Otezla

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Apremilast 30 mg;  
Available from:
Amgen New Zealand Limited
INN (International Name):
Apremilast 30 mg
Dosage:
30 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Apremilast 30 mg   Excipient: Croscarmellose sodium Lactose monohydrate Magnesium stearate Microcrystalline cellulose Opadry beige 85F17424 Purified water
Prescription type:
Prescription
Manufactured by:
Celgene Chemicals GmbH
Therapeutic indications:
For the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phytotherapy or systemic therapy.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC blisters with aluminium push through foil 30mg - 56 tablets - 36 months from date of manufacture stored at or below 30°C - Blister pack, PVC blisters with aluminium push through foil 30mg - 168 tablets - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-9787
Authorization date:
2015-06-17

Read the complete document

Otezla

(apremilast) film coated tablets

New Zealand Consumer Medicine Information

Otezla

®

(apremilast) film coated tablets

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Otezla.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Otezla

against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

WHAT OTEZLA IS USED FOR

Otezla is used to treat adults with the following conditions:

Moderate to severe plaque psoriasis (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)

Psoriatic arthritis (an inflammatory disease of the joints, often accompanied by psoriasis)

Psoriasis and psoriatic arthritis are usually lifelong conditions and there is currently no cure. 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 and psoriatic arthritis. By

regulating the immune response, Otezla can help to control the signs and symptoms of these

conditions.

In psoriasis, treatment with Otezla results in a reduction in psoriatic skin plaques and other signs and

symptoms of the disease.

In psoriatic arthritis, treatment with Otezla results in an improvement in swollen and painful joints,

and can improve your general physical function.

Otezla has also been shown to improve the quality of life in patients with psoriasis or psoriatic

arthritis. This means that the impact of your condition on daily activities, relationships and other

factors should be less than it was before.

Ask your doctor if you have any questions about how Otezla works, or why this medicine has

been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

Otezla

(apremilast) film coated tablets

BEFORE YOU TAKE OTEZLA

When you must not take it

Do not take Otezla if you have an allergy to apremilast, the active ingredient of Otezla, or any

of the other ingredients of Otezla listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue or other parts of the body

rash, itching or hives on the skin.

If you think you may be allergic to Otezla, ask your doctor for advice.

Do not take Otezla if you are pregnant or think you may be pregnant.

Do not breast-feed if you are taking Otezla.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Follow your doctor’s instructions carefully.

If you have not fully understood these instructions, ask your doctor again before taking Otezla.

Tell your doctor if you have or have had any kidney problems.

Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a

baby.

There is little information about the effects of Otezla in pregnancy. You should not use Otezla if you

are pregnant. You should not become pregnant while taking this medicine

Tell your doctor before taking this medicine if you are breast-feeding or intend to breast-feed.

It is not known whether Otezla passes into the mother's milk. You should not use Otezla while

breast-feeding.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

During treatment with Otezla, if you experience diarrhoea, nausea or vomiting, tell your

doctor.

Tell your doctor if you have rare hereditary problems to some sugars (e.g., galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption).

Otezla contains lactose (a type of sugar). Tell your doctor if you have lactose intolerance.

Do not give this medicine to a child or adolescent under the age of 18 years.

Safety and effectiveness of Otezla in children under the age of 18 years have not been established.

Otezla

(apremilast) film coated tablets

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines or have recently taken any

other medicines, including any medicines that you buy without a prescription from a pharmacy,

supermarket or health food shop

In particular, tell your doctor or pharmacist before taking Otezla if you are taking any of the

following medicines:

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 Otezla or may affect how well it works. You may need different

amounts of these medicines, or you may need to take different medicines. Your doctor and

pharmacist have more information on medicines to be careful with or avoid while taking Otezla.

HOW TO TAKE OTEZLA

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how much Otezla to take and for how long you will need to take it. Your

doctor will monitor your progress.

When you first start taking Otezla, you will receive a treatment initiation pack which contains

all the doses as listed in the table below.

This pack is clearly labelled to make sure you take the correct tablet at the correct time.

Your treatment will start at a lower dose and will gradually be increased (also called ‘titrated’)

over the first 6 days of treatment.

This initiation pack will also contain enough tablets for another 8 days at the recommended

dose (Days 7 to 14).

The final recommended dose of Otezla is a 30 mg tablet twice a day; one 30 mg dose in the

morning and one 30 mg dose in the evening. This is a total daily dose of 60 mg.

