week 16, compared with
placebo. Clinical improvements measured by sPGA and PASI-50 responses were also
demonstrated at Week 16 (Table 6).
The proportions of patients who discontinued by Week 16 were 12% in the placebo group
and 11% in the OTEZLA® group in ESTEEM 1 and 18% in the placebo group and 13%
in the OTEZLA® group in ESTEEM 2.
Table 6: Clinical Response at Week 16a in Studies ESTEEM 1 and ESTEEM 2
(FASb; LOCFc)

Study ESTEEM 1
Study ESTEEM 2
OTEZLA®
Placebo OTEZLA®
PASId -75, n (%)
sPGAe of Clear or
Almost Clearf, n (%)
PASId -50f, n (%)
a All p values <0.0001
b FAS = Full Analysis Set
c LOCF = Last Observation Carried Forward
d PASI = Psoriasis Area and Severity Index
e sPGA = Static Physician Global Assessment
f Secondary endpoint
The clinical benefit of OTEZLA® on the primary endpoint (i.e. PASI-75) was
demonstrated across subgroups defined by baseline demographics, baseline clinical
disease characteristics (including psoriasis disease duration and patients with a history of
psoriatic arthritis), prior psoriasis medication usage and response to prior psoriasis
treatments. Similar response rates were observed across all weight subgroups, and
baseline disease severity classifications including BSA.
Page 19 of 28 Mean percent changes in PASI score from Weeks 0 to 16 are shown in Figure 1.
The efficacy of OTEZLA® beyond Week 32 has not been adequately investigated.

Figure 1: Studies ESTEEM 1 and ESTEEM 2: Mean Percent Change
(Improvement) in PASI Score from Baseline over 16 Weeks ± Standard
Error (FAS, LOCF)
-6.9 (N=408) -12.8 (N=414) -23.0 (N=809) -35.5 (N=828) Treatment Placebo Last observation carried forward (LOCF) method was used to impute missing PASI score percent change at each week. DETAILED PHARMACOLOGY
Animal Pharmacology
Apremilast is a selective small-molecule inhibitor of phosphodiesterase (PDE) 4, which is
the dominant PDE in inflammatory cells. PDE4 functions to terminate the action of
cyclic AMP (cAMP); an intracellular second messenger that maintains immune
homeostasis by suppressing the release of pro-inflammatory mediators and promoting the
release of anti-inflammatory mediators.
Page 20 of 28 Phosphodiesterase 4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis. In cellular models, apremilast inhibits production of TNF-α in human peripheral blood mononuclear cells, synovial cells, plasmacytoid dendritic cells, epidermal keratinocytes, lamina propria mononuclear cells, and whole blood. Other effects include the inhibition of IFN-γ and IL-23A (IL-23p19) production and the elevation of IL-10 production by mononuclear cells, inhibition of GM-CSF, IFN-γ, TNF-α, IL-5, IL-13 and IL-17 by T cells, and the inhibition of IL-8 production by polymorphonuclear cells. Apremilast also inhibited the formation of osteoclasts, cells that can cause bone resorption. Apremilast has been tested in animal models of acute, rheumatologic, and dermatologic inflammation. In the mouse and the rat, apremilast reduced acute systemic TNF-α production in a dose-dependent manner. In a mouse arthritis model, apremilast significantly inhibited arthritic activity (paw edema) and reduced the histological evidence of arthritis damage in the joint. In a xenograft mouse model of psoriasis, apremilast reduced the severity and incidence of psoriasiform lesions, reduced epidermal skin thickening and proliferation, and reduced the expression of TNF-α, and other inflammatory markers, on the engrafted skin. Investigations of secondary pharmacodynamics found that apremilast did not significantly bind to any of the cell surface receptors or inhibit any of the other enzymes tested. Human Pharmacology
