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Apremilast - Uses, Side Effects, Risk Factors and Restrictions

Published on Apr 23, 2022 and last reviewed on Jul 13, 2022   -  20 min read

Abstract

Apremilast is an immunosuppressant drug indicated for inflammatory disorders like psoriasis. Read the article below for more information.

Contents

Overview:

Apremilast is an oral phosphodiesterase-4 (PDE-4) inhibitor, initially manufactured by Celgene Corporation. Amgen Incorporated acquired it in November 2019.

The drug is indicated for the following disorders in adults:

Apremilast suppresses the immune system and reduces inflammation. It belongs in the DMARDs (disease-modifying antirheumatic drugs) group of drugs. Although not strictly indicated for rheumatoid arthritis (like most other DMARDs drugs), Apremilast is used in psoriatic arthritis treatment. It may be used alone or in combination with biologic agents in patients who do not show sufficient changes in response to the biologic agents alone.

Apremilast was approved for psoriatic arthritis and plaque psoriasis by the U.S. Food and Drug Administration (FDA) in March 2014 and the European Medicines Agency (EMA) in November 2014. FDA approval of Apremilast for oral ulcers in Behçet's disease was obtained in July 2019. The drug has also been approved for use in Behçet's disease (with modifications) in the pediatric population.

The FDA approved a low-cost generic version of Apremilast in 2021, but it is not available in U.S. markets as yet. However, other low-cost generic options have been developed and marketed in countries like India and Bangladesh.

How Does Apremilast Work?

The exact mechanism of action of Apremilast is unclear and incompletely established.

However, it is known that PDE4 influences the cytokine mediators involved in causing disorders like psoriatic arthritis. PDE4 acts as a mediator for cyclic adenosine monophosphate (cAMP) activity. cAMP is a second messenger responsible for regulating inflammatory mediators. When PDE4 inhibits its action, it can result in the dysregulation of the inflammatory mediators responsible for psoriatic arthritis and plaque psoriasis.

Apremilast is a PDE4 inhibitor - inhibition of PDE4 results in increased intracellular cAMP levels, which in turn suppresses TNF-α, IL-17, and other inflammatory mediators responsible for psoriatic diseases and Behçet's disease. Figure 1 displays a simplified illustration of Apremilast's mechanism of action.

Does Apremilast Work

PDE-4:Phosphodiesterase inhibitor-4 is an enzyme present in the immune cells, brain cells, and epithelial cells that regulates inflammatory functions in the body. Inhibition of PDE-4 through several targeted drugs suppresses its overactivity in inflammatory cells, thereby offering treatment for inflammatory conditions.

cAMP:cAMP is a second messenger responsible for regulating inflammatory mediators. It suppresses inflammatory mediator activity.

TNF- α:Tumor necrosis factor - α is an inflammatory cytokine produced during acute inflammation and can lead to cell damage and death.

IL: Interleukins are a group of proteins that regulate immune responses. The interleukins commonly associated with psoriatic conditions include:

Uses Of Apremilast

Psoriatic Arthritis: Adult patients who have displayed intolerance to other DMARDs or have shown insignificant responses to these drugs can be prescribed Apremilast alone or in combination with other DMARDs.

Plaque Psoriasis:Adult patients with moderate to severe plaque psoriasis (chronic) who display intolerance to other therapies, including Methotrexate and Cyclosporin, may be prescribed Apremilast, provided they are also eligible to undergo systemic therapy or phototherapy.

Mouth Ulcers in Behçet’s Disease:Apremilast is also indicated for mouth ulcers in adult patients with Behçet’s disease, who may receive systemic therapy.

Dosage Restrictions

Route of Administration: Oral.

Dosage Form: Diamond-shaped, film-coated tablets.

Available Strengths:

The recommended dosage of Apremilast for psoriatic conditions and Behçet’s disease are titrated with gastrointestinal concerns in mind. The initial dosage titration covers the first five days and begins at 10 mg, followed by 20 mg. From Day 6, the recommended maintenance dosage is 30 mg twice daily.

Dosage Restrictions

Special Considerations

Dosage Adjustment:

Drug Safety Concerns:

Pediatric Population:While contraindicated in children between 0 years - 17 years of age (owing to a lack of information), Phase II studies have indicated that weight-based dosing of Apremilast can achieve good results, and safety is consistent with that of the expected safety profile in adults. However, these studies require further exploration. Apremilast is contraindicated in children until concrete results are obtained from other large-scale studies.

