Otezla inhibits an enzyme called phosphodiesterase-4. This enzyme breaks down a chemical messenger in the body called cyclic adenosine monophosphate.
By inhibiting phosphodiesterase-4, less cyclic adenosine monophosphate gets broken down in the body. This increases cyclic adenosine monophosphate levels, especially in inflammatory cells where phosphodiesterase-4, is the dominant enzyme responsible for breaking down cyclic adenosine monophosphate.
An increase in cyclic adenosine monophosphate levels “turns down” (or down-regulates) a number of cellular signals called cytokines that increase inflammation, including Tumor Necrosis Factor Alpha, interleukin 17, interleukin 23, and others.
The increase in cyclic adenosine monophosphate levels also “turns up” (or up-regulates) the cellular signal interleukin 10 which can reduce inflammation.
It is not understood how exactly these changes produces the specific effects seen in patients that take Otezla. However, it is understood that this medication can improve psoriasis symptoms, and can reduce the joint pain and tenderness experienced by psoriatic arthritis patients.
- Otezla, Warts and All, Racks Up Sales and Eyes Blockbuster Status
- Otezla helps scalp, hand and feet psoriasis
- What is Apremilast (Otezla®)?
- How do I take it?
- What about side effects?
- What about other medications?
- What else should I know?
- 5 Things I Wish My Psoriatic Arthritis Patients Knew
- When Not to Use Biologics for Psoriasis
- How to avoid severe diarrhea from apremilast
- Efficacy appears to increase at least out to 1 year
- What Is Otezla (Apremilast)?
- How does Otezla (apremilast) work to treat psoriasis?
- Who can take Otezla (apremilast)?
- What are the possible side effects of taking Otezla (apremilast)?
- Can Otezla (apremilast) be used with other treatments or drugs?
Otezla, Warts and All, Racks Up Sales and Eyes Blockbuster Status
Otezla was approved by the FDA in 2014 as a treatment for plaque psoriasis and psoriatic arthritis. Right out of the starting gate it captured some attention for being the first new small-molecule drug for psoriasis in decades. Otezla—the generic name is apremilast—also exploited a new mechanism of action as the first inhibitor of phosphodiesterase 4 (PDE4) that results in increased expression of both anti-inflammatory proteins and reduced expression of their pro-inflammatory counterparts.
But despite the glow of the limelight and its uniqueness, Otezla found itself in a predicament.
Among some clinicians it came to be viewed as an expensive, plain-Jane drug that didn’t really produce any major gains in the clinical outcomes that mattered. This rather dim view was reflected in a study published last year in the Journal of the American Academy of Dermatology.
The study, funded by Abbvie, was an indirect comparison of two agents using results from existing studies for each drug. The results showed no statistically significant difference between Otezla and methotrexate in the Psoriasis Area and Severity Index 75 (PASI 75) score, a measure of the degree of skin plaque improvement in patients with 75 meaning 75% clearance. Lead investigator April Armstrong, MD, at the University of Southern California and her colleagues calculated that the annual incremental cost for Otezla to achieve one additional PASI 75 responder would be $187,888.
Otezla got better news from the Institute for Clinical and Economic Review (ICER) in Boston. ICER studied the value of Otezla relative to the increasing number biologics for plaque psoriasis, which include Humira (adalimumab), Enbrel (etanercept), and Remicade (infliximab) plus relative newcomers like Stelara (ustekizumab) and Cosentyx (secukinumab). ICER reported in November 2016 that the wholesale acquisition cost of a month’s supply of Otezla was $2,586 and that the net cost after discounts was $2,069. At those prices, the comparative effectiveness gurus determined that Otezla is cost effective within an acceptable quality-adjusted life year (QALY) range of between $100,000 and $150,000. And if the net cost of $2,069 per month is used, Otezla looked to be a relative bargain, coming in at a cost of less than $100,000 per QALY gained.
But doctors, other clinicians, and patients don’t typically have QALY calculators at their fingertips (although perhaps there can and should be an app for that).
Because Otezla’s price was set at about $2,600, many clinicians look at it in comparison to the biologic agents. And Otezla, despite having the nice sheen of a newcomer, does not match the performance of the biologics.