Clinical Pharmacodynamics In an open-label psoriasis study in 19 patients, apremilast treatment was associated with a decrease in dendritic cells and T cells infiltrating the skin lesions within the epidermis and the dermis, a significant decrease in the ex vivo production of TNF-α by the blood, and a significant decrease in iNOS gene expression in the skin after 29 days. In a subgroup of 20 patients from an open-label study of apremilast for recalcitrant plaque psoriasis, apremilast decreased lesional skin epidermal thickness, reduced the infiltration of myeloid dendritic cells, T cells, and natural killer cells, and decreased the expression of pro-inflammatory genes, including genes encoding iNOS, IL-12/IL-23p40, IL-23p19, IL-17A, IL-22, and IL-8. Page 21 of 28 Clinical Pharmacokinetics Apremilast is well absorbed, with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in systemic exposure and less than dose proportional increase in Cmax between the dose range of 10 to 100 mg daily in healthy volunteers. Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular distribution. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. TOXICOLOGY
Acute Toxicity
Apremilast has low potential for acute toxicity. In mice, the minimum lethal oral dose was > 2000 mg/kg, and the minimum lethal intravenous (IV) doses were 120 mg/kg and > 120 mg/kg for males and females, respectively. In rats, the minimum lethal IV dose was > 60 mg/kg and < 75 mg/kg, and the minimum lethal oral doses were 2000 mg/kg and > 300 mg/kg for males and females, respectively. Repeat-Dose Toxicity
Apremilast was evaluated in a series of repeat-dose oral toxicity studies of up to 6 months duration in mice (dose levels of 10, 100 and 1000 mg/kg/day; equivalent to 0.8-, 3.7- and 10-fold clinical exposure based on AUC), 12 months duration in monkeys (dose levels of 60, 180 and 600 mg/kg/day; equivalent to 2.3-, 3.2- and 4.8-fold clinical exposure based on AUC) and 90 days duration in rats. Apremilast-related mortality was observed in mice and rats and was primarily attributed to vascular and/or perivascular inflammation. Dose-related inflammatory responses were predominantly observed in mice and rats and included neutrophilia, lymphopenia, and changes in serum proteins (decreased albumin, increased globulin, and increased hapotoglobin, C-reactive protein [CRP], and/or fibrinogen). These inflammatory responses were associated with arteritis and perivascular inflammation in various tissues and organs (e.g. mesentery, heart, lungs, thymus, liver, skeletal muscle, mammary gland, skin and pancreas) in mice and rats, but not in monkeys, even at higher systemic exposures than those achieved in mice and rats. Complete or partial reversibility of the inflammatory findings in mice and rats was observed. Other target organs of apremilast toxicity include non-adverse centrilobular hepatocellular hypertrophy in the liver (mouse) and variable lymphoid depletion in lymphoid tissues (mouse and rat). The no observed adverse effect level (NOAEL) for the 6-month mouse and 12-month monkey studies, were 10 and 600 mg/kg/day, respectively. Page 22 of 28 Based on the finding that apremilast induced inflammation in rodents, an investigative in vitro study was conducted. The study demonstrated that apremilast stimulates IL-6 production in rodents, but not in monkeys or humans. Carcinogenicity Studies
Apremilast is not carcinogenic. Daily oral administration to male and female mice at 100 mg/kg/day for 103 or 99 weeks, respectively, at 300/200 mg/kg/day (lowered to 200 mg/kg/day in Week 73) for 98 or 96 weeks, respectively, at 1000 mg/kg/day to males for 73 weeks (dosing was terminated in Week 73), or at 1000/500 mg/kg/day (lowered to 500 mg/kg/day in Week 73) to females for 102 weeks, followed by necropsy in Weeks 102/103, did not show any evidence of carcinogenicity (up to 8.8-fold clinical exposure based on AUC). In rats, daily oral administration to males at 3 mg/kg/day for 91 weeks, 10/6 mg/kg/day (lowered to 6 mg/kg/day in Week 66) for 89 weeks, and 20 mg/kg/day for 66 weeks followed by euthanasia in Weeks 95 to 100 did not show any evidence of carcinogenicity (up to 0.08-fold clinical exposure based on AUC). Likewise, daily oral administration to female rats at 0.3, 1, and 3 mg/kg/day until Weeks 103, 101, and 94, respectively, followed by necropsy in Week 104, showed no evidence of carcinogenicity (up to 1.1-fold clinical exposure based on AUC). Genotoxicity Studies
Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg/day. Male Fertility
In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility. The NOAEL was greater than 50 mg/kg/day (3-fold clinical exposure based on AUC). Female Fertility and Embryo-fetal Development
