Consumer medicine information

Otezla

Apremilast

BRAND INFORMATION

Brand name

Otezla

Active ingredient

Apremilast

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Otezla.

SUMMARY CMI

Otezla®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

1. Why am I taking Otezla?

Otezla contains the active ingredient apremilast. Otezla is used to treat adults with plaque psoriasis, Psoriatic arthritis, or mouth ulcers associated with Behçet's Disease.

For more information, see Section 1. Why am I taking Otezla? in the full CMI.

2. What should I know before I take Otezla?

Do not use if you have ever had an allergic reaction to apremilast or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take Otezla? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Otezla and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Otezla?

  • Swallow Otezla tablets whole with a glass of water, either with or without food.

More instructions can be found in Section 4. How do I take Otezla? in the full CMI.

5. What should I know while taking Otezla?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Otezla.
  • If you have any questions, ask your doctor, pharmacist or nurse
  • Keep all your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop taking this medicine or change the dose without speaking to your doctor.
  • Do not take Otezla when pregnant or breast feeding.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Otezla affects you.
Looking after your medicine
  • Store below 30°C.
  • Keep Otezla in a cool, dry place out of the reach of children.

For more information, see Section 5. What should I know while taking Otezla? in the full CMI.

6. Are there any side effects?

Common side effects: diarrhoea, nausea, vomiting, stomach pain, indigestion, decrease in appetite, cough, cold, runny nose, inflammation/infection of the nose, throat, sinus, or upper respiratory tract, tiredness, difficulty sleeping, headaches, migraines, and back pain.

Serious side effects: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue, or other parts of the body.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Otezla®

Active ingredient: apremilast


Consumer Medicine Information (CMI)

This leaflet provides important information about taking Otezla. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking Otezla.

Where to find information in this leaflet:

1. Why am I taking Otezla?
2. What should I know before I take Otezla?
3. What if I am taking other medicines?
4. How do I take Otezla?
5. What should I know while taking Otezla?
6. Are there any side effects?
7. Product details

1. Why am I taking Otezla?

Otezla contains the active ingredient apremilast. Otezla is a selective immunosuppressant which helps to reduce inflammation.

Otezla is used to treat adults with the following conditions:

  • Plaque psoriasis
  • Psoriatic arthritis
  • Mouth ulcers associated with Behçet's disease.

Plaque psoriasis

Plaque psoriasis is an inflammatory disease of the skin, which can cause red, scaly, thick, itchy, painful patches on your skin, and can also affect your scalp and nails. Plaque psoriasis can look different depending on skin tone, people with skin of colour may have grey or white scaly patches.

Treatment with Otezla can result in a reduction in psoriasis skin plaques, nail and scalp psoriasis and other signs and symptoms of psoriasis, such as itching, skin pain or discomfort.

Psoriatic arthritis

Psoriatic arthritis is an inflammatory disease of the joints, often accompanied by psoriasis, an inflammatory disease of the skin.

Treatment with Otezla can result in an improvement in swollen and painful joints, swollen and painful fingers / toes, signs and symptoms of psoriasis, and can improve your general physical function.

Behçet's disease

Behçet's disease is a rare type of inflammatory disease which affects many parts of the body. The most common problem is mouth ulcers.

Treatment with Otezla can result in fewer and less painful mouth ulcers.

How Otezla works

Otezla works by reducing the activity of a natural substance in the body's cells called phosphodiesterase 4. This helps regulate the immune response associated with psoriasis, psoriatic arthritis, and Behçet's disease and helps to control the signs and symptoms of these conditions.

Psoriasis, psoriatic arthritis, and Behçet's disease are usually lifelong conditions. There is currently no cure. Otezla has been shown to improve the quality of life in patients with psoriasis, psoriatic arthritis and Behçet's disease. This means that the impact of your condition on daily activities, relationships and other factors should be less than it was before.

2. What should I know before I take Otezla?

Warnings

Do not take Otezla if:

  • You are allergic to apremilast, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include, rash, itching or hives on the skin, swelling of the face, lips, tongue, mouth or throat that may lead to difficulty breathing or swallowing.
  • You are pregnant or breastfeeding.

Check with your doctor if you:

  • Have kidney problems
  • Experience severe diarrhoea, nausea or vomiting.
  • Have experienced depression or have had suicidal thoughts now or in the past.
  • Have intolerance to some sugars, Otezla contains lactose (a type of sugar).
  • Take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy

Otezla must not be taken during pregnancy. Check with your doctor if you are pregnant or intend to become pregnant.

Breastfeeding

Do not breastfeed whilst taking Otezla. Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Otezla and affect how it works.

Medicines that may reduce the effect of Otezla include:

  • rifampicin, an antibiotic used for tuberculosis
  • carbamazepine, phenytoin and phenobarbitone, medicines used in the treatment of seizures or epilepsy
  • St. John's Wort, a herbal medicine for mild anxiety and depression.

These medicines may affect how well Otezla works. You may need different amounts of your medicines, or you may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Otezla.

4. How do I take Otezla?

How much to take

Follow the instructions given to you by your doctor or pharmacist carefully. Take Otezla until your doctor tells you to stop. Your doctor will monitor your progress.

  • When you first start taking Otezla, you will receive a 'treatment starter pack' which contains all the doses for the first 14 days of therapy as listed in the table below.
  • The 'treatment starter pack' is clearly labelled to help you take the correct tablet at the right time.
  • Your treatment will start at a lower dose and will gradually be increased over the first 6 days of treatment.
  • The starter pack also contains enough tablets for a further 8 days at the daily recommended dose (days 7 to 14).
  • After the titration phase is complete the recommended dose of Otezla is 30 mg twice a day - one 30 mg tablet in the morning and one 30 mg tablet in the evening. This is a total daily dose of 60 mg.
  • Once the recommended dose has been reached, you will only get the 30 mg tablet strength in your prescribed packs.
  • You will only ever need to go through this stage of gradually increasing your dose once, even if you re-start treatment following a (longer) break.

If you have severe kidney problems, the recommended daily dose is 30 mg once a day (morning dose). Your doctor will talk to you about how to increase your dose when you first start taking Otezla.

When to take Otezla

  • Take Otezla at about the same time each day, following the instructions provided.
  • Most people should take one tablet in the morning and one tablet in the evening each day, approximately 12 hours apart.
  • Take Otezla until your doctor tells you to stop.

How to take Otezla

  • Swallow the tablets whole, preferably with water, either with or without food, as directed by your doctor.
  • Do not crush, break or chew the tablets.
  • Take Otezla at about the same time each day, one tablet in the morning and one tablet in the evening.

If you forget to take Otezla

If you miss a dose of Otezla, take it as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much Otezla

If you think that you have taken too much Otezla, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking Otezla?

Things you should do

Your doctor will monitor your progress while you are taking Otezla. Keep all your doctor's appointments so that your progress can be checked.

Tell your doctor if you have experienced depression or have had suicidal thoughts in the past.