Warnings and Contraindications

Contraindications:Apremilast is contraindicated in patients who display hypersensitivity to the drug.

Warnings and Precautions: The effects of Apremilast that need to be considered include:

For Patients:

What Is Psoriasis?

Psoriasis is a long-term skin disease that is mediated by your immune system. The condition causes your skin cells to grow at least ten times faster than is usual - and build up as a result. This build-up of skin cells then appears in the form of red, itchy, and scaly patches on the scalp, trunk, elbows, and knees. Occasionally, the nails and joints may also be affected.

What Is Psoriatic Arthritis?

Psoriatic arthritis is an inflammatory condition that affects your large joints. Arthritis itself refers to the swelling and tenderness of joints, leading to stiffness. Psoriatic arthritis usually occurs in those patients who have previously been diagnosed with psoriasis. That is to say, psoriatic arthritis primarily affects people who have psoriasis. However, it has also been reported in patients whose family members are affected with psoriasis.

How Does Psoriatic Arthritis Affect the Body?

Psoriatic arthritis is a lifelong disease, occasionally punctuated with periods of remission. However, the condition worsens with time.

The features of psoriatic arthritis are characterized by the way it affects the joints of your body. It causes painful swelling of the joints and often mimics rheumatoid arthritis in terms of the symptoms displayed.

The signs and symptoms of psoriatic arthritis include:

  1. Swelling: Psoriatic arthritis can cause the fingers and toes to swell painfully - giving them a sausage-like appearance. The condition is termed dactylitis.

  2. Pain: Given its effects on joints and tendons, psoriatic arthritis can cause severe pain in the foot (where tendons and ligaments are attached to the bones). It can also cause pain in the lower back region due to inflammation of the joints in your spine and pelvis.

  3. Inflammation: Apart from inflamed joints, psoriatic arthritis can also cause an inflammatory eye condition called uveitis, which can result in pain and blurry vision and cause vision loss in extreme untreated cases.

  4. Nail Changes: The nails may display pitting or may be separated from the nail beds.

  5. Arthritis Mutilans: A rare and severe form of psoriatic arthritis called arthritis mutilans may develop in some people. Arthritis mutilans is extremely painful and eventually disables the sufferer by destroying the small bones in the hands. The fingers are particularly affected and become permanently deformed.

How Is Psoriatic Arthritis Treated?

Psoriatic arthritis cannot be cured entirely. Treatment is directed at inflammation control and prevention of disability.

What Is Plaque Psoriasis?

The commonest form of psoriasis, plaque psoriasis, presents as rough, itchy, thick red patches with silvery-white scales. Although patches may also occur in other body parts, the elbows, knees, and scalp are commonly affected.

Why Is Apremilast Prescribed For Plaque Psoriasis?

Apremilast is a potent medication that reduces the redness, scaliness, and thickness of your psoriatic patches. It may be prescribed when other drugs for psoriasis fail to provide relief from the symptoms.

What Is Behcet’s Disease?

Behçet's disease or Behçet's syndrome is an inflammatory disorder of the blood vessels in your body that can cause a variety of apparently unrelated signs and symptoms. These may include:

Why Take Apremilast For Behcet’s Disease?

Apremilast is recommended as a treatment option for mouth sores in Behçet's disease.

The recommended treatment options for Behçet's disease include Colchicine and other immune-modulating drugs like DMARDs. However, these treatment lines are not always practical. Apremilast can modulate the inflammatory mediators that cause inflammation in Behçet's disease and effectively control mouth ulcers and sores. It may be used in case of failure of other treatment options.

Facts One Should Know About Apremilast

Apremilast usually comes in tablet form and is generally taken twice daily. Your doctor will start with a lower dose and gradually increase the dose over the week. It can be taken even without meals.

How Should You Take Apremilast?

What Should You Discuss With Your Doctor Before Beginning Apremilast Therapy?

Your doctor must be made aware of your medical history and relevant personal details that can impact how Apremilast affects your body.

These details may include:

  1. Drug History: Your doctor will need a complete and accurate list of all the medication you may be taking in order to determine if drug interactions may occur and cause reactions or reduce the effectiveness of Apremilast. This should also include non-prescription medications, herbal and non-allopathic medications, vitamins, and nutritional supplements.