In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, altered estrous cycling and increased time to mating was observed from 20 mg/kg/day. Nevertheless, all mice mated and pregnancy rates were unaffected. The no observed effect level (NOEL) for female fertility was 10 mg/kg/day (1-fold clinical exposure based on AUC). Page 23 of 28 Pregnant female mice exhibited increased absolute and/or relative heart weights from 20 mg/kg/day. Increased numbers of early resorptions and reduced numbers of ossified tarsals were observed at doses ≥ 20 mg/kg/day (2-fold clinical exposure). Reduced fetal weights and retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day, doses higher than the currently recommended highest human dose. The maternal and developmental NOEL was 10 mg/kg/day (1.3-fold clinical exposure based on AUC). Developmental malformations were not observed up to the highest dosage of 80 mg/kg/day (4.0-fold clinical exposure). Apremilast crosses the maternal blood-placental barrier in mice. Apremilast was not teratogenic in mice. In a monkey embryo-fetal developmental toxicity study, oral dosages of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) from 50 mg/kg/day (2-fold clinical exposure). Prenatal loss was not observed at 20 mg/kg/day (1.4-fold clinical exposure). No treatment-related fetal developmental effects or malformations were observed in the monkey up to the highest dosage of 1000 mg/kg/day in the study (3.5-fold clinical exposure based on AUC). Apremilast crosses the blood-placental barrier in monkeys. Apremilast was not teratogenic in monkeys. Pre- and Post-natal Development
In a pre- and post-natal development study, apremilast was administered orally to pregnant female mice at dosages of 0, 10, 80 and 300 mg/kg/day from GD 6 to Day 20 of lactation. One mortality associated with difficulty in delivering pups was observed at 300 mg/kg/day. Clinical signs of maternal toxicity associated with delivering pups were also observed in one mouse in each of the 80 and 300 mg/kg/day dose groups. Apremilast was detected in the milk of lactating mice. Increased peri- and post-natal pup mortality and reduced pup body weights during the first week of lactation were observed at doses ≥ 80 mg/kg/day (≥ 4.0-fold clinical exposure). Pup mortality and developmental effects observed during the first week of the post-natal period were likely related to the apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milk in the stomach of pups). There were no apremilast-related effects on duration of pregnancy, number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, or any developmental effects in the pups beyond post-natal day 7 during the remaining pre- and post-weaning periods. The NOEL for maternal toxicity and the F1 generation was 10 mg/kg/day (1.3-fold clinical exposure based on AUC). Page 24 of 28 REFERENCES
1. Canadian Psoriasis Guidelines Committee. Canadian Guidelines for the Management of Plaque Psoriasis, 1st Edition, June 2009. 2. Chang SE, Han SS, Jung HJ, Choi JH. Neuropeptide and their receptor in psoriasis skin in relation to pruritus. Br J Dermatol 2007 June; 156(6):1272-7. 3. Gottlieb AB, Strober B, Krueger JG, Rohane P, Zeldis JB, Hu CC, et al. An open- label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 2008; 24(5):1529-38. 4. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009; 61(3):451-85. 5. Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, Hu C, Day RM. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet 2012; 380 (9843): 738-46. Page 25 of 28 IMPORTANT: PLEASE READ
What the nonmedicinal ingredients are:
PART III: CONSUMER INFORMATION
Pr OTEZLA®
croscarmellose sodium, lactose monohydrate, magnesium apremilast tablets
stearate, microcrystalline cellulose, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, This leaflet is part III of a three-part "Product
iron oxide yellow (20 and 30 mg only) and iron oxide black Monograph" published when OTEZLA (apremilast)
(30 mg only). was approved for sale in Canada and is designed
What dosage forms it comes in:
specifically for Consumers. This leaflet is a summary and
will not tell you everything about OTEZLA . Contact
Tablets: 10 mg, 20 mg and 30 mg. your doctor or pharmacist if you have any questions
about the drug.