Moreover, a new cohort of biologics with potentially better performance was in the offing. Cosentyx arrived in 2015. Its phase 3 studies showed 70% of patients achieved clear skin (PASI 100) or almost clear skin (PASI 90) at the end of 16 weeks. The clinical trial for the newest biologic, Tremfya (guselkumab), has shown that 80% of patients achieved the PASI 100 or PASI 90 measures. In Otezla’s clinical trials, only 40%, 33%, and 29% of patients achieved the PASI 75 score. Taltz (ixekizumab) and Siliq (brodalumab) are the two other new biologics.
Tally marks in the plus column
Yet despite all of this competition, Otezla is solidly on track to achieve blockbuster status.Celgene’s recent financial report says Otezla’s worldwide sales increased to $358 million in the quarter ending June 30, 2017, up from $241 million the year before. Express Scripts’ 2016 drug trend reported a one-year 79% increase in utilization.
Celgene has been aggressively detailing the drug and offering assistance programs, and those efforts explain some of the growth. But experts say several other factors have come into play.
“Otezla’s growing popularity may be related to the diverse nature of treating and managing plaque psoriasis.”
For one thing, Otezla is considered to have a better safety profile than its old-school competitor, methotrexate, which requires lab monitoring for signs of liver damage. Experts also recommend taking folic acid with methotrexate to reduce the risk of other side effects such as upset stomach. Otezla does not require laboratory prescreening or ongoing monitoring. An added bonus is that Otezla has the potentially advantageous side effect of causing some weight loss.
Otezla also has a few advantages over the biologics. It doesn’t, for example, require testing for tuberculosis and other infections.
Otezla’s most common side effects are diarrhea, nausea, upper respiratory infection, and headache. Patients are at some risk for depression and suicidal thoughts, and reduced dosing is required in cases of kidney impairment.
Fewer on biologics than expected
Ultimately, though, Otezla’s growing popularity may be related to the diverse nature of treating and managing plaque psoriasis. The National Psoriasis Foundation says 50% of patients are not satisfied with their treatment. All the available treatments have their limitations when it comes to long-term efficacy, tolerability, safety, route of administration—and expense. Even if patients respond well to a particular medication, that response may taper off. Frequent changes in treatment are sometimes necessary.
For this and other reasons, the treatment guidelines for psoriasis are not a simple, step-by-step strategy of first do this, then do that, and so on, explains Andy Behm, an Express Scripts vice president. Treatment recommendations are flexibly tied to the severity of disease. Mild disease is treated with topical therapies such as corticosteroids, vitamin D analogues, or tazarotene alone or in combination with phototherapy. Moderate to severe disease usually requires use of systemic agents such as methotrexate, cyclosporine, acitretin or the biologics.
The variability in treatment strategies and the availability of many different products and medications along with the option of combination therapy can benefit dermatologists financially, and influence treatment choices.
This flexibility in the use of traditional treatments has an impact on the use of biologics. “If you read the drug trend reports or news sources, you get the impression everyone is on a biologic,” says Behm. “But that is not the case. Our data show a very small percentage of dermatologists dabble in biologics. They tend to be conservative with biologics.”
Michael Siegel, vice president at the National Psoriasis Foundation, says that “a lot of patients and providers are not comfortable with biologics. There is still a lot of interest in topicals and the full range of oral medications—and light therapy is developing as well.” He says an underlying reason for this interest is that providers want to have the option to change treatments and move to higher levels of therapy if their patients are not responding.
So Otezla may find a sweet spot because of the limited use of biologics along with flexible treatment strategies that allow for a lot of judgment about what’s best for the patient.
Otezla helps scalp, hand and feet psoriasis
The data presented at the meeting analyzed findings from the ESTEEM 2 trial, which was a Phase III, randomized placebo-controlled study of Otezla as a treatment for moderate-to-severe plaque psoriasis.
Patients with nail psoriasis enrolled in the trial experienced significantly greater improvement on Otezla than on the placebo, according to the findings. After four months, patients on Otezla experienced an average of 29 percent improvement in their nails, while the placebo group on average experienced 7.1 percent improvement.