  2. Allergic History: This is particularly relevant in the case of drug allergies. If you are aware of being allergic to Apremilast or any other medications, make sure your doctor is equally aware.

  3. Medical History: All medical conditions you may be suffering from need to be mentioned to your doctor. This includes your psychological history - particularly depression.

  4. Pregnancy and Breastfeeding: If you are pregnant or breastfeeding or planning for the possibility of either, you need to ensure your doctor knows about it so that they can prescribe accordingly.

  5. Weight Considerations: Apremilast has been known to cause weight loss. Discuss this possibility with your doctor and keep an eye on your weight. Arrange to contact your doctor if you notice an unexplained weight loss of over 10 % body weight.

Is Apremilast Safe?

The side effects associated with Apremilast have generally been mild. Patients who terminate their medication usually do so if they develop severe nausea, headache, or diarrhea. Patients who experience depressive episodes or suicidal thoughts and behavior may also be advised to terminate the medication if their life is at risk.

Is Apremilast Effective?

Clinical trials on the effectiveness of Apremilast have shown promising results:

What Side Effects Can You Expect With Apremilast?

Clinical trials have shown that Apremilast may commonly cause the following side effects:

Can You Stop Taking Apremilast Without Your Doctor's Say-So and What Happens if You Do?

It is not advisable to stop taking Apremilast without consulting your doctor first. If you are experiencing severe side effects that are difficult to handle, tell the dermatologist about it, and they will either reduce the dosage or prescribe an alternative. Patients who have stopped taking Apremilast have experienced a reversal of its therapeutic effects within five weeks of quitting.

Is Your Age a Factor to Consider When Taking Apremilast?

Evidence from clinical trials differs on this point. While some suggest that there are no differences whatsoever between older and younger patients in terms of their reaction to Apremilast, other studies have noted that people over 65 may show increased incidence and severity of side effects. It is best to consult your doctor and find a solution best suited to your age and medical history.

What Are the Long-term Effects of Taking Apremilast?

There is not much data available on the long-term effects of Apremilast since most clinical trials have been conducted for only as long as a year. Further studies are required to resolve this question.

Are There Any Dietary Restrictions to Consider When Taking Apremilast?

There are no dietary restrictions as such, but you may consult your doctor for advice that may be specific to your nutritional needs or concurrent illnesses.

How Should You Store and Dispose Apremilast?

What Can You Do If You Suffer From These Disorders?

There are some things that you can do apart from taking your medication to improve the quality of your life with psoriatic conditions or Behçet's disease:

  1. Exercise: Your joints and muscles suffer the most damage with these conditions. Regular, low-stress exercise forms can make a difference and improve your flexibility and mobility. Some forms of exercise that you can try are swimming, tai chi, and yoga.

  2. Weight Maintenance: Try to keep excess weight off as it places less stress on your joints and improves the effectiveness of your medication.

  3. Give Your Joints a Break: When lifting weights or performing activities that may place some stress on your joints, try to use the whole body to perform these tasks rather than just the joints and muscles of the hand.

  4. Limit or Avoid Substance Use: Smoking can increase your chances of developing psoriasis and greater severity of symptoms, while alcohol can diminish the effectiveness of your treatment. Keep your consumption of alcohol limited or avoid it altogether, and work towards giving up smoking to prevent worsening symptoms of psoriasis.

  5. Rest: Living with a painful chronic inflammatory disorder can make it hard to work or perform regular daily activities and exercise. Be sure to take adequate rest and not tire yourself out with too many activities.

  6. Physical and Occupational Therapy: Physical and occupational therapy may relieve pain and stress to some degree.

  7. Massage Therapy: It is also possible to obtain some relief from massage therapy.

What Can You Do in Case of Overdose?

What Else Should You Keep in Mind?

For Doctors:

Indications:

Psoriatic Arthritis: Apremilast may be prescribed alone or in combination with Disease-Modifying Antirheumatic Drugs (DMARDs) in adult patients who have displayed intolerance or inadequate response to previous treatment with DMARD.

Psoriasis: Adult patients with moderate to severe chronic plaque psoriasis who have displayed intolerance or inadequate response to treatment with drugs such as Cyclosporin, Methotrexate, or Ultraviolet-A light (PUVA).