By the end of Day 6 you will have reached this recommended dose.

Once the recommended dose has been reached, you will only get the 30 mg tablet strength in

your prescribed packs.

You will only ever go through a titration stage once, even if you re-start treatment after a break.

If you have severe kidney problems

, the recommended dose of Otezla is 30 mg

once a day

. Your

doctor will tell you how to gradually increase (titrate) your dose when you first start taking Otezla.

Day

Morning Dose

Afternoon or

Evening Dose

Total Daily

Dose

Day 1

10 mg (pink tablet)

Do not take a dose

10 mg

Day 2

10 mg (pink tablet)

10 mg (pink tablet)

20 mg

Day 3

10 mg (pink tablet)

20 mg (brown tablet)

30 mg

Day 4

20 mg (brown tablet)

20 mg (brown tablet)

40 mg

Day 5

20 mg (brown tablet)

30 mg (beige tablet)

50 mg

Day 6 onwards

30 mg (beige tablet)

30 mg (beige tablet)

60 mg

Otezla

(apremilast) film coated tablets

Your doctor may advise that you only take the morning dose shown in the table above, and that you

skip the afternoon or evening dose.

How to take it

Swallow the tablets whole, preferably with water, either with or without food, twice a day as

directed by your doctor.

Do not crush, split or chew the tablets.

When to take it

Take Otezla at about the same time each day, one tablet in the morning and one tablet in the

evening.

How long to take it

Your doctor will tell you how long to continue taking Otezla.

If you forget to take it

Take it as soon as you remember. If it is close to the time for the next dose, just skip the missed

dose. Take the next dose at the regular time. Do not take a double dose to make up for the dose

that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

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

hints.

If you take too much (overdose)

Immediately telephone your doctor or the National Poisons Centre (telephone 0800 POISON or

0800 64 766) for advice, or go to Accident and Emergency at your nearest hospital, if you think

that you or anyone else may have taken too much Otezla.

Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for

these places handy

Take the medicine pack with you.

WHILE YOU ARE TAKING OTEZLA

Things you must do

Tell any other doctors, dentists and pharmacists who are treating you that you are taking

Otezla

If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist

that you are taking Otezla

Keep all of your doctor’s appointments so that your progress can be checked.

Things you must not do

Do not breast-feed or become pregnant whilst taking Otezla

Do not stop taking Otezla or change the dose without first checking with your doctor.

Otezla

(apremilast) film coated tablets

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or

shows signs of tampering. In that case, return it to your pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Otezla affects you.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking

Otezla.

Like all medicines, Otezla can have side effects, although not everybody gets them and some are

uncommon. Sometimes they are serious, most of the time they are not. You may need medical

attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

diarrhoea; nausea; vomiting; stomach pain; indigestion; decrease in appetite

weight decrease

cough; cold; runny nose; inflammation/infection of the nose, throat, sinus, or upper respiratory

tract

if you feel tired; if you have trouble or difficulty sleeping

headaches and migraine headaches

back pain; joint pain; painful, swollen joints

Increased blood pressure

skin rash

allergic reactions.

The above list mainly includes the more common side effects of your medicine.

Tell your doctor immediately if you notice the following:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue or other parts of the body.

Tell your doctor or pharmacist immediately if any of the side effects gets worse, or if you notice

any other side effects not listed in this leaflet.

AFTER TAKING OTEZLA

Storage

Keep your tablets in a dry place where the temperature stays below 30

C.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Otezla

(apremilast) film coated tablets

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, take any

unused Otezla tablets to your pharmacist.

Medicines should not be disposed of via wastewater or household waste. These measures will help to

protect the environment.

PRODUCT DESCRIPTION

What Otezla looks like

Apremilast 10 mg Tablets: Pink, diamond shaped film-coated tablet with “APR” engraved on one

side and “10” on the opposite side.

Apremilast 20 mg Tablets: Brown, diamond shaped film-coated tablet with “APR” engraved on one

side and “20” on the opposite side.

Apremilast 30 mg Tablets: Beige, diamond shaped film-coated tablet with “APR” engraved on one

side and “30” on the opposite side.

The tablets are provided in packs as follows.

A titration pack that will last for two weeks. This pack will contain 4 x 10 mg, 4 x 20 mg and

5 x 30 mg tablets for the first week and 14 x 30 mg tablets for the second week.

A four-week pack (56 x 30 mg tablets).