At that point, patients who had begun the trial on placebo switched to Otezla. When measurements were taken four months later, the rates of improvement in both groups jumped. Patients who had switched to Otezla now showed 47.6 percent improvement on average, while patients who were on Otezla from the beginning showed an average of 60 percent improvement, the researchers report.
Improvement was evaluated using the Nail Psoriasis Severity Index (NAPSI), which measures symptoms such as nail pitting and discoloration. Eight months after the start of the trial, more than half of patients in both groups experienced a 50 percent improvement in their NAPSI score, also known as NAPSI-50.
Improvements in psoriasis on the palms of the hands and soles of the feet, called palmoplantar psoriasis, and on the scalp were measured using the Physician’s Global Assessment (PGA), which measures severity on a scale of zero to 10, with 10 being the most severe.
Patients with scalp psoriasis experienced significant improvement on Otezla compared to the placebo. After four months, 40.9 percent of patients on Otezla scored zero or one for their scalp PGA, which means that their scalp was clear or almost clear, according to the data. However, only 17.2 percent of patients on placebo achieved this score.
After eight months, 50.7 percent patients who switched to Otezla halfway through the trial achieved clear or almost clear skin. Among patients who stayed on the drug, researchers report that 32.4 percent achieved clear or almost clear skin.
This lower percentage among patients who stayed on the drug could be due to a number of factors, including the possibility that some patients may not have taken the drug consistently, or that the drug could have become less effective in some patients, according to Dr. Jeffrey Crowley of the Bakersfield Dermatology and Skin Cancer Medical Group, the lead author of the study. Crowley is a member of the National Psoriasis Foundation Medical Board.
For patients with palmoplantar psoriasis, Otezla was again significantly more effective than a placebo, according to researchers. After four months, almost two-thirds of patients on Otezla achieved clear or almost clear skin, while less than a third of patients on placebo did. After eight months, 69.2 percent of patients who switched to Otezla achieved clear or almost clear skin. For patients who stayed on the drug, 53.8 percent achieved clear or almost clear skin, the researchers report.
Side effects for patients on Otezla and patients taking the placebo were similar, according to researchers, and, during the first four months of the study, occurred more often in patients taking the placebo. The most common side effects included nausea, diarrhea and the common cold.
What is Apremilast (Otezla®)?
Otezla is a pill that may help people with plaque psoriasis or active psoriatic arthritis (PsA). It may improve certain conditions of these diseases, such as joint pain, stiffness, swelling and skin plaques.
How do I take it?
When you first start Otezla, your doctor will give you a 14-day Starter Pack. All of the instructions are printed on the pack. During the first 5 days you gradually increase your dose until you reach the 30 mg twice a day. People with severe kidney disease will follow a different schedule for increasing their dose. Be sure to take Otezla exactly as directed by your doctor.
By starting slowly, people have less trouble with any nausea and diarrhea.
Otezla can be taken with or without food. Do not crush, chew or split the pill.
What about side effects?
Some patients taking Otezla reported depression. Before you start Otezla, tell your doctor if you have had feelings of overwhelming sadness, thoughts or behaviors like wanting to killing yourself or, or other mood changes. After starting Otezla, tell your doctor if any of these symptoms develop or worsen.
The most common side effects of Otezla were diarrhea, headache, and nausea. Side effects usually occur within the first 2 weeks of treatment, and get better as you continue to take it. You may use over-the-counter medication such as immodium to treat diarrhea, or Tylenol® to treat headaches.
Tell your doctor about any side effect that bothers you or does not go away.
What about other medications?
You should not take certain medicines when you are taking Otezla as they may decrease its effectiveness. Tell your doctor if you are taking any other medication. This include prescription and non-prescription medicines as well as vitamins and herbal supplements.
What else should I know?
You must continue your regular visits to the rheumatologist. Your doctor will monitor you for any improvements in your disease or adverse effects of your medication.
A Federal Drug Administration approved medication guide can be found at:
- Whether your PsA has limited your mobility (such as how you are able to use your hands or your ability to walk)
- How often you feel pain or swelling in your fingers, knees, feet, or other joints
- If PsA keeps you from doing daily activities such as driving a car, brushing your teeth, or combing your hair
- Over time, will my psoriatic arthritis get worse?
- What are the different options available to manage my PsA?