Behçet's Disease: Apremilast is used to treat adult patients with mouth ulcers associated with Behçet's disease - particularly if previous treatment with immunomodulatory drugs and Colchicine has failed to show adequate response.

Pharmacology

1. Components

Tablet Core: Cellulose, microcrystalline Lactose, monohydrate Croscarmellose, Sodium, Magnesium stearate.

Film-Coating: Poly (vinyl alcohol), Titanium dioxide (E171), Macrogol (3350), Talc, Iron oxide red (E172).

Other:

20 mg tablet: Iron oxide yellow (E172).

30 mg tablet: Iron oxide yellow (E172) and iron oxide black (E172).

2. Mechanism of Action

Clinical Pharmacology

Apremilast is an inhibitor of phosphodiesterase-4 (PDE-4), specific for cyclic adenosine monophosphate (cAMP). It is an oral small-molecule PDE4 inhibitor. The inhibition of PDE4 causes intracellular cAMP molecules to rise. The exact mechanism of action is unclear.

3. Pharmacokinetics

a. Absorption: In oral form, Apremilast is absorbed with an absolute bioavailability of ~73 %.

b. Peak plasma concentration (Cmax): Achieved at ~2.5 hours [median time (Tmax)].

c. Co-administration With Food: No effect on the absorption of Apremilast.

d. Distribution: Human plasma protein binding - 68 %. Mean apparent volume of distribution (Vd) - 87 liters.

e. Metabolism: Apremilast is a major circulating component (45 %) when taken orally. It is well-metabolized in humans. 23 metabolites of Apremilast have been identified in the urine, feces, and plasma.

f. Metabolization Mechanisms:

g. Elimination:

Special Considerations

Hepatic Impairment: Hepatic impairment does not impact Apremilast pharmacokinetics.

Renal Impairment: Mild to moderate renal impairment does not impact Apremilast pharmacokinetics.

Drug Interactions:

In Vitro Data:

Apremilast does not inhibit:

Apremilast does not induce:

Apremilast is a substrate of but does not inhibit P-glycoprotein (P-gp).

It is neither a substrate nor an inhibitor of:

Clinical Trials:

1. Age:

Apremilast 30 mg (single-dose) was administered in young adults (18 years to 55 years) and elderly individuals (65 years to 85 years).

Exposure:

Area under the curve (AUC) or extent of exposure: 13 % higher in the elderly than in the young adult population.

Peak plasma concentration (Cmax):6 % higher in the elderly than in the young adult population.

2. Gender:

Pharmacokinetic trials have been conducted in healthy patients (volunteers).

AUC: 31 % higher for females than males.

Cmax:8 % higher for females than males.

3. Race and Ethnicity:

Pharmacokinetic trials have compared Asian (Chinese and Japanese subjects) males to Caucasian male subjects; trials have also been performed among Hispanic and non-Hispanic Caucasians and African-Americans. Results have shown that Apremilast exposure shows no significant differences and is similar in all these populations.

4. Drug Interaction:

Apremilast AUC reduced by 72 %.

Apremilast Cmax reduced by 43 %.

5. Comorbidities:

In patients with severe renal impairment, who were given Apremilast (30 mg single dose):

Apremilast AUC: Increased by 88 %.

Apremilast Cmax: Increased by 42 %.

Disease-specific Trials:

Psoriatic Arthritis: The PALACE 3 trial (Phase 3) evaluated the efficacy and safety of Apremilast in patients with psoriatic arthritis who had received previous therapy with conventional DMARDs or biologic agents.

Study Design:

Primary Outcome Measures:Percentage of participants with at least 20 % American College of Rheumatology (ACR20) response at Week 16. Response measures included:

  1. ≥ 20 % improvement in 78 tender joint counts.

  2. ≥ 20 % improvement in 76 swollen joint counts.

  3. ≥ 20 % improvement in at least 3 of 5 parameters:

Results:

Week 16 (p=0.0295, p<0.0001):

Sustained response of improvements as observed at Week 16, with continued Apremilast treatment.

Adverse Events Profile:

Mild to moderate severity of:

Plaque Psoriasis: The LIBERATE trial evaluated the efficacy and safety of Apremilast in patients with moderate to severe plaque psoriasis.

Type of Study:Randomized, double-blinded, placebo-controlled trial (Phase IIIb).

Week 104 crossover: All placebo and Etanercept patients switched to Apremilast through Week 104.

Primary Outcome Measures: Percentage of participants with at least 75 % Psoriasis Area Severity Index (PASI) response at Week 16.

Outcomes Assessment: Through Week 52.

Results:

Week 16:

Adverse Event Profile With Apremilast:

Oral Ulcers in Behçet's Disease:A Phase 3 trial evaluated the change in the total number of mouth ulcers over 12 weeks, comparing Apremilast with a placebo.

Study Design:

Primary Outcome Measures:Area under the curve (AUC) for oral ulcers (total number) during the 12-week placebo-controlled period.

Extension Phase:52 weeks.

Secondary Outcome Measures included:

Results:

Adverse Event Profile With Apremilast:

Patient Counseling Information:

Administration Instructions:

Complications/Side Effects:

Nausea, Diarrhea, Vomiting:

Depression:

Weight Loss:

Pregnancy and Breastfeeding:

Hypersensitivity:

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Frequently Asked Questions


1.

What Type of Drug Is Apremilast Classified As?

Apremilast is an oral phosphodiesterase-4 (PDE-4) inhibitor or an immunosuppressant drug that is used to suppress the immune system and reduce inflammation. It falls under the disease-modifying anti-rheumatic drugs (DMARDs) category and is classed as a novel oral DMARD.

2.

Is Apremilast a Steroid Medication?

Apremilast belongs to a class of medications known as steroids. It blocks the action of chemical messengers that cause inflammation in psoriatic conditions, including plaque psoriasis, psoriatic arthritis, and oral ulcers in Behçet's disease.

3.

What Side Effects Can One Expect With Apremilast?

The typical side effects one may expect to see with the use of Apremilast are:

- Nausea.

- Vomiting.

- Diarrhea.

- Weight loss.

- Stomach pain.

- Headache.

- Infections of the respiratory tract.

- Symptoms of cold (sneezing, runny nose, sore throat).

- Depression.

- Suicidal ideation.

4.

What Is the Expected Time Until Apremilast Action Is Effective?

One must remember that Apremilast controls the symptoms of psoriatic disease rather than cures the disease completely. The symptom-controlling benefits of Apremilast are usually achieved within twelve to sixteen weeks (about four months) of beginning treatment.

5.

Is the Liver Affected by Apremilast?

While psoriatic conditions have been linked to chronic liver disease,

- Apremilast itself is not known to cause any damage or clinically apparent liver injury.

- No dose adjustments of Apremilast are required in patients with liver disease.

- The consumption of alcohol with Apremilast has also not been known to cause overt liver damage. However, alcohol consumption can worsen psoriasis and is, therefore, contraindicated in psoriatic patients.

6.

What Is the Drug Apremilast Indicated For?

Apremilast is indicated for the following conditions:

- Psoriatic Arthritis: Apremilast may be prescribed either alone or in combination with other DMARDs in adult patients with intolerance or inadequate response towards other DMARDs.

- Plaque Psoriasis: Adult patients with moderate to severe chronic plaque psoriasis who are intolerant to Methotrexate and Cyclosporin and eligible for systemic therapy or phototherapy may be prescribed Apremilast.

- Mouth Ulcers in Behçet’s Disease: Apremilast is also indicated in adult patients (who may receive systemic therapy) with Behçet’s disease for mouth ulcers.

7.

Is Apremilast Effective in the Treatment of Psoriasis?

- Apremilast is an effective single-drug therapy in mild to moderate psoriasis and can also provide relief in severe psoriatic conditions when administered in combination with other drugs.

- It is also effective in treating the symptoms of psoriasis in difficult-to-treat areas like the palms, soles, and scalp.

8.

What Is the Safe Duration of Time to Take Apremilast?

In some patients, Apremilast does not cause any side effects and may be used for long-term treatment to keep their disease under control. Studies reporting on long-term Apremilast use have lasted for as long as three to five years, with no relevant safety or efficacy concerns. Apremilast is therefore well-tolerated (for well over 156 weeks) and indicated for prolonged use in most patients.

Article Resources

Last reviewed at:
13 Jul 2022  -  20 min read

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