Ingredients

Otezla tablets contain an active ingredient called apremilast.

The other ingredients are:

lactose monohydrate

microcrystalline cellulose

croscarmellose sodium

magnesium stearate.

The film coat contains:

Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red. In addition iron oxide

yellow (in 20 mg and 30 mg tablets only) and iron oxide black (in 30 mg tablets only).

SPONSOR DETAILS

Supplier

The sponsor in New Zealand is:

Amgen (New Zealand) Limited

Level 22, PwC Tower

15 Customs Street West

Auckland 1010

Telephone 0800 443 885

Email: medinfo.JAPAC@amgen.com

Otezla

(apremilast) film coated tablets

DATE OF PREPARATION

This leaflet was updated in Jan 2021.

Otezla

is a registered trademark of Amgen.

Read the complete document

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 1 of 29

1.

PRODUCT NAME

Otezla

30 mg tablets

Otezla titration pack 10 mg, 20 mg, 30 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 10 mg tablet contains 10 mg apremilast.

Each 20 mg tablet contains 20 mg apremilast.

Each 30 mg tablet contains 30 mg apremilast.

For the full list of excipients, see section 6.1 List of excipients.

Excipient(s) with known effect

Otezla 10 mg, 20 mg and 30 mg tablets contain 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.

Description

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.

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 moderate to severe plaque psoriasis who are

candidates for phototherapy or systemic therapy.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 2 of 29

4.2

Dose and method of administration

Treatment with Otezla should be initiated by specialists experienced in the diagnosis and

treatment of psoriasis or psoriatic arthritis.

Dose

The recommended dose of Otezla is 30 mg twice daily taken orally approximately

12 hours apart. An initial titration schedule is required as shown below in Table 1. No

re-titration is required after initial titration.

Table 1:

Dose Titration Schedule

Day 1

Day2

Day 3

Day 4

Day 5

Day 6 &

thereafter

AM

AM

PM

AM

PM

AM

PM

AM

PM

AM

PM

10 mg

10 mg

10 mg

10 mg

20 mg

20 mg

20 mg

20 mg

30 mg

30 mg

30 mg

Dose modification or interruption

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.

Special populations

Elderly

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 Cockroft-Gault equation). For initial dosage titration in this

group, it is recommended that apremilast 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) or psoriasis (PSOR) patients with

hepatic impairment.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 3 of 29

In the event of intolerable adverse events, interruption or discontinuation of Otezla

should be considered.

Paediatric population

No data are available.

Method of administration

Otezla tablets should be swallowed whole, either with or without food. The tablets

should not be crushed, split or chewed.

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

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.

Depression

Treatment with Otezla is associated with an increase in occurrences of depression (see

section 4.8 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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 4 of 29

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 renal impairment

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

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 [Undesirable effects]).

4.5

Interaction with other medicines and other forms of interaction

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 µM).

In vitro, apremilast has little to no inhibitory effect (IC

> 10 µM) 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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 5 of 29

concentration (C

) 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 AUC

0-∞

and C

approximately 36% and by 5%, respectively, which is not clinically meaningful. Otezla

can be co-administered with a potent CYP3A4 inhibitor like ketoconazole.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy (Pregnancy 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 (see section 5.3 [Preclinical safety data]).

Breast-feeding

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 breast-feeding.

Fertility

No fertility data is available in humans.

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

Undesirable effects

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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 6 of 29

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.

Hypersensitivity reactions were observed infrequently in clinical studies with Otezla.

Summary of safety profile

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%).

Tabulated summary of treatment emergent adverse events

The observed Treatment Emergent Adverse Events (TEAEs) with patient incidence of at

least 2% in any treatment group during 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 psoriasis Phase 3 studies during weeks 0-16 of therapy.

The highest incidence from either indication is shown below. The most frequently

reported TEAEs were gastrointestinal related. The overall incidence of serious adverse

events was low and similar to placebo.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 7 of 29

Table 2:

Otezla Data Pool: TEAEs with Patient Incidence of at Least 2% in

Psoriatic Arthritis or Psoriasis Phase 3 studies in any Treatment Group

(highest incidence from either indication) During Weeks 0-16

Preferred Term

a

Placebo

n (%)

Otezla 30 mg twice daily

n (%)

Diarrhoea

28 (6.7)

186 (15.7)

Nausea

28 (6.7)

164 (13.9)

Upper respiratory tract infection

27 (6.5)

100 (8.4)

Headache

24 (3.6)