- Are these options appropriate for me?
- What are the side effects of the medication you’ve prescribed?
- What should I do if I experience any side effects?
- How does the medication you’ve prescribed for me work?
- How long do I need to be on my management plan before I see results?
- In addition to medication, what else can I do to help manage my PsA?
- Keep your medication someplace you can see it so that you remember to take it.
- Connect taking your medication to something you do each day so it becomes part of your routine, such as after you brush your teeth.
- Download an app to your Smart Phone. Recently, Celgene launched GOtezla, a free app for patients available on Google Play and the Apple App Store. GOtezla provides patient-specific support during medication initiation as well as patient-friendly tools like a symptom tracker and medication reminders.
- headache, including tension headache
- upper respiratory tract infection
- oral birth control
- ketoconazole, an antifungal medicine
It is very important to let your healthcare provider know about any and all prescription medicines, over-the-counter medicines, vitamins or supplements that you are taking monitor for any drug interactions.
5 Things I Wish My Psoriatic Arthritis Patients Knew
(BPT) – By Dr. Joseph Markenson, Rheumatologist at Hospital for Special Surgery
When it comes to managing your psoriatic arthritis (PsA), a doctor-patient relationship is key. The two of you are a team. I wanted to share some valuable tips that will help you make the most of your time with your physician and help ensure you are receiving optimal care.
1. SPEAK UP
It is important that you feel comfortable talking to your doctor how to manage the symptoms of your PsA, and asking him/her any questions and concerns you might have. Here are some things you may wish to discuss during our visits:
Remember, each person is different. A treatment plan that may work for someone else may not work for you. You know yourself best; only you are able to feel if and when your symptoms are getting better. The more information you share with your physician, the better he/she can help you – so don’t be afraid to speak up.
2. ASK QUESTIONS ABOUT YOUR MANAGEMENT PLAN
Living with PsA can be challenging. For those with PsA whose condition has been accurately diagnosed, the symptoms of PsA can be managed under the advice of your doctor. Prescription medicines offer one such treatment option. Therefore, it’s important that you understand everything about the condition and your options for managing your PsA. Below are examples of questions that you may wish to discuss with your doctor:
If you have concerns or are unsure about anything – ask questions! With several prescription medications available for treating PsA, together, you and your physician can determine a management plan that works for you.
3. MAKE OUR TIME COUNT
During your visit, you and your doctor should discuss your symptoms; you should feel comfortable to ask any questions you might have. To make the most out of our time, it may be beneficial to think about what you’d like to cover ahead time. One of the ways not to forget the things you’d like to discuss is to write them down. There are a number of resources available to help you through that process. For example, Otezla, a prescription medicine also known as apremilast is approved for the treatment of adult patients with active PsA. On Otezla.com, you can download the Doctor Discussion Guide, which you can take with you to our appointment. This guide can help you remember to ask these questions to your doctor during your visit.
People who are allergic to any of its components should not take Otezla. Otezla is associated with serious side effects like depression, weight decrease, and interacting with other medicines that can make Otezla less effective. Common side effects of Otezla are diarrhea, nausea, and headache. Please see Approved Use and Important Safety Information for Otezla below.
4. STAY ON TRACK
A report by the Mayo Clinic found “approximately 50% of patients do not take their medications as prescribed.” It can be hard to remember to take your medication every day, but it’s important to take your medication as prescribed and not just when you feel symptoms. Otherwise, you aren’t giving the medication the best chance to work. Here are a few ways to help you remember to take your medication:
5. WE’RE IN THIS TOGETHER
We’re a team – so let’s work together! Help your physician help you by telling him/her when your symptoms are getting better, when they’re not improving, or when they’re getting worse. Don’t hesitate to share how you’re feeling or to ask about a medication you’re interested in trying. We’re in this together.
APPROVED USE OF OTEZLA
Otezla® (apremilast) is a prescription medicine approved for the treatment of adult patients with active psoriatic arthritis.
IMPORTANT SAFETY INFORMATION
You must not take Otezla® (apremilast) if you are allergic to apremilast or to any of the ingredients in Otezla.
