4.1. Therapeutic indications

Psoriatic arthritis

Apremilast, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1).

Psoriasis

Apremilast is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).

Behçet's disease

Apremilast is indicated for the treatment of adult patients with oral ulcers associated with Behçet's disease (BD) who are candidates for systemic therapy.

4.2. Posology and method of administration

Treatment with Apremilast should be initiated by specialists experienced in the diagnosis and treatment of psoriasis, psoriatic arthritis or Behçet's disease.

Posology

The recommended dose of apremilast is 30 mg taken orally twice daily, approximately 12 hours apart (morning and evening), with no food restrictions. 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

Day 2

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

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.

During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment for PsA and PSOR and within the first 12 weeks of treatment for BD. If a patient shows no evidence of therapeutic benefit after this time period, treatment should be reconsidered. The patient's response to treatment should be evaluated on a regular basis.

Special populations

Elderly patients

No dose adjustment is required for this patient population (see sections 4.8 and 5.2).

Patients with renal impairment

No dose adjustment is needed in patients with mild and moderate renal impairment. The dose of apremilast should be 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 dose 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 (see section 5.2).

Patients with hepatic impairment

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. No data are available.

Method of administration

Apremilast is for oral use. The film-coated tablets should be swallowed whole and can be taken either with or without food.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Diarrhoea, nausea, and vomiting

There have been post-marketing reports of severe diarrhoea, nausea, and vomiting associated with the use of apremilast. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalised. Patients 65 years of age or older may be at a higher risk of complications. If patients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment with apremilast may be necessary.

Psychiatric disorders

Apremilast is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression (see section 4.8). The risks and benefits of starting or continuing treatment with apremilast should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with apremilast.

Severe renal impairment

Apremilast should be dose reduced to 30 mg once daily in patients with severe renal impairment (see sections 4.2 and 5.2).

Underweight patients

Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin and St. John's Wort) with apremilast is not recommended. Co-administration of apremilast 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) and may result in reduced clinical response.

In clinical studies, apremilast has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy.

There was no clinically meaningful interaction between ketoconazole and apremilast. Apremilast can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole.

There was no pharmacokinetic interaction between apremilast and methotrexate in psoriatic arthritis patients. Apremilast can be co-administered with methotrexate.

There was no pharmacokinetic interaction between apremilast and oral contraceptives containing ethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Pregnancy should be excluded before treatment can be initiated. Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment.

Pregnancy

There are limited data about the use of apremilast in pregnant women.

Apremilast is contraindicated during pregnancy (see section 4.3). 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).

Breast-feeding

Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whether apremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot be excluded, therefore apremilast should not be used during breast-feeding.

Fertility

No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility were observed in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-fold clinical exposure. For pre-clinical fertility data, see section 5.3.

4.7. Effects on ability to drive and use machines

Apremilast has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with apremilast in PsA and PSOR are gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). The other most commonly reported adverse reactions include upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%) and are mostly mild to moderate in severity.

The most commonly reported adverse drug reactions with apremilast in BD are diarrhoea (41.3%), nausea (19.2%), headache (14.4%), upper respiratory tract infection (11.5%), upper abdominal pain (8.7%), vomiting (8.7%) and back pain (7.7%) and are mostly mild to moderate in severity.

The gastrointestinal adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks.

Hypersensitivity reactions are uncommonly observed (see section 4.3).

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with apremilast 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 apremilast clinical development programme and post-marketing experience. The frequencies of adverse drug reactions are those reported in the apremilast arms of the four Phase III studies in PsA (n = 1,945) or the two Phase III studies in PSOR (n = 1184), and in the phase III study in BD (n = 207) the highest frequency from either data pool is represented in table 2).

Frequencies are defined as:

- very common (≥ 1/10);

- common (≥ 1/100 to < 1/10);

- uncommon(≥ 1/1 000 to < 1/100);

- rare (≥ 1/10 000 to < 1/1 000);

- not known (cannot be estimated from the available data).

Table 2. Summary of adverse reactions in psoriatic arthritis (PsA), psoriasis (PSOR) and Behçet's disease (BD)

System Organ Class

Frequency

Adverse reaction

Infections and infestations

Very common

Upper respiratory tract infectiona

Common

Bronchitis

Nasopharyngitis*

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition disorders

Common

Decreased appetite*

Psychiatric disorders

Common

Insomnia

Depression

Uncommon

Suicidal ideation and behaviour

Nervous system disorders

Very common

Headache*, a

Common

Migraine*

Tension headache*

Respiratory, thoracic, and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Very Common

Diarrhoea*

Nausea*

Common

Vomiting*

Dyspepsia

Frequent bowel movements

Upper abdominal pain*

Gastroesophageal reflux disease

Uncommon

Gastrointestinal haemorrhage

Skin and subcutaneous tissue disorders

Uncommon

Rash

Urticaria

Not known

Angioedema

Musculoskeletal and connective tissue disorders

Common

Back pain*

General disorders and administration site conditions

Common

Fatigue

Investigations

Uncommon

Weight decrease

* At least one of these adverse reactions was reported as serious

a Frequency reported as common in PSA and PSOR

Description of selected adverse reactions

Psychiatric disorders

In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. Patients and caregivers should be instructed to notify the prescriber of any suicidal ideation (see section 4.4).

Body weight loss

Patient weight was measured routinely in clinical studies. The mean observed weight loss in PsA and PSOR 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. The mean observed weight loss in BD patients treated with apremilast for 52 weeks was 0.52 kg. A total of 11.8% of patients receiving apremilast had observed weight loss between 5-10% while 3.8% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences from weight loss. None of the patients discontinued the study due to adverse reaction of weight decreased.

Please see additional warning in section 4.4 for patients who are underweight at beginning of treatment.

Special populations

Elderly patients

From post-marketing experience, elderly patients ≥ 65 years of age may be at a higher risk of complications of severe diarrhoea, nausea and vomiting (see section 4.4).

Patients with hepatic impairment

The safety of apremilast was not evaluated in PsA, PSOR or BD patients with hepatic impairment.

Patients with renal impairment

In the PsA, PSOR or BD clinical studies, the safety profile observed in patients with mild renal impairment was comparable to patients with normal renal function. The safety of apremilast was not evaluated in PsA, PSOR or BD patients with moderate or severe renal impairment in the clinical studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme

Website: yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Apremilast 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. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.