77 (7.9)

Nasopharyngitis

29 (6.9)

89 (7.5)

Tension headache

14 (3.3)

85 (7.2)

Vomiting

7 (1.7)

39 (3.3)

Fatigue

6 (1.4)

32 (2.7)

Dyspepsia

4 (1.0)

31 (2.6)

Hypertension

15 (2.2)

25 (2.6)

Decreased appetite

4 (1.0)

28 (2.4)

Arthralgia

7 (1.7)

25 (2.1)

Back pain

4 (1.0)

25 (2.1)

Migraine

4 (1.0)

25 (2.1)

Sinusitis

6 (1.4)

25 (2.1)

Abdominal discomfort

6 (1.4)

24 (2.0)

Frequent bowel movements

1 (0.2)

24 (2.0)

Gastroenteritis

9 (2.2)

20 (1.7)

Urinary tract infection

9 (2.2)

17 (1.4)

Psoriasis

13 (3.1)

10 (0.8)

Preferred Terms are coded using the MedDRA (Version 14.0)

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with Otezla are listed below 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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 8 of 29

the two Phase 3 studies in 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).

Table 3:

Summary of Adverse Reactions in Phase 3 Psoriatic Arthritis and

Psoriasis Clinical Studies

System Organ Class

Frequency

Preferred Term

a

Infections and infestations

Common

Bronchitis

Upper respiratory tract infection

Nasopharyngitis

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition

disorders

Common

Decreased appetite

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Common

Migraine

Tension headache

Headache

Respiratory, thoracic, and

mediastinal disorders

Common

Cough

Gastrointestinal disorders

Very Common

Diarrhoea

Nausea

Common

Vomiting

Frequent bowel movements

Abdominal pain upper

Gastroesophageal reflux disease

Dyspepsia

Skin and subcutaneous

tissue disorders

Uncommon

Rash

Musculoskeletal and

connective tissue disorders

Common

Back pain

General disorders and

administrative site conditions

Common

Fatigue

Investigations

Uncommon

Weight decrease

Preferred Terms are coded using the MedDRA (Version 14.0)

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 9 of 29

Description of selected adverse reactions

Weight decrease

Patient weight was measured routinely in clinical studies.

The mean observed weight loss in patients treated for up to 52 weeks with apremilast

was 1.99 kg. A total of 14.3% of patients receiving apremilast had observed weight loss

between 5-10% while 5.7% of the patients receiving apremilast had observed weight loss

greater than 10%. None of these patients had overt clinical consequences resulting from

weight loss. A total of 0.1% of patients treated with apremilast 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 3 controlled clinical trials,

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, 0.1% (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,

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.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 10 of 29

Other special populations

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important.

It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals are asked to report any suspected adverse reactions

https://nzphvc.otago.ac.nz/reporting/.

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.

In New Zealand, contact the National Poisons Centre on 0800 POISON or 0800 764 766

for advice on management.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA32

Pharmacodynamic effects

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,

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 11 of 29

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 efficacy and safety

This section presents data from three (3) multi-centre, randomised, double-blind,

placebo-controlled studies in patients with active PsA despite previous treatment with

disease modifying antirheumatic drugs (DMARDs) including biologics, one (1)

multi-centre, randomised, double-blind, placebo-controlled study in patients with active

PsA who were DMARD-naive and two (2) multi-centre, randomised, double-blind,

placebo-controlled studies in patients with moderate to severe plaque psoriasis. More

details on the individual studies are provided in the sections below.

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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 12 of 29

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 study for a total duration of up to 5 years.

These studies did not investigate the effects of Otezla on structural progression.

Clinical responses

Treatment with apremilast 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 apremilast 30 mg twice daily at Week 16, are

shown in Table 4. ACR 20/50/70 responses were maintained at Week 24.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 13 of 29

Table 4:

Proportion of Patients with ACR Responses in Studies PALACE 1,

PALACE 2 and PALACE 3 at Week 16

*p ≤ 0.01 for apremilast vs. placebo.

**p ≤ 0.001 for apremilast vs. placebo.

N is the number of randomised and treated patients at Week 16.