Otezla is associated with an increase in adverse reactions of depression. In clinical studies, some patients reported depression, suicidal thoughts, and suicidal behavior while taking Otezla. Some patients stopped taking Otezla due to depression. Before starting Otezla, tell your doctor if you have had feelings of depression, suicidal thoughts, or suicidal behavior. Be sure to tell your doctor if any of these symptoms or other mood changes develop or worsen during treatment with Otezla.
Some patients taking Otezla lost body weight. Your doctor should monitor your weight regularly. If unexplained or significant weight loss occurs, your doctor will decide if you should continue taking Otezla.
Some medicines may make Otezla less effective, and should not be taken with Otezla. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines.
Side effects of Otezla were diarrhea, headache, and nausea.
These are not all the possible side effects with Otezla. Ask your doctor about other potential side effects. Tell your doctor about any side effect that bothers you or does not go away.
Tell your doctor if you are pregnant, planning to become pregnant, or planning to breastfeed. Otezla has not been studied in pregnant women or in women who are breastfeeding.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-332-1088.
Please click here for Full Prescribing Information
© 2016 Celgene Corporation 04/16 USII-APR160045
When Not to Use Biologics for Psoriasis
Reasons for considering alternatives to biological therapy vary from valid clinical issues to demographic considerations to personal preferences and idiosyncrasies. At one time, patients’ aversion to needles made adherence to injectable therapies problematic, although that issue has subsided, Russell Cohen, MD, of Mount Sinai Health System in New York City, said during a forum on biologic therapy at the American Academy of Dermatology meeting.
In contrast, direct-to-consumer advertising has emerged as a major influence on patients’ perceptions about therapies, contributing to opposition to biologic therapy that lacks a scientific base but nonetheless makes sense to the patient.
More often, individual patient and disease characteristics influence treatment decisions. As many as 30% of patients with psoriasis develop psoriatic arthritis, and the condition becomes severe in up to 30% of cases. For those patients, methotrexate remains widely used, either as initial therapy or in combination with a biologic or other systemic therapy. The drug decreases inflammation but does not prevent x-ray progression of arthritis, said Cohen. Cyclosporine can be helpful when used with methotrexate or etanercept (Enbrel). Acitretin (Soriatane) has moderate efficacy in combination therapy.
Apremilast (Otezla) has two advantages — an oral medication that has two indications: patients with moderate-severe psoriasis who are candidates for phototherapy or systemic medication and adults with psoriatic arthritis. The drug works after failure of biologic therapy and has particular efficacy for scalp and nail psoriasis, said Cohen.
“No long-term safety issues after 3 years of follow-up, no routine labs for safety monitoring — patients love that,” he said.
Tofacitinib (Xeljanz) has an indication for adults with psoriatic arthritis (after failure of disease-modifying drugs), but no approved indication for psoriasis. Clinical trials of the drug focused on improvement in arthritis status (American College of Rheumatology criteria) but some studies also documented improvement in the Psoriasis Area and Severity Index, said Cohen. Tofacitinib cannot be used in combination with another immunosuppressant.
For patients with psoriasis complicated by inflammatory bowel disease, apremilast has been used, with no reports of adverse effects on psoriasis control. Methotrexate outperformed placebo in randomized trials. Cyclosporine has been shown to induce remissions in refractory Crohn’s disease.
Patients with psoriasis have an increased risk of lymphoma, but little data have accumulated to provide guidance about solid tumors, said Cohen. The general rule is not to use biologic agents, particularly if a patient is less than 5 years out from diagnosis. Methotrexate is a good option, as is cyclosporine, at least in the short term. However, long-term use in transplant patients has been associated with an increased risk of malignancy.
Acitretin probably is the best option for patients with psoriasis and a history of malignancy, Cohen continued, as the drug was shown to prevent or delay progression of nonmelanoma skin cancer in transplant patients. Apremilast has limited data to support its use in patients with malignancy, but no safety signals have emerged.
With respect to infections, acute episodes should be treated first, then the psoriasis, said Cohen. For patients with chronic infection, methotrexate, apremilast, and acitretin are options, but not cyclosporine because of its immunosuppressive properties. Methotrexate is contraindicated for patients with hepatitis B or C. Cyclosporine should not be used by a patient with hepatitis B, but data regarding hepatitis C are mixed. No data have emerged for apremilast and hepatitis, but it “should be OK.” Acitretin also should be acceptable but requires monitoring with liver function tests.