WARNINGS AND PRECAUTIONS
ABOUT THIS MEDICATION
BEFORE you use OTEZLA talk to your doctor or
pharmacist if you:
What the medication is used for:
 have kidney problems. OTEZLA® is used in adults to treat moderate to severe
 have a history of the heart condition, tachyarrhythmia plaque psoriasis. (fast heartbeat or heart palpitations). OTEZLA® is not approved for use in combination with any
have heart disease or congestive heart failure. other medicines taken by mouth used to treat psoriasis,  have tuberculosis or a viral infection such as viral biological therapies (such as TNF antagonists and anti-IL- hepatitis, herpes infection or shingles. 12/23 p40 antibodies) or with phototherapy (light therapy  are using immunosuppressive drugs (such as using UV light). What it does:
 have a history of depression and/or suicidal thoughts or OTEZLA belongs to a class of drugs called  have any other medical conditions. phosphodiesterase 4 (PDE4) inhibitors. It contains the active ingredient apremilast which works by reducing the activity of are less than 18 years old or 75 years of age or older. PDE4. This results in less inflammation in the skin. OTEZLA can cause weight loss. Your doctor will need to When it should not be used:
regularly monitor your weight. Do not take OTEZLA® if you:

INTERACTIONS WITH THIS MEDICATION
are allergic to apremilast or to any non-medicinal ingredient in the formulation. As with most medicines, interactions with other drugs are  have one of the following rare hereditary diseases: possible. Tell your doctor or pharmacist about all the Galactose intolerance medicines you take, including drugs prescribed by other Lapp lactase deficiency doctors, vitamins, minerals, natural supplements, or Glucose-galactose malabsorption alternative medicines. because lactose is a non-medicinal ingredient in OTEZLA®.
are breastfeeding. It is not known if OTEZLA passes The following may interact with OTEZLA : into your breast milk. OTEZLA should not be used if  Rifampin, used to treat tuberculosis. you are breastfeeding.  Medicines used to control seizures such as  are pregnant or intend to become pregnant. It is not phenobarbital, carbamazepine and phenytoin. known if OTEZLA will harm your unborn baby. If  Medicines that suppress your immune system such as you take OTEZLA while you are pregnant, talk to your cyclosporine and tacrolimus. doctor about how you can be included in the OTEZLA Other medications that you take to treat your psoriasis, Pregnancy Registry. such as methotrexate, and biological therapies, such as TNF antagonists and anti-IL-12/23 p40 antibodies. What the medicinal ingredient is:
 The botanical medicine St. John's Wort. Page 26 of 28 IMPORTANT: PLEASE READ
PROPER USE OF THIS MEDICATION
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
Take OTEZLA exactly as your healthcare provider tells you to take it. OTEZLA should be taken by mouth and Symptom / effect
Talk with
swallowed whole, with or without food. The tablets should your doctor
not be crushed, split, or chewed. or pharmacist
In all seek
Usual adult dose:
immediate
The recommended dose is 30 mg twice a day. When you first start taking OTEZLA , the dose needs to be increased gradually; therefore, you must follow the instructions below. Dose titration schedule:
Overdose:
If you think you have taken too much OTEZLA , contact your doctor, nurse or pharmacist, hospital emergency department or regional Poison Control Centre This is not a complete list of side effects. For any
immediately, even if there are no symptoms. unexpected effects while taking OTEZLA , contact your
doctor or pharmacist.
Missed Dose:

HOW TO STORE IT
If you miss a dose of OTEZLA , take it as soon as you remember. If it is close to the time for your next dose, just Store OTEZLA at 15 to 30 °C. skip the missed dose. Take the next dose at your regular Keep OTEZLA tablets and all medicines out of the reach time. Do not double dose. and sight of children. SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Side effects may include: upper respiratory tract infection (e.g. common cold)  decreased appetite  abdominal discomfort, indigestion  fatigue, trouble sleeping If any of these affect you severely, tell your doctor, nurse
or pharmacist.
Page 27 of 28 IMPORTANT: PLEASE READ
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions
associated with the use of health products to the Canada
Vigilance Program by one of the following 3 ways:
--------------------------------------------------------------------------
 Report online at www.healthcanada.gc.ca/medeffect
 Call toll-free at 1-866-234-2345
 Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to 1-866-678-6789, or
- Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, Ontario
Postage paid labels, Canada Vigilance Reporting
Form and the adverse reaction reporting guidelines
are available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the
management of side effects, contact your health
professional. The Canada Vigilance Program does not
provide medical advice.


MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found at: or by contacting the sponsor, Celgene Inc., at: This leaflet was prepared by Celgene Inc. Last revised: November 12, 2014 Page 28 of 28

Source: https://www.otezla.com.au/content/uploads/sites/2/Otezla_Product_Monograph_English_Version.pdf