ACR 20/50/70 response through Week 52

Among 497 patients initially randomised to apremilast 30 mg twice daily,

(75%)

patients were still on this treatment at Week 52. In these patients,

20/50/70 responses at week 52 were 57%, 25%, and 11% respectively (see

figure

PALACE 1

PALACE 2

PALACE 3

Placebo

+/-

DMARDs

Apremilast

30 mg BID

+/-

DMARDs

Placebo

+/-

DMARDs

Apremilast

30 mg BID

+/-

DMARDs

Placebo

+/-

DMARDs

Apremilast

30 mg BID

+/-

DMARDs

N

a

168

168

159

162

169

167

ACR 20

Week 16

19.0%

38.1%**

18.9%

32.1%*

18.3%

40.7%**

ACR 50

Week 16

6.0%

16.1%*

5.0%

10.5%

8.3%

15.0%

ACR 70

Week 16

1.2%

4.2%

0.6%

1.2%

2.4%

3.6%

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 14 of 29

Figure 1:

Proportion of ACR 20/50/70 Responders Through Week 52 in the

Pooled Studies PALACE 1, PALACE 2 and PALACE 3

Note: n/m is the number of responders/number of subjects with sufficient data for definitive determination of

response status at each time point, which includes subjects who discontinued early between the preceding

time point and the time point in question.

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-naïve) 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

Proportion of Responders (% with 95% CI)

Endpoint

ACR 20

ACR 50

ACR 70

Study Week

Endpoint

ACR 20

Study Week

Endpoint

n/m (%)

ACR 20

185/449 (41.2)

Study Week

Endpoint

n/m (%)

ACR 20

196/428 (45.8)

Study Week

Endpoint

n/m (%)

ACR 20

223/392 (56.9)

Study Week

Endpoint

n/m (%)

ACR 20

212/373 (56.8)

Study Week

Endpoint

ACR 50

Study Week

Endpoint

n/m (%)

ACR 50

70/453 (15.5)

Study Week

Endpoint

n/m (%)

ACR 50

93/432 (21.5)

Study Week

Endpoint

n/m (%)

ACR 50

102/393 (26.0)

Study Week

Endpoint

n/m (%)

ACR 50

92/374 (24.6)

Study Week

Endpoint

ACR 70

Study Week

Endpoint

n/m (%)

ACR 70

15/457 ( 3.3)

Study Week

Endpoint

n/m (%)

ACR 70

33/432 ( 7.6)

Study Week

Endpoint

n/m (%)

ACR 70

44/396 (11.1)

Study Week

Endpoint

n/m (%)

ACR 70

39/373 (10.5)

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 15 of 29

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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 16 of 29

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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 17 of 29

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.

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 apremilast 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.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 18 of 29

Clinical responses

The percent of patients achieving ACR 20/50/70 responses at Week 16 in Study

PALACE 4 is presented below 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.

Table 5:

Proportion of Patients with ACR Responses at Week 16 in Study

PALACE 4

PALACE 4

Placebo

Otezla 30 mg twice daily

N

a

176

176

ACR 20

Week 16

ACR 50

Week 16

ACR 70

Week 16

N is number of randomised and treated patients

p ≤ 0.05 for Otezla vs. placebo.

p ≤ 0.001 for Otezla vs. placebo.

ACR 20/50/70 response through Week 52

Among 176 patients initially randomised to apremilast 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).

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 19 of 29

Figure 2

Proportion of ACR 20/50/70 Responders Through Week 52 in Study

PALACE 4 (Data as Observed)

Note: n/m is the number of responders/number of subjects with sufficient data for definitive determination of

response status at each time point, which includes subjects who discontinued early between the preceding

time point and the time point in question.

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.

Proportion of Responders (% with 95% CI)

Endpoint

ACR 20

ACR 50

ACR 70

Study Week

Endpoint

ACR 20

Study Week

Endpoint

n/m (%)

ACR 20

54/164 (32.9)

Study Week

Endpoint

n/m (%)

ACR 20

71/153 (46.4)

Study Week

Endpoint

n/m (%)

ACR 20

84/144 (58.3)

Study Week

Endpoint

n/m (%)

ACR 20

81/138 (58.7)

Study Week

Endpoint

ACR 50

Study Week

Endpoint

n/m (%)

ACR 50

20/164 (12.2)

Study Week

Endpoint

n/m (%)

ACR 50

26/154 (16.9)

Study Week

Endpoint

n/m (%)

ACR 50

39/145 (26.9)

Study Week

Endpoint

n/m (%)

ACR 50

44/138 (31.9)

Study Week

Endpoint

ACR 70

Study Week

Endpoint

n/m (%)

ACR 70

7/164 ( 4.3)

Study Week

Endpoint

n/m (%)

ACR 70

9/154 ( 5.8)

Study Week

Endpoint

n/m (%)

ACR 70

24/145 (16.6)

Study Week

Endpoint

n/m (%)

ACR 70

25/138 (18.1)

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 20 of 29

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.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 21 of 29

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 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.