During treatment with Otezla, tell your doctor or nurse if you experience severe diarrhoea, nausea or vomiting. These side effects are usually noticed at the start of treatment. Inform your doctor, nurse or pharmacist if you experience these side effects.

Call your doctor straight away if during treatment you:

  • Feel depressed, have suicidal thoughts, experience other mood changes or notice that these events have worsened.
  • Experience any serious side effects listed in the table below.

Remind any doctor, dentist or pharmacist you visit that you are taking Otezla.

Things you should not do

  • Do not take Otezla when pregnant or breastfeeding.
  • Do not take Otezla if you are under the age of 18 years. Safety and effectiveness in children have not been established.
  • Do not take Otezla after the expiry date printed on the pack or if the packaging shows signs of tampering.
  • Do not stop taking this medicine suddenly or change the dose without speaking to your doctor.
  • Do not give Otezla to anyone else, even if they have the same condition as you.
  • Do not take Otezla to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Otezla affects you.

Looking after your medicine

Follow the instructions on the carton on how to take care of your medicine properly.

Store Otezla below 30°C.

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it in:

  • the bathroom or near a sink, or
  • the car or on windowsills.

Keep it where children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gut and digestion:
  • diarrhoea; nausea; vomiting; stomach pain; indigestion
  • decrease in appetite
  • weight loss
Lungs and upper airway:
  • cough; cold; runny nose
  • inflammation/infection of the nose, throat, sinus, or upper respiratory tract
Other:
  • tiredness; trouble or difficulty sleeping
  • headaches or migraine headaches
  • back pain
  • skin rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Otezla contains

Active ingredient
(main ingredient)
apremilast
Other ingredients
(inactive ingredients)
microcrystalline cellulose
lactose monohydrate
croscarmellose sodium
magnesium stearate (vegetable grade)
polyvinyl alcohol
titanium dioxide
polyethylene glycol
talc
iron oxide red
iron oxide yellow (20 mg and 30 mg tablets only)
iron oxide black (30 mg tablets only)
Potential allergensContains lactose

Do not take this medicine if you are allergic to any of these ingredients.

What Otezla looks like

Otezla 10 mg - Pink, diamond shaped film-coated tablet with “APR” engraved on one side and “10” on the opposite side.

Otezla 20 mg - Brown, diamond shaped film-coated tablet with “APR” engraved on one side and “20” on the opposite side.

Otezla 30 mg - Beige, diamond shaped film-coated tablet with “APR” engraved on one side and “30” on the opposite side.

The tablets are provided in blister packs as follows.

  • Otezla titration starter pack, a folding wallet containing 27 film-coated tablets: 4 × 10 mg tablets, 4 × 20 mg tablets and 19 × 30 mg tablets (AUST R 220424)
  • Otezla 30 mg standard trade pack contains 56 x 30mg film-coated tablets. (Aust R 220423).

Sponsor

Amgen Australia Pty Ltd
Level 11, 10 Carrington St
Sydney NSW 2000
Ph: 1800 803 638
www.amgenmedinfo.com.au

This leaflet was prepared in August 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Otezla

Active ingredient

Apremilast

Schedule

S4

 

1 Name of Medicine

Apremilast.

2 Qualitative and Quantitative Composition

See Section 6.1 List of Excipients.

Excipients with known effect.

Sugars (as lactose).

3 Pharmaceutical Form

Otezla 10 mg tablets.

Pink, diamond shaped 10 mg film-coated tablet with "APR" engraved on one side and "10" on the opposite side.

Otezla 20 mg tablets.

Brown, diamond shaped 20 mg film-coated tablet with "APR" engraved on one side and "20" on the opposite side.

Otezla 30 mg tablets.

Beige, diamond shaped 30 mg film-coated tablet with "APR" engraved on one side and "30" on the opposite side.

4 Clinical Particulars

4.1 Therapeutic Indications

Otezla is indicated for:
The treatment of signs and symptoms of active psoriatic arthritis in adult patients.
The treatment of adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy.
The treatment of adult patients with oral ulcers associated with Behcet's disease who are candidates for systemic therapy.

4.2 Dose and Method of Administration

Dosage (dose and interval).

For psoriasis, psoriatic arthritis and Behcet's disease, treatment with Otezla should be initiated by physicians experienced in the diagnosis and treatment of these diseases.
The recommended dose of Otezla is 30 mg twice daily taken orally approximately 12 hours apart. An initial titration schedule is required as shown in Table 1. No re-titration is required after initial titration.

Method of administration.

Otezla tablets should be swallowed whole, either with or without food. The tablets should not be crushed, split or chewed.
If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time.

Dosage adjustment.

No dosage adjustment is necessary for elderly patients.

Renal impairment.

No dose adjustment is needed in patients with mild renal impairment. There are limited data on moderate renal impairment. Otezla should be dose reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockcroft-Gault equation). For initial dosage titration in this group, it is recommended that Otezla be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped.

Hepatic impairment.

Dose adjustment is not required in patients with hepatic impairment. The safety of Otezla was not evaluated in psoriatic arthritis (PsA), psoriasis (PSOR) or Behcet's disease patients with hepatic impairment.

Monitoring advice.

In the event of intolerable adverse events, interruption or discontinuation of Otezla should be considered.

4.3 Contraindications

Otezla is contraindicated:
in patients with known hypersensitivity to the active substance or to any of the excipients;
during pregnancy and in nursing women.

4.4 Special Warnings and Precautions for Use

Weight decrease.

In some patients treatment with Otezla has been associated with weight decrease. Patients treated with Otezla should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of Otezla should be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).

Depression.

Treatment with Otezla is associated with an increase in occurrences of depression (see Section 4.8 Adverse Effects (Undesirable Effects)). Before using Otezla in patients with a history of depression and/or suicidal thoughts or behaviour, 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.

Diarrhoea, nausea and vomiting.

There have been post‐marketing reports of severe diarrhoea, nausea, and vomiting associated with the use of Otezla. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalised. 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. Patients who reduced dosage or discontinued Otezla generally improved quickly. Consider Otezla dose reduction or suspension if patients develop severe diarrhoea, nausea or vomiting.

Use in patients with lactose intolerance.

Otezla tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Use in renal impairment.

Assessment of renal function is recommended prior to initiation of Otezla.

Use in the elderly.

Otezla was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for Otezla than that in young subjects (18 to 55 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.
No dosage adjustment is necessary for elderly patients.

Paediatric use.

The safety and effectiveness of Otezla has not been established in patients under the age of 18 years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Otezla has not been studied in combination with cyclosporin or biologic therapies.

Effect of Otezla on other medicinal products.

There was no pharmacokinetic drug-drug interaction between Otezla and methotrexate. Otezla can be co-administered with methotrexate.
There was no pharmacokinetic drug-drug interaction between Otezla and oral contraceptives containing ethinyl oestradiol and norgestimate. Otezla can be taken with oral contraceptives without clinically relevant drug-drug interaction.
In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co-administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of drugs that are metabolised by CYP enzymes.
In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC > 50 microM).
In vitro, apremilast has little to no inhibitory effect (IC50 > 10 microM) on 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) and is not a substrate for these transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co-administered with drugs that are substrates or inhibitors of these transporters.