Patients with a history of tuberculosis should be screened before, during, and after treatment, said Cohen. Apremilast and acitretin are safe to use, and methotrexate and cyclosporine can be used only after patients have received TB prophylaxis.
Obese patients “love” apremilast because they often lose weight, as much as 10-15% in some cases, Cohen said. Cyclosporine and acitretin are riskier, and methotrexate should be avoided because of a risk of fatty liver disease.
Studies have shown that older patients on biologic therapy have low adherence rates and high discontinuation rates, reaching 50% during the first 12 months of therapy. At the opposite end of the age spectrum, pediatric patients have fewer approved options. Methotrexate, cyclosporine, and acitretin are not approved for use in pediatric patients but are nonetheless considered safe, said Cohen. Phototherapy is a good option because of its safety. Apremilast is not approved for use in pediatric populations, but “probably is safe.”
“There are so many options today, what are you going to do?” Cohen said in conclusion. “Talk to your patients; let them know what’s available. Consider comorbidities, and look at the different patient populations. Talk to your patients about the cost, because it’s a lot of money to spend.”
When he started clinical practice, hydroxyurea was a mainstay of treatment for psoriasis, he said, explaining that methotrexate and cyclosporine were his personal favorites for years. With the advent of biologic therapy, “sometimes we need to step back and pause,” he said. “There are still a lot of great drugs that you should be using.”
Cohen disclosed relationships with AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharmaceuticals, and UCB.
American Academy of Dermatology
Source Reference: Cohen R “So many biologics, so little time: How to pick your poison in an era of biologic overload. When not to use biologics” AAD 2019; Forum F042.
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 of similar design in adult patients with active psoriatic arthritis . 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 . 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)
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 . 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)
Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.
Read the entire FDA prescribing information for Otezla (Apremilast Tablets)
How to avoid severe diarrhea from apremilast
KAUAI, HAWAII – Physicians have become much more cognizant of severe diarrhea and nausea as potential side effects of apremilast since the Food and Drug Administration–approved change in the warnings and precautions section of the drug’s labeling in June 2017. Jashin J. Wu, MD, director of the psoriasis clinic at Kaiser Permanente Los Angeles Medical Center, has a tip for avoiding these problems: Delay up-titrating.
Dr. Jashin J. Wu
During the first 5 days patients are on apremilast (Otezla), they are supposed to titrate up from 10 mg/day to 50 mg on day 5 before starting full-dose therapy at 30 mg twice daily on day 6.
“In my opinion, that may be too quick of an up-titration. I tell patients that, if they feel the GI issues are still a problem for them on day 6, they should take 30 mg just once a day for the first 1-2 months. After that we’ll see how they’re doing, and if they feel they can make the jump to twice a day, then they can go for it. Of course, I also tell them that maybe their psoriasis will not clear as well as if they’d been on apremilast twice a day right from day 6, but if they’re able to tolerate it and can continue to take it, they can improve while they’re on it,” the dermatologist said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Dr. Wu presented an update on recent developments regarding the newest oral drugs for psoriasis and one of the oldest: apremilast and methotrexate, respectively.
The revised warning label highlighting the risks of severe diarrhea and nausea associated with the oral phosphodiesterase-4 inhibitor says that most such events have occurred within the first few weeks of therapy. The guidance also notes that patients who reduced the dosage or discontinued treatment outright generally improved rapidly.
“I see this in a lot of my patients. They have to go to the bathroom pretty often. It’s actually unusual for me for a patient not to have any GI issues at all,” according to Dr. Wu.
He shared a number of other fresh insights into apremilast’s safety and efficacy derived from recent studies.
Efficacy appears to increase at least out to 1 year
A report from the phase 3b, randomized, placebo-controlled, 250-patient LIBERATE trial showed that the week 16 PASI 75 response rate was 39.8% with apremilast, 48.2% with etanercept (Enbrel), and 11.9% with placebo. After week 16, everyone switched to apremilast. The PASI 75 rate in patients on apremilast all along climbed from 39.8% at week 16 to 52.7% at week 52. That result was in the same ballpark as the 57% rate in those switched from etanercept to apremilast and the 53.4% PASI 75 rate at week 52 in patients switched from placebo to apremilast (J Eur Acad Dermatol Venereol. 2017 Mar;31:507-17).