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).

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 22 of 29

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 below. 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.

Table 6:

Clinical Response at Week 16 in Studies ESTEEM 1 and ESTEEM 2

a

ESTEEM 1

ESTEEM 2

Placebo

30 mg twice

daily APR

#

Placebo

30 mg twice

daily APR

#

N

282

562

137

274

PASI 75

b

, n (%)

15 (5.3)

186 (33.1)

8 (5.8)

79 (28.8)

sPGA

c

of clear or

Almost clear, n (%)

11 (3.9)

122 (21.7)

6 (4.4)

56 (20.4)

PASI 50, n (%)

48 (17.0)

330 (58.7)

27 (19.7)

152 (55.5)

PASI 90, n (%)

1 (0.4)

55 (9.8)

2 (1.5)

24 (8.8)

Percent change

BSA

d,h

(%)

- 6.9

± 38.95

- 47.8

± 38.48

- 6.1

± 47.57

- 48.4

± 40.78

Change in Pruritus

VAS

e,h

(mm)

- 7.3

± 27.08

- 31.5

± 32.43

- 12.2

± 30.94

- 33.5

± 35.46

Change in DLQI

f,h

- 2.1

- 6.6

- 2.8

- 6.7

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 23 of 29

± 5.69

± 6.66

± 7.22

± 6.95

Change in SF-36

MCS

g,h

- 1.02

± 9.161

2.39

± 9.504

± 10.498

2.58

± 10.129

p < 0.0001 for all comparisons vs. placebo, except for ESTEEM 2 PASI 90 and change in SF-36 MCS

where p = 0.0042 and p = 0.0078, respectively.

Full Analysis Set, Last Observation Carried Forward

PASI = Psoriasis Area and Severity Index

sPGA = Static Physician Global Assessment

BSA = Body Surface Area

VAS = Visual Analog Scale; 0 = best, 100 = worst

DLQI = Dermatology Life Quality Index; 0 = best, 30 = worst

SF-36 MCS = Medical Outcome Study Short Form 36-Item Health Survey, Mental Component Summary

mean +/- standard deviation

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.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 24 of 29

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.

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.

Paediatric population

The safety and effectiveness of Otezla has not been established in patients under the

age of 18 years.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 25 of 29

5.2

Pharmacokinetic properties

Absorption

Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%,

with peak plasma concentrations (C

) occurring at a median time (t

) 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.

Biotransformation

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.

Elimination

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.

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 26 of 29

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 C

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.

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 C

for apremilast than that in young subjects (18 to 55 years of age).

5.3

Preclinical safety data

Fertility and early embryonic development

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, 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).

Embryo-foetal development

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).

In a monkey embryo-foetal 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

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 27 of 29

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).

Pre- and Post-natal development

In a pre- and post- natal 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 post-natal

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).

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

Molecular formula:

Molecular weight:

460.5

CAS number:

608141-41-9

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:

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 28 of 29

6.1

List of excipients

Otezla tablets contain microcrystalline cellulose, lactose, croscarmellose sodium,

magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, iron oxide red,

iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

24 months

6.4

Special precautions for storage

Store below 30

6.5

Nature and contents of container

Presentation

A two-week titration pack (4 × 10 mg, 4 × 20 mg and 5 × 30 mg for the first week for

dose titration and 14 × 30 mg tablets for the second week).

A four-week pack (56 × 30 mg tablets).

A 12week pack (168 × 30 mg tablets).

Not all pack sizes are marketed in New Zealand

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

foil.

6.6

Special precautions for disposal <and other handling>

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

NEW ZEALAND DATA SHEET

Otezla Data Sheet

Page 29 of 29

8.

SPONSOR

Amgen (New Zealand) Limited

Level 22, PwC Tower

15 Customs Street West

Auckland 1010 Telephone: 0800 443 885

Email: medinfo.JAPAC@amgen.com

9.

DATE OF FIRST APPROVAL

Date of publication in the New Zealand Gazette of consent to distribute the medicine:

03 November 2016

10.

DATE OF REVISION OF THE TEXT

19 October 2020

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Sponsor address revision

Similar products

Search alerts related to this product

View documents history

Share this information