Effect of other medicinal products on Otezla.

Co-administration of Otezla with multiple doses of rifampicin resulted in a decrease in apremilast area under the concentration time curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%, respectively. Apremilast exposure is decreased when administered concomitantly with strong inducers of CYP3A4 (e.g. rifampicin, phenobarbitone, carbamazepine, phenytoin and St. John's wort) and may result in reduced clinical response.
Ketoconazole co-administration increased mean apremilast AUC0-∞ and Cmax by approximately 36% and by 5%, respectively, which is not clinically meaningful. Otezla can be co-administered with a potent CYP3A4 inhibitor like ketoconazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility data is available in humans.
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 no observed adverse effect level (NOAEL) for male fertility was greater than 50 mg/kg/day (3-fold clinical exposure).
In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates were unaffected. The no observed effect level (NOEL) for female fertility was 10 mg/kg/day (1.0-fold clinical exposure).
(Category B3)
There are no adequate and well controlled studies of Otezla in pregnant women.
Otezla is contraindicated in pregnant women, and should not be used in women attempting to become pregnant.
Apremilast was not teratogenic in mice or monkeys. Other effects of apremilast on pregnancy included embryofoetal loss in mice and monkeys, and reduced foetal weights and delayed ossification in mice at doses higher than the currently recommended highest human dose. No such effects were observed when exposure in animals was at 1.3-fold the clinical exposure.
In a combined female mouse fertility and embryofoetal developmental toxicity study, the maternal and developmental NOEL observed was 10 mg/kg/day (1.3-fold clinical exposure). No treatment-related developmental malformations were observed up to the highest dosage of 80 mg/kg/day (4.0-fold clinical exposure).
In a monkey embryofoetal developmental toxicity study, oral dosages of 20, 50, 200, and 1,000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at dosages of 50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day (1.4-fold clinical exposure). No treatment-related foetal developmental effects or malformations were observed in the monkey up to the highest dosage of 1,000 mg/kg/day in the study (3.5-fold clinical exposure).
In a pre- and postnatal study, in which apremilast was administered orally to pregnant female mice, clinical signs of maternal toxicity associated with delivering pups were observed in one mouse at each of 80 and 300 mg/kg/day. Increased pre- and postnatal pup mortality and reduced pup body weights during the first week of lactation were observed at ≥ 80 mg/kg/day (≥ 4.0-fold clinical exposure). The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-fold clinical AUC).
Apremilast was detected in milk of lactating mice.
It is not known whether apremilast or its metabolites are excreted in human milk. Therefore, the use of Otezla is contraindicated in mothers who are breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use of machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Psoriatic arthritis and plaque psoriasis.

Otezla was evaluated in 4 multi-centre, randomised, double-blind, placebo-controlled trials (Studies PALACE 1, PALACE 2, PALACE 3 and PALACE 4) of similar design in adult patients with active psoriatic arthritis. Across the 4 studies, there were 1,945 patients who received at least one dose of Otezla 20 mg twice daily or Otezla 30 mg twice daily.
Otezla was evaluated in 2 multi-centre, randomised, double-blind, placebo-controlled trials (Studies ESTEEM 1 and ESTEEM 2) of similar design in adult patients with moderate to severe plaque psoriasis. Across the two studies, 1,184 psoriasis patients were exposed to Otezla 30 mg twice daily.
Otezla was evaluated in a Phase 3, placebo-controlled study (ADVANCE) in adult patients with mild to moderate plaque psoriasis. A total of 544 patients received Otezla 30 mg twice daily.
Hypersensitivity reactions were observed infrequently in clinical studies with Otezla.

Tabulated list of adverse events.

The observed Treatment Emergent Adverse Events (TEAEs) with patient incidence of at least 2% in any treatment group during ESTEEM and PALACE clinical studies is presented in Table 2. The frequencies of TEAEs are based on those reported in the Otezla 30 mg twice daily arm in either psoriatic arthritis or moderate to severe plaque psoriasis Phase 3 studies during weeks 0-16 of therapy. The highest incidence from either indication is shown. The most frequently reported TEAEs were gastrointestinal related. The overall incidence of serious adverse events was low and similar to placebo.
In the Phase 3 study in adults with mild to moderate plaque psoriasis, the safety profile observed in the Otezla group during the placebo controlled phase was overall consistent with the safety profile previously established in adult patients with moderate to severe plaque psoriasis. This safety profile remained similar throughout the study.
In STYLE the most commonly reported TEAEs that occurred at a higher rate in the Otezla group than in the placebo group were: diarrhoea (31% vs. 11%), nausea (22% vs. 6%), headache (12% vs. 5%), and vomiting (6% vs. 2%), which are considered to be adverse reactions for apremilast. The proportion of subjects who discontinued treatment because of any TEAE during the 16 week placebo controlled period of the trial was 6% for subjects who received Otezla 30 mg twice daily and 3% for subjects who received placebo. In the Otezla group compared to the placebo group, gastrointestinal adverse reactions that led to discontinuation of treatment were diarrhoea (3% vs. 0%), nausea (1.5% vs. 1%), and vomiting (1.5% vs. 0%).

Behcet's disease.

Otezla was evaluated in a Phase 3, placebo-controlled trial (RELIEF) in adult patients with Behcet's disease (BD) with active oral ulcers. A total of 207 patients were randomised to receive Otezla 30 mg twice daily (104 patients) or placebo twice daily (103 patients) during the placebo-controlled phase of the study. The study also included an open-label extension phase during which all patients received Otezla 30 mg twice daily. During the placebo-controlled period, very common adverse reactions in the Otezla group included diarrhoea (41.3%), nausea (19.2%), headache (14.4%) and upper respiratory tract infection (11.5%). Most of these were mild to moderate in severity. The incidence of serious adverse reactions in the Otezla group was low (2.9%) and did not indicate any specific system organ involvement.

Adverse reactions.

Tabulated list of adverse reactions.

The adverse reactions observed in patients treated with Otezla are listed by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The adverse drug reactions were determined based on data from the Otezla Phase 3 clinical development program. The frequencies of adverse drug reactions are those reported in the Otezla arms of the four Phase 3 studies in psoriatic arthritis (n = 1,945) or the two Phase 3 studies in moderate to severe plaque psoriasis (n = 1,184) (highest frequency from either data pool is represented in Table 3).
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); and uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).
The most commonly reported adverse reactions in Phase 3 (Studies PALACE 1, PALACE 2, PALACE 3, PALACE 4 and ESTEEM 1 and ESTEEM 2) clinical studies have been gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions were mostly mild to moderate in severity, with 0.3% of patients reporting severe diarrhoea and 0.3% of patients reporting severe nausea. These adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. The other most commonly reported adverse reactions included upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%).
Overall, most adverse reactions were considered to be mild or moderate in severity. The most common adverse reactions leading to discontinuation during the first 16 weeks of treatment were diarrhoea (1.7%) and nausea (1.5%).