“It was interesting to see that, as the study continued on for 1 year, the PASI 75 rate continued to improve. That’s worth noting: In general, I tell patients you have to be on a drug for about 3 months before we’re going to say if it worked or not, and that’s true even with drugs for other conditions, like doxycycline for acne. But this study seems to indicate that you have much better improvement at the 1-year point, and that’s not so much true for the biologics,” the dermatologist observed.
Safety to 3 years looks reassuringly good: 3-year follow-up of the 1,184-patient, phase 3, randomized, controlled ESTEEM 1 and 2 trials provided by far the longest look to date at apremilast’s safety. There were no surprises, no serious opportunistic infections, and no significant changes in laboratory values (J Am Acad Dermatol. 2017 Aug;77:310-17.e1).
Of note, 21.9% of patients on apremilast lost more than 5% of their baseline body weight. Most of the weight loss occurred during year 1 of treatment and mostly in patients with a higher baseline body mass index.“It seems like apremilast is definitely a good option if patients can tolerate the GI upset,” Dr. Wu said.
Apremilast can safely and effectively be combined with other psoriasis therapies: Dermatologists at the University of Toronto reported on a retrospective analysis of 81 biologic-naive psoriasis patients treated with apremilast in combination with methotrexate, acitretin (Soriatane), cyclosporine, narrowband UVB, etanercept, infliximab (Remicade), adalimumab (Humira), and/or ustekinumab (Stelara). Of these patients, 81% achieved a PASI 75 response at week 12 (J Cutan Med Surg. 2016 Jul;20:313-6).
“That’s pretty good. It’s certainly better than apremilast by itself. So if you can get the payer to cover a combination of apremilast and something else, it may help get to PASI 75,” Dr. Wu noted.
Session chair Craig L. Leonardi, MD, said he hasn’t had any luck in going that route.
“The insurance industry just won’t give me apremilast in combination with a biologic drug. Even though it makes complete sense to use it in place of methotrexate with a biologic, I just can’t get it,” according to Dr. Leonardi, a dermatologist at Saint Louis University.“I don’t have those limitations at Kaiser,” according to Dr. Wu. “I personally have only used apremilast and methotrexate and apremilast and acitretin in combination. I just want to be kind to Kaiser and not give two branded medications to a patient, but I certainly think it’s a feasible option.”
A simple response prediction rule: Kenneth B. Gordon, MD, professor and chair of dermatology at the Medical College of Wisconsin in Milwaukee, and his coinvestigators at AbbVie developed a methotrexate response/nonresponse prediction rule using data on 110 participants in the phase 3 CHAMPION trial. Then they validated the rule in the phase 3 M10-255 trial. They found that a PASI 25 response to methotrexate at week 4 was associated with an 8.9-fold increased likelihood of a week-16 PASI 75 response. Patients with a predicted response probability of less than 30% were asked to discontinue the drug; their week 16 PASI 75 rate was only 21.1%, compared with a 65.8% response rate in patients with a prediction rating (J Am Acad Dermatol. 2017 Dec;77:1030-7).
“Four weeks of methotrexate may be sufficient to determine the long-term response. It may not be necessary to put them on the drug for 3 months,” Dr. Wu commented.
Subcutaneous methotrexate: European investigators demonstrated that an intensified dosing schedule of subcutaneous methotrexate was safe and effective for treatment of moderate to severe plaque psoriasis in the 52-week, phase 3, randomized, 16-center, double-blind, 120-patient, placebo-controlled METOP study.The intensified subcutaneous regimen consisted of 17.5 mg/week initially, escalated to 22.5 mg/week after 8 weeks if a patient hadn’t achieved at least a PASI 50 response at that point. The primary outcome, the PASI 75 response at week 16, was 41% in the subcutaneous methotrexate group and 10% in controls, with a maximum PASI 75 rate of 51% seen beginning at week 24. The week 4 and 8 PASI 50 rates were 50% and 58%, respectively, with methotrexate versus 3% and 17% in placebo-treated controls. The subcutaneous regimen was generally well tolerated, with no serious infections or malignancies arising during 52 weeks (Lancet. 2017 Feb 4;389:528-37).
Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.
The Global Academy for Medical Education/SDEF and this news organization are owned by the same parent company.
What Is Otezla (Apremilast)?
Otezla is the brand name for an oral medication used to treat both plaque psoriasis and active psoriatic arthritis. The active ingredient in Otezla is apremilast. It is a relatively new treatment option that was approved by the US Food and Drug Administration in 2014.
Otezla is approved for treating patients with moderate or severe plaque psoriasis who are candidates for a systemic medication or light therapy1.
Otezla is taken by mouth twice daily in the form of a tablet. The dose of the drug prescribed by your healthcare provider is gradually increased over the first 5 days of treatment until the recommended dose of 30 mg per day is reached. The gradual increase in dose is done in order to reduce possible gastrointestinal side-effects. The drug is meant to be taken as a maintenance treatment, which means it is taken every day to help control symptoms2. You can take Otezla with or without eating, but you should not crush, split, or chew the tablets.
How does Otezla (apremilast) work to treat psoriasis?
Psoriasis is a chronic autoimmune condition in which a person’s immune system is overactive and produces too much inflammation in the body. This inflammation triggers the production of an excessive amount of new skin cells that are created more quickly than older skin cells can die and be shed naturally. The skin cells build up and cause plaques to form on the surface of the skin.
Otzela (apremilast) works differently than other types of oral systemic medicines for psoriasis, which affect the entire immune system. Instead, Otezla works by specifically targeting only certain molecules within immune system cells that are involved in causing inflammation, an enzyme called phosphodiesterase 4 (PDE4). By affecting the inflammatory processes within cells, Otezla can reduce the activity in the immune system that causes chronic inflammation and the formation of plaques, and thus reduce flaking and scaling of skin1.
Clinical studies were carried out to test the effectiveness of Otezla. After 4 months, around 1 in 3 patients who were treated with the medicine had a 75% reduction in symptoms such as redness, thickening, and scaliness2.
Who can take Otezla (apremilast)?
Otezla (apremilast) is approved for treating adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic medication.1 It is also approved for adult patients with active psoriatic arthritis.
Otezla is not currently approved for patients under 18 years of age. People who have kidney disease may need to take a lower dose of Otezla. People who are allergic to the active ingredient, apremilast, or any other ingredients in Otezla should not take the medicine2. Otezla has not been studied in pregnant women, or in women who are breastfeeding. Tell your doctor if you are pregnant, planning to become pregnant, or planning to breastfeed.
What are the possible side effects of taking Otezla (apremilast)?
In the clinical studies that tested Otezla for psoriasis, the most common side effects that patients reported were:
These side effects were more common during the first two weeks of treatment and then tended to go away over time as patients continue to take their medication. When you first start taking Otezla, your healthcare provider may advise you to gradually increase your dose over a 5 day period in order to minimize any gastrointestinal symptoms you may experience from starting a new medication.
About 12% of the patients with psoriasis treated with Otezla experienced weight loss of between 5%-10% of their body weight during treatment. Healthcare providers should monitor patients during treatment to make sure that they maintain a healthy body weight2.
A small number (1.3%) of patients in the clinical studies who were treated with Otezla experienced depression. Patients and their caregivers should be aware of this risk and watch out for signs of depression or mood changes, and contact a healthcare provider if any of those signs of symptoms develop. Patients with a history of depression may choose to avoid treatment with Otezla. This is not an exhaustive list of side effects experienced by those taking Otezla.
Can Otezla (apremilast) be used with other treatments or drugs?
The studies demonstrated that Otezla is generally safe for use at the same time as1:
In clinical trials for Otezla, people with psoriasis were allowed to continue taking low-potency topical corticosteroids, and people with scalp psoriasis were allowed to continue to use coal tar shampoo and/or salicylic acid preparations2. Safety concerns were not reported with the use of these other medications in combination with Otezla.
Otezla may not be as effective if it is used at the same time as cytochromeP450 enzyme inducer medicines2, including: