Otezla

Apremilast is used to treat psoriatic arthritis (a condition that causes joint pain and swelling and scales on the skin). Apremilast is in a class of medications called phosphodiesterase inhibitors. It works by blocking the action of certain natural substances in the body that cause inflammation.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

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.

Oral Administration

To reduce risk of GI symptoms associated with initial therapy, titrate to recommended dose (30 mg PO BID) according to the dosage schedules listed above

Can be administered without regard to meals

Swallow tablet whole; do not crush, split, or chew

Serious side effects have been reported with Otezla including the following:

• Depression. Tell your healthcare provider right away if you have some or all of the following symptoms of depression.
  • Worsening of depression
  • Suicidal thoughts
  • Mood changes
• Weight Decrease. Patients treated with Otezla should have their weight monitored regularly. Tell your healthcare provider right away if you have unexplained or significant weight loss. Your healthcare provider may have to discontinue Otezla.
• Drug Interactions
  • Medications that increase the activity of the enzyme CYP3A4 such as phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, are not recommended.

Do not take Otezla if you are allergic to Otezla or to any of this medication’s ingredients.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of apremilast in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of apremilast in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Carbamazepine
• Enzalutamide
• Fosphenytoin
• Mitotane
• Phenytoin
• Primidone
• Rifabutin
• Rifampin
• Rifapentine
• St John's Wort

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Depression, or history of or
• Mental illness, or history of—Use with caution. May make these conditions worse.

• Hypotension (low blood pressure) or
• Hypovolemia (low blood volume)—Use with caution. May cause side effects to become worse.

• Kidney disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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.

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)].

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.

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.

Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with Otezla.

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.

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).

Usual Adult Dose for Psoriatic Arthritis:

Initial dose:
-Day 1: 10 mg orally once a day (AM)
-Day 2: 10 mg orally twice a day (AM and PM)
-Day 3: 10 mg orally once a day (AM); 20 mg orally once a day (PM)
-Day 4: 20 mg orally twice a day (AM and PM)
-Day 5: 20 mg orally once a day (AM); 30 mg orally once a day (PM)

Maintenance dose: 30 mg orally twice a day (AM and PM)

Comments: This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have any of these signs of an allergic reaction to Otezla: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• unexplained weight loss, or if you lose a lot of weight;

• mood changes, new or worsening depression; or

• thoughts of suicide or hurting yourself.

Common Otezla side effects may include:

• nausea, diarrhea;

• headache; or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.