Description of selected adverse reactions.

Weight decrease. Patient weight was measured routinely in clinical studies.
In Studies ESTEEM 1 and ESTEEM 2, the mean observed weight loss in patients treated for up to 52 weeks with Otezla was 1.99 kg. A total of 14.3% of patients receiving Otezla had observed weight loss between 5-10% while 5.7% of the patients receiving Otezla had observed weight loss greater than 10%. None of these patients had overt clinical consequences resulting from weight loss. A total of 0.2% of patients treated with Otezla discontinued due to adverse reaction of weight decreased. Weight decreases of greater than 5% of baseline body weight were observed more frequently in women than in men.
Depression.

Psoriatic arthritis.

During the 0 to 16 week placebo controlled period of the phase 3 controlled clinical trials, (PALACE 1, PALACE 2, PALACE 3, and PALACE 4), 0.9% (18/1,945) of subjects treated with Otezla reported depression or depressed mood compared to 0.7% (5/671) treated with placebo. During the clinical trials, 0.2% (4/1,945) of subjects treated with Otezla discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/671). Depression was reported as serious in 0.2% (3/1,945) of subjects exposed to Otezla, compared to none in placebo treated subjects (0/671). Instances of suicidal ideation and behaviour have been observed in 0.2% (3/1,945) of subjects while receiving Otezla, compared to none in placebo treated subjects (0/671). 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 2 controlled clinical trials, (ESTEEM 1 and ESTEEM 2), 1.2% (14/1,184) of subjects treated with Otezla reported depression compared to 0.5% (2/418) treated with placebo. During the clinical trials, 0.1% (1/1,184) of subjects treated with Otezla discontinued treatment due to depression compared with none in placebo treated subjects (0/418). Depression was reported as serious in 0.1% (1/1,184) of subjects exposed to Otezla, compared to none in placebo treated subjects (0/418). Instances of suicidal behaviour have been observed in 0.1% (1/1,184) of subjects while receiving Otezla, compared to 0.2% (1/418) in placebo treated subjects. In the clinical trials, one subject treated with Otezla attempted suicide while one who received placebo committed suicide.
Safety in elderly patients. No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies.

Long-term experience.

The long-term safety of Otezla 30 mg twice daily in patients with psoriatic arthritis and plaque psoriasis was assessed for a total duration of treatment up to 5 years (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Overall, the long-term safety profile of Otezla was consistent with the safety profile previously established in patients with psoriatic arthritis and plaque psoriasis.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Otezla was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. Patients should be managed by symptomatic and supportive care should there be an overdose.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group: Selective immunosuppressants.

5.1 Pharmacodynamic Properties

Mechanism of action.

Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 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 PsA and PSOR.

Clinical pharmacodynamics.

In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL-23, and an increase in 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 inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8.

Cardiac electrophysiology.

Apremilast administered at doses of up to 50 mg twice daily did not prolong the QT interval in healthy subjects.

Clinical trials.

Clinical trial experience in psoriatic arthritis patients previously treated with DMARDs. The safety and efficacy of Otezla were evaluated in 3 multi-centre, randomised, double-blind, placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design in 1,493 adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior DMARD treatment, including biologic DMARD treatment (e.g. TNF-blockers), or current treatment with oral DMARD therapy.
Patients in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion (at least 2 cm in diameter) was also required in PALACE 3. The patients who were therapeutic failures of > 3 agents for PsA (small molecules or biologics), or > 1 biologic TNF blocker, were excluded. Patients with each subtype of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (26.9%), distal interphalangeal (DIP) joint arthritis (6.2%), arthritis mutilans (2.7%), and predominant spondylitis (2.1%). Patients with pre-existing enthesitis (63%) and pre-existing dactylitis (42%) were enrolled. Patients were allowed to receive stable doses of concomitant methotrexate (MTX) (≤ 25 mg/week), sulfasalazine (SSZ) (≤ 2 g/day), leflunomide (LEF) (≤ 20 mg/day), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial; the combination of apremilast with biologic DMARDs was not studied.
Across the 3 studies, patients were randomly assigned to placebo (n = 496), Otezla 20 mg (n = 500), or Otezla 30 mg (n = 497) given orally twice daily. Treatment assignments were stratified based on small molecule DMARD use at baseline in Studies PALACE 1, PALACE 2 and PALACE 3. There was an additional stratification of body surface area (BSA ≥ 3% with psoriasis in PALACE 3).
Patients received concomitant therapy with at least one DMARD (total 65.2%), MTX (54.5%), SSZ (9.0%), LEF (7.4%), low dose oral corticosteroids (13.9%), and NSAIDs (70.7%). Prior treatment with only small molecule DMARDs was reported in 76.4% of patients and prior treatment with biologic DMARDs was reported in 22.4% of patients, which includes 7.8% who had a therapeutic failure with a prior biologic DMARD. The median duration of PsA disease was 5 years.
The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomised 1:1 in a blinded fashion to either Otezla 20 mg twice daily or 30 mg twice daily. Otezla patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomised to either Otezla 20 mg twice daily or Otezla 30 mg twice daily. At the end of 52 weeks, patients could enter a long-term open label extension of the PALACE 1, PALACE 2, and PALACE 3 studies for a total duration of treatment up to 5 years (260 weeks). These studies did not investigate the effects of Otezla on structural progression.

Clinical responses.

Treatment with Otezla resulted in significant improvements in the signs and symptoms of PsA, as assessed by the ACR 20 response criteria, compared to placebo at Week 16. The proportion of patients with ACR 20/50/70 responses in Studies PALACE 1, PALACE 2 and PALACE 3, for Otezla 30 mg twice daily at Week 16, are shown in Table 4. ACR 20/50/70 responses were maintained at Week 24.

ACR 20/50/70 response through week 52.

Among 497 patients initially randomised to Otezla 30 mg twice daily, 373 (75%) patients were still on this treatment at Week 52. In these patients, ACR 20/50/70 responses at week 52 were 57%, 25%, and 11% respectively (see Figure 1).
ACR 20 responses were higher in patients treated with Otezla than in patients treated with placebo when used alone or in combination with DMARDs. In Study PALACE 1, the proportion of patients with an ACR 20 response at Week 16 with concomitant DMARD use was 33.0% for Otezla 30 mg twice daily and 23.6% for placebo. The proportion of patients with an ACR 20 response at Week 16 without concomitant DMARD use was 46.8% for Otezla 30 mg twice daily and 10.3% for placebo. Similar results were observed in Studies PALACE 2 and PALACE 3.
A greater proportion of patients achieved an ACR 20 response with the use of Otezla 30 mg twice daily, irrespective of prior small molecule or prior biologic DMARD use. In Study PALACE 1, the proportion of patients with prior treatment of only small molecule DMARDs (biologic naive) with an ACR 20 response at Week 16 were 41.1% for Otezla 30 mg twice daily and 23.3% for placebo and the proportion of patients with prior biologic use with an ACR 20 response at Week 16 were 26.8% for Otezla 30 mg twice daily and 4.9% for placebo. Similar results were observed in Studies PALACE 2 and PALACE 3.
Similar ACR 20 responses were observed in patients with different PsA subtypes including distal interphalangeal (DIP); however, the number of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allow for a meaningful assessment.
Otezla 30 mg twice daily resulted in greater improvement for each ACR component [number of swollen and tender joints, physician and patient assessment of disease activity and patient assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI) scores and CRP values], compared to placebo at Weeks 16 and 24 in Study PALACE 1. Among patients who were continuously treated with Otezla, sustained improvements in individual ACR components were observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
The proportion of patients achieving modified PsA response criteria (PsARC) was significantly greater in the Otezla 30 mg twice daily group compared to placebo at Week 16 (46.4% and 29.8% respectively; p < 0.01) in Study PALACE 1. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, a PsARC response of 73.6% was observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
A greater proportion of patients treated with Otezla 30 mg twice daily achieved remission, as measured by a DAS28 (CRP) less than 2.6, compared to placebo at Weeks 16 (13.1% and 3.6% respectively; p < 0.01) in Study PALACE 1. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, a DAS28 (CRP) response of 23.3% was observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
In patients with pre-existing enthesitis or dactylitis, treatment with Otezla 30 mg twice daily resulted in improvement in enthesitis and dactylitis. Among patients who were continuously treated with Otezla, improvement in enthesitis and dactylitis continued through Week 52.

Physical function responses and health-related quality of life.

Patients treated with Otezla 30 mg twice daily demonstrated a significantly greater improvement in physical function compared to placebo treated patients, as shown in the mean change from baseline in HAQ-DI score at Week 16 (-0.244 and -0.086 respectively; p < 0.01) and Week 24 (-0.258 vs, -0.076, respectively; p < 0.001) in Study PALACE 1. Among patients who were continuously treated with Otezla, a mean change from baseline in HAQ-DI score of -0.318 was observed at Week 52. In addition, there was a greater proportion of HAQ-DI responders who showed improvement (≥ 0.3 improvement from baseline) at Week 16 for the Otezla 30 mg twice daily group compared to the placebo group (38.1% vs 26.8% respectively, p < 0.05). The response was maintained at Week 24. Among patients who were continuously treated with Otezla, the proportion of HAQ-DI responders was 44.7% at Week 52. Similar results in the mean change from baseline in HAQ-DI and in the proportion of HAQ-DI responders were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
Patients treated with Otezla 30 mg twice daily demonstrated a significantly greater improvement compared to placebo treated patients in the mean change from baseline in the SF-36v2 Physical Functioning (PF) Domain Score at Week 16 (4.23 and 1.81 respectively; p < 0.01) in Study PALACE 1. A greater improvement, compared to placebo, in the mean change from baseline was also observed in the Physical Component Summary (PCS) Score at Week 16 (4.59 and 2.39 respectively; p < 0.01). The responses were maintained at Week 24. Among patients who were continuously treated with Otezla, mean changes from baseline in SF-36v2 PF and PCS scores of 5.69 and 6.45, respectively, were observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
There was no worsening observed in the mean change from baseline in the Mental Component Summary score (MCS) in patients treated with Otezla 30 mg twice daily in comparison to placebo patients at Week 16 (0.69 and 0.07 respectively) and Week 24 in Study PALACE 1. Among patients who were continuously treated with Otezla, a mean change from baseline in the MCS score of 0.34 was observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.
A greater improvement was observed in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scores in the patients treated with Otezla 30 mg twice daily when compared with the placebo group at Weeks 16 (3.88 and 1.55 respectively; p < 0.05) in Study PALACE 1. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, a mean change from baseline in the FACIT-fatigue score of 3.67 was observed at Week 52. Similar results were observed in Studies PALACE 2 and PALACE 3 at Weeks 16, 24 and 52.

PASI-75 response.

Treatment with Otezla 30 mg twice daily resulted in improvement in the skin manifestations of psoriasis. Patients with psoriasis involvement of at least 3% BSA were evaluated using the PASI-75 responses. In Study PALACE 3, a significantly greater proportion of patients achieved a PASI-75 in the Otezla group compared to the placebo group (22.2% and 7.9%, respectively; p < 0.01) at Week 16. The response was maintained at Week 24. There were more patients with PASI-75 responses in the Otezla group than in patients treated with placebo, with or without concomitant DMARD treatment. Among patients who were continuously treated with Otezla, a PASI-75 response of 39.1% was observed at Week 52. Similar responses were observed in Studies PALACE 1 and PALACE 2 at Weeks 16, 24 and 52.

Long-term experience.

Among 497 patients initially randomised to Otezla 30 mg twice daily, 351 (71%) patients entered the long-term extension studies, and of these 351 patients, 221 patients (63%) were still on this treatment at week 260 (5 years).
Clinical trial experience in DMARD naive psoriatic arthritis patients. The safety and efficacy of Otezla were evaluated in a multi-centre, randomised, double blind, placebo controlled study (Study PALACE 4) in 527 adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) who were DMARD naive. Patients enrolled in this study had a diagnosis of PsA for at least 3 months. Previous treatment with DMARDs or biologics was not allowed.
Patients were randomly assigned to placebo (n = 176), Otezla 20 mg (n = 175), or Otezla 30 mg (n = 176) given orally twice daily. Patients were allowed to receive stable doses of prednisone (equivalent to ≤ 10 mg/day) and/or nonsteroidal anti-inflammatory drugs (NSAIDs). The use of other DMARDs including methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), or biologics was prohibited. Patients with each subtype of PsA were enrolled, including symmetric polyarthritis (61.3%), asymmetric oligoarthritis (30%), distal interphalangeal (DIP) joint arthritis (6.6%), arthritis mutilans (0.8%), and predominant spondylitis (1.3%). Patients with pre-existing enthesitis (65%) and pre-existing dactylitis (50%) were enrolled. The median duration of PsA disease was 1.1 years.
Patients received concomitant therapy including low dose oral corticosteroids (7.2%) and NSAIDs (73.1%); the combination of Otezla with small molecule or biologic DMARDs was not studied.
The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomised 1:1 in a blinded fashion to either Otezla 20 mg twice daily or 30 mg twice daily. Otezla patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomised to either Otezla 20 mg twice daily or Otezla 30 mg twice daily. At the end of 52 weeks, patients could enter a long-term open-label extension study for a total duration of up to 5 years. This study did not investigate the effects of Otezla on structural progression.

Clinical responses.

The percent of patients achieving ACR 20/50/70 responses at Week 16 in Study PALACE 4 is presented in Table 5. Otezla, compared with placebo, resulted in significantly greater improvement in signs and symptoms of psoriatic arthritis, as demonstrated by the proportion of patients with ACR 20 response at Week 16. Improvement in ACR 50/70 responses were also demonstrated at Week 16. ACR 20/50/70 responses were maintained at Week 24.

ACR 20/50/70 response through week 52.

Among 176 patients initially randomised to Otezla 30 mg twice daily, 138 (78%) patients were still on this treatment at Week 52. In these patients, ACR 20/50/70 responses at week 52 were 59%, 32% and 18% respectively (see Figure 2).
Treatment with Otezla 30 mg twice daily resulted in greater improvement for each ACR component [number of swollen and tender joints, physician and patient assessment of disease activity and patient assessment of pain, HAQ-DI score and CRP value], compared to placebo at Weeks 16 and 24 in Study PALACE 4. Among patients who were continuously treated with Otezla, sustained improvements in individual ACR components were observed at Week 52.
The proportion of patients achieving a modified PsARC was significantly greater in the Otezla 30 mg twice daily group compared with placebo at Week 16 (45.5% and 24.4% respectively; p < 0.001) in Study PALACE 4. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, the modified PsARC response was 75.9% at Week 52.
In patients with pre-existing enthesitis or dactylitis, treatment with Otezla 30 mg twice daily resulted in improvement in enthesitis and dactylitis, compared to placebo at Week 16. The responses were maintained at Week 24. Among patients who were continuously treated with Otezla, sustained improvement in enthesitis and dactylitis was observed through Week 52.

Physical function response and health-related quality of life.

Patients treated with Otezla 30 mg twice daily demonstrated a significantly greater improvement in physical function compared to placebo treated patients, as shown in the mean change from baseline in HAQ-DI score at Week 16 (-0.205 and -0.012, respectively; p < 0.001) and Week 24 (-0.207 vs. -0.012, respectively; p < 0.001) in Study PALACE 4. Among patients who were continuously treated with Otezla, the mean change from baseline in HAQ-DI score was -0.392 at Week 52. In addition, there was a greater proportion of HAQ-DI responders who showed improvement (≥ 0.3 improvement from baseline) at Week 16 for the Otezla 30 mg twice daily group compared to the placebo group (34.7% and 19.3%, respectively). The response was maintained at Week 24. Among patients who were continuously treated with Otezla, the proportion of HAQ-DI responders was 48.9% at Week 52.
Treatment with Otezla 30 mg twice daily demonstrated a significantly greater improvement, compared to placebo, in the mean change from baseline in the SF-36v2 PF at Week 16 (3.19 and 0.01 respectively; p < 0.001) in Study PALACE 4. In addition, treatment with Otezla 30 mg twice daily demonstrated a greater improvement, compared to placebo in the mean change from baseline in the PCS at Week 16 (4.20 and 0.93 respectively; p < 0.001). The responses were maintained at Week 24. Among patients who were continuously treated with Otezla, the mean change from baseline in SF-36v2 PF and PCS scores of 6.41 and 6.67, respectively, were observed at Week 52.
There was no worsening observed in the mean change from baseline in the SF-36v2 MCS at Week 16 and Week 24 in Study PALACE 4. Among patients who were continuously treated with Otezla 30 mg twice daily, the mean change from baseline in the SF-36v2 MCS score was 2.19 at Week 52.
There was greater improvement in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scores in the Otezla group when compared with placebo at Week 16 (2.62 and 0.07 respectively; p < 0.01) in Study PALACE 4. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, the mean change from baseline in the FACIT-fatigue score was 5.89 at Week 52.

PASI-75 response.

Treatment with Otezla 30 mg twice daily resulted in improvement in the skin manifestations of psoriasis. Patients with psoriasis involvement of at least 3% BSA were evaluated using the PASI-75 response. At Week 16, there was a greater proportion of patients achieving a PASI-75 in the Otezla 30 mg twice daily group compared to the placebo group (26.6% and 10.8% respectively; p < 0.01) in Study PALACE 4. The response was maintained at Week 24. Among patients who were continuously treated with Otezla, the PASI-75 response was 31.9% at Week 52.
Clinical trial experience in moderate to severe plaque psoriasis patients. The safety and efficacy of Otezla were evaluated in two multi-centre, randomised, double blind, placebo controlled studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1,257 patients 18 years of age and older with moderate to severe plaque psoriasis who had a BSA involvement of ≥ 10%, Psoriasis Area and Severity Index (PASI) score ≥ 12, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe), and who were candidates for phototherapy or systemic therapy. The studies did not include an active comparator arm.
These studies had a similar design through Week 32. In both studies, patients were randomised 2:1 to Otezla 30 mg twice daily or placebo for 16 weeks (placebo controlled phase) and from Weeks 16-32, all patients received Otezla 30 mg twice daily (maintenance phase). During the Randomised Treatment Withdrawal Phase (Weeks 32-52), patients originally randomised to Otezla who achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reduction in their PASI score (PASI-50) (ESTEEM 2) were re-randomised at week 32 to either placebo or Otezla 30 mg twice daily. Patients who were re-randomised to placebo and who lost PASI-75 response (ESTEEM 1) or lost 50% of the PASI improvement at Week 32 compared to baseline (ESTEEM 2) were retreated with Otezla 30 mg twice daily. Patients who did not achieve the designated PASI response by Week 32, or who were initially randomised to placebo, remained on Otezla until Week 52. The use of low potency topical corticosteroids on the face, axillae, and groin, coal tar shampoo and/or salicylic acid scalp preparations was permitted throughout the studies. In addition, at Week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50 response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy in addition to Otezla 30 mg twice daily treatment.
Following 52 weeks of treatment, patients could continue within the long-term extension of the ESTEEM 1 and ESTEEM 2 studies for a total duration of treatment up to 5 years (260 weeks).
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. Other endpoints included BSA, Pruritus VAS, nail disease (NAPSI), scalp involvement (ScPGA), and quality of life measures (DLQI and SF-36 MCS).
Across both studies, patients ranged in age from 18 to 83 years, with an overall median age of 45.8 years. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of patients with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. Approximately 30% of all patients had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis (including treatment failures), with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one third of patients had not received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patients had a history of psoriatic arthritis.

Clinical response.

The proportion of patients achieving PASI-50, 75 and 90 responses, and sPGA score of clear or almost clear, are presented in Table 6. Otezla resulted in significant improvements in moderate to severe plaque psoriasis as demonstrated by the proportion of patients with PASI-75 response at Week 16 compared with placebo. Clinical improvement measured by sPGA, PASI-50 and PASI-90 responses were also demonstrated at Week 16. In addition, Otezla demonstrated a treatment benefit across multiple manifestations of psoriasis including pruritus, nail disease, scalp involvement and quality of life measures.
The clinical benefit of Otezla was demonstrated across multiple 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 ranges.
Significantly greater improvements compared to placebo in mean % change in PASI from baseline, skin discomfort/pain and pruritus were observed at Week 2. In general, PASI responses were achieved by Week 16 and were sustained through Week 32.
During the Randomised Treatment Withdrawal Phase (Weeks 32-52) in Study ESTEEM 1, the mean percent improvement in PASI from baseline remained stable (81-88%) for patients re-randomised to Otezla at Week 32. Approximately 61% of these patients had a PASI-75 response at Week 52. Of the patients re-randomised to placebo at Week 32, 11.7% achieved PASI-75 response at Week 52. Patients who were re-randomised to placebo lost PASI-75 response faster than patients re-randomised to Otezla. The median time to first loss of PASI-75 response for patients re-randomised to placebo and Otezla at Week 32 was 5.1 and 17.7 weeks, respectively.
In study ESTEEM 2, 80.3% of patients re-randomised to Otezla at Week 32 had a PASI-50 response at Week 52. Of the patients with at least a PASI-50 response who were re-randomised to placebo at week 32, 24.2% were PASI-50 responders at Week 52. Patients who were re-randomised to placebo lost 50% of their Week 32 PASI response significantly faster than patients re-randomised to Otezla. The median time to first loss of PASI-50 response for patients re-randomised to placebo and Otezla at Week 32 was 12.4 and 21.9 weeks, respectively.
After randomised withdrawal from therapy at Week 32, approximately 70% of patients in Study ESTEEM 1, and 65.6% of patients in Study ESTEEM 2, regained PASI-75 (Study ESTEEM 1) or PASI-50 (Study ESTEEM 2) responses after re-initiation of Otezla treatment. The duration of re-treatment was variable, and ranged from 3.4 to 22.1 weeks in Study ESTEEM 1 and from 2.6 to 18.3 weeks in Study ESTEEM 2.
Among 832 patients initially randomised to Otezla 30 mg twice daily, 443 patients (53%) entered the open-label extension studies of ESTEEM 1 and ESTEEM 2 studies, and of these 115 patients (26%) were still on treatment at week 260.

Nail psoriasis.

In Study ESTEEM 1, significant improvements (reductions) in nail psoriasis, as measured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, were detected in patients receiving Otezla compared with placebo treated patients at Week 16 (Otezla 30 mg twice daily: -22.5%; placebo: +6.5%; p < 0.0001). Similar improvements were observed in Study ESTEEM 2 (Otezla 30 mg twice daily: -29.0%; placebo: -7.1%, p = 0.0052). Further improvements in nail psoriasis were observed in patients continuously treated with Otezla, with mean percent changes from baseline in NAPSI at Week 32 of -43.6% in Study ESTEEM 1 and -60.0% in Study ESTEEM 2.

Scalp psoriasis.

In Study ESTEEM 1, significant improvements in scalp psoriasis of at least moderate severity (≥ 3), measured by the proportion of patients achieving Scalp Psoriasis Physician's Global Assessment (ScPGA) of clear (0) or minimal (1) at Week 16, were detected in patients receiving Otezla compared with placebo treated patients (46.5% and 17.5%, respectively, p < 0.0001). Similar results were observed in Study ESTEEM 2 (APR 30 twice daily 40.9%; placebo 17.2%, p < 0.0001).

Quality of life.

In Studies ESTEEM 1 and 2, significant improvements in quality of life as measured by the Dermatology Life Quality Index (DLQI) and the SF-36v2 MCS were demonstrated in patients receiving Otezla compared with placebo treated patients. In addition, in Study ESTEEM 1, significant improvement in the Work Limitations Questionnaire (WLQ-25) index was achieved in patients receiving Otezla compared with placebo.
Clinical trial experience in mild to moderate plaque psoriasis. A Phase 3, randomised, double-blind, placebo-controlled study (ADVANCE) was conducted in 595 adult patients with mild to moderate plaque psoriasis (sPGA score of 2 (mild) or 3 (moderate), BSA involvement of 2-15%, PASI score of 2-15). Enrolled patients had an inadequate response or intolerance to at least one topical therapy and were biologic naïve to plaque psoriasis. Patients were allowed to use unmedicated emollients for lesions on non-scalp areas of the body and nonmedicated shampoos for lesions on the scalp.
Patients were randomised 1:1 to receive either Otezla 30 mg twice daily (n = 297) or placebo (n = 298) for 16 weeks (placebo-controlled phase). At week 16, the placebo group was switched to Otezla and patients in the Otezla group continued taking the drug through week 32. The primary endpoint was the proportion of patients with sPGA response (defined as a score of clear [0] or almost clear [1] and with at least a 2-point reduction from baseline) at week 16. Other evaluated endpoints include the proportion of patients with a Whole Body Itch numeric rating scale (NRS) response (defined as a ≥ 4 point reduction from baseline) at week 16 among patients with a baseline Whole Body Itch NRS ≥  4 and the proportion of patients with an ScPGA response (defined as an ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at Week 16 among patients with a baseline ScPGA score ≥ 2.
Patients ranged in age from 18 to 85, with a median age of 50 years at baseline. The mean baseline BSA involvement was 6.4%, the mean baseline PASI score was 6.5, and the proportions of patients with a sPGA score of 2 (mild) to 3 (moderate) at baseline were 30.6% and 69.4%, respectively.

Clinical response.

Otezla 30 mg twice daily resulted in significant improvement in mild to moderate psoriasis as demonstrated by the proportion of patients with sPGA response, Whole Body Itch NRS response, and an ScPGA at week 16 (see Table 7).
Among patients originally randomised to Otezla, the sPGA, ScPGA, and Whole Body Itch responses were maintained through week 32.

Quality of life.

At week 16, a statistically significantly greater improvement in quality of life as measured by change from baseline in the DLQI total score (Otezla twice daily, compared with placebo-treated patients).
Psoriasis involving the scalp area. A randomized, double-blind, placebo-controlled trial (STYLE) was conducted in 303 adult subjects with moderate to severe plaque psoriasis of the scalp. Enrolled subjects had a Scalp Physician Global Assessment (ScPGA) score of ≥ 3, Scalp Surface Area (SSA) involvement of ≥ 20%, an inadequate response or intolerance to at least one topical therapy for plaque psoriasis of the scalp and moderate to severe plaque psoriasis (BSA involvement of ≥ 10%, sPGA of ≥ 3 [moderate or severe disease], and PASI score ≥ 12).
Subjects were randomized 2:1 to receive either Otezla 30 mg twice daily (n=201) or placebo twice daily (n=102) for 16 weeks. The primary endpoint was the proportion of subjects who achieved ScPGA response at Week 16 (defined as ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline at Week 16).
Secondary endpoints included the proportion of subjects with Whole Body Itch Numerical Rating Scale (NRS) response (defined as ≥ 4 point reduction from baseline) at Week 16 and the proportion of subjects with a Scalp Itch NRS response (defined as ≥ 4 point reduction from baseline) at Week 16. The secondary endpoints also included assessment of Whole Body Itch NRS response and Scalp Itch NRS response at each of the other post-baseline visits during the placebo-controlled phase (Weeks 2, 4, 8, 12, and 16).
Subjects had a mean age of 46.9 years, 61.7% were men and 75.6 % were white. At baseline, 76.9% of subjects had moderate scalp psoriasis (ScPGA of 3), 23.1% having severe scalp psoriasis (ScPGA of 4), 71.6% of subjects were biologic naive, and 58.8% had failed 1 or 2 topicals. At baseline, the mean Whole Body Itch NRS score was 7.2 (median [min, max]: 8.0 [0, 10]) and the mean Scalp Itch NRS score was 6.7 (median [min, max]: 7.0 [0, 10]) with the scales ranging from 0 to 10. The mean baseline SSA involvement was 60.6% (median [min, max]: 60.0% [20%, 100%]) and the mean baseline BSA involvement was 19.8% (median [min, max]: 15.5% [10.0%, 91.0%]).
Otezla 30 mg twice daily resulted in significant improvement in scalp psoriasis as demonstrated by the proportion of subjects with a ScPGA response, Whole Body Itch NRS response, and Scalp Itch NRS response at Week 16 (p < 0.0001), compared with placebo (see Table 8).
Otezla 30 mg twice daily resulted in significant improvements in Whole Body Itch as demonstrated by the proportion of subjects with Whole Body Itch NRS response as early as Week 2 and at every visit through Week 16, compared with placebo (see Figure 3). Otezla 30 mg twice daily achieved similar improvement in Scalp Itch as demonstrated in Figure 4.
Behcet's disease. The safety and efficacy of Otezla were evaluated in a Phase 3, randomised, placebo-controlled study (RELIEF) in adult patients with active Behcet's disease (BD) with oral ulcers. Patients were previously treated with at least one non-biologic BD medication for oral ulcers and were candidates for systemic therapy. Concomitant treatment for BD was not allowed. The population studies met the International Study Group (ISG) criteria for BD. Patients had at least 2 oral ulcers at screening and at least 2 oral ulcers at randomization without currently active major organ involvement. Patients with severe BD, defined as those with active major organ involvement (for ex. meningoencephalitis or pulmonary artery aneurysm) were excluded.
A total of 207 BD patients were randomised 1:1 to receive either Otezla 30 mg twice daily (n = 104) or placebo (n = 103) for 12-weeks (placebo-controlled phase) and from weeks 12 to 64, all patients received Otezla 30 mg twice daily (active treatment phase).
The primary endpoint was the area under the curve (AUC) for the number of oral ulcers from baseline through week 12. Secondary endpoints included other measures of oral ulcers (oral ulcer pain Visual Analog Scale (VAS)), proportion of patients who are oral ulcer-free (complete response), time to onset of oral ulcer resolution, and proportion of patients achieving resolution of oral ulcers by week 6, and who remain oral ulcer free at every visit for at least 6 additional weeks during the 12-week placebo-controlled treatment phase). Other endpoints included Behcet's Syndrome Activity Score (BSAS), BD current activity form (BDCAF), including the BD current activity index (BDCAI) score, the Patient's Perception of Disease Activity, the Clinician's Overall Perception of Disease Activity and the BD Quality of Life Questionnaire (BD QoL).
Patients ranged in age from 19 to 72, with a mean age of 40 years. The mean duration of BD was 6.84 years. All patients had a history of recurrent oral ulcers that were currently active. Patients had a history of skin lesions (98.6%), genital ulcers (90.3%), musculoskeletal manifestations (72.5%), ocular manifestations (17.4%), central nervous system (9.7%), GI manifestations (9.2%) and vascular involvement (1.4%). The mean baseline oral ulcer counts were 4.2 and 3.9 in the Otezla and placebo groups, respectively.

Measure of oral ulcers.

Otezla 30 mg twice daily resulted in significant improvement in oral ulcers as demonstrated by the AUC for the number of oral ulcers from baseline through Week 12 (p < 0.0001), compared with placebo. Significant improvements in other measures of oral ulcers were demonstrated at week 12, see Table 9.
Among 104 patients originally randomised to Otezla 30 mg twice daily, 75 patients (approximately 72%) remained on this treatment at week 64. Among patients who were continuously treated with Otezla and remained in the study, improvements in oral ulcers and reduction of oral ulcer pain were maintained through week 64 (see Figure 5 and Figure 6).
Among patients originally randomised to Otezla 30 mg twice daily who remained in the study, the proportion of patients with a complete response of oral ulcers was maintained through week 64.

Quality of life.

Otezla 30 mg twice daily, compared with placebo, resulted in significantly greater improvement in quality of life (QoL) at week 12, as demonstrated by the BD QoL Questionnaire (p = 0.0003).

5.2 Pharmacokinetic Properties

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 is linear, with a dose proportional increase in systemic exposure in the dose range of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice daily.
Co-administration with food does not alter the bioavailability; 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 extra vascular distribution.

Metabolism.

Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major circulating component following oral administration. Apremilast undergoes extensive metabolism with only 3% and 7% of the administered drug recovered in urine and faeces, respectively. The major circulating metabolite, M12, is the glucuronide conjugate of O-demethylated apremilast which is inactive.

Excretion.

The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 9 hours. There is approximately 30% reduction in apremilast clearance observed in female subjects compared to male subjects. No dose adjustment is necessary for female patients.
Following oral administration of radiolabelled apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively.

Renal impairment.

No formal studies have been conducted in subjects with mild to moderately impaired renal function. In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 89% and 42%, respectively. See Section 4.2 Dose and Method of Administration for dose adjustments for patients with severe renal impairment.

Hepatic impairment.

The pharmacokinetics of apremilast and its major metabolite M12 is not affected by moderate or severe hepatic impairment. No dosage adjustment is necessary for patients with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

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 2,000 mg/kg/day.

Carcinogenicity.

Carcinogenicity studies showed no evidence of treatment related tumours following oral treatment with apremilast at plasma exposure levels (AUC) that were 7 to 10-fold (mice) and 0.1 to 1-fold (rats) than anticipated clinically.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Otezla tablet contains either 10 mg, 20 mg or 30 mg of apremilast with the following excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, iron oxide red, iron oxide yellow (20 mg and 30 mg only) and iron oxide black (30 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Presentation.#

A two-week titration pack (4 x 10 mg, 4 x 20 mg and 5 x 30 mg for the first week for dose titration and 14 x 30 mg tablets for the second week).
A two-week titration starter pack (4 x 10 mg, 4 x 20 mg and 5 x 30 mg for the first week for dose titration and 14 x 30 mg tablets for the second week).
A four-week pack (56 x 30 mg tablets).
A 12-week pack (168 x 30 mg tablets).
# Not all pack sizes are marketed in Australia.

Container type.

The tablets are provided in polyvinylchloride (PVC) blisters with push through aluminium foil.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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. Apremilast is the S-enantiomer with a specific rotation of +28.1° in acetonitrile at a concentration of 20 mg/mL.
Molecular formula: C22H24N2O7S.
Molecular weight: 460.5.
ATC code: L04AA32.
Chemical name: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl] acetamide.

Chemical structure.


CAS number.

608141-41-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes