Apremilast

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 (C_max) 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.

Adult patients with psoriatic arthritis, psoriasis, or Behçet’s disease

No dose adjustment is needed in adult patients with mild and moderate renal impairment. The dose of apremilast should be reduced to 30 mg once daily in adult 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 and the PM doses be skipped.

Paediatric patients with moderate to severe psoriasis

No dose adjustment is needed in paediatric patients 6 years of age and older with mild or moderate renal impairment. In paediatric patients 6 years of age and older with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft–Gault equation), dose adjustment is recommended. The apremilast dose should be reduced to 30 mg once daily for paediatric patients who weigh at least 50 kg and to 20 mg once daily for paediatric patients who weigh 20 kg to less than 50 kg. For initial dose titration in these groups, it is recommended that apremilast be titrated using only the AM schedule for the appropriate body weight category and the PM doses be skipped.

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

Apremilast is contraindicated during pregnancy. 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.

Apremilast was detected in milk of lactating mice. 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.

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.

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.

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

Summary of the safety profile

The most commonly reported adverse reactions with apremilast in adults with 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 adults with 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.

Tabulated list of adverse reactions

The adverse reactions observed in adult 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 in adult patients. 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=1 184), and in the phase III study in BD (n=207). The highest frequency from either data pool is represented in the table below.

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).

Summary of adverse reactions in psoriatic arthritis (PsA), psoriasis (PSOR) and Behçet’s disease (BD):

^* 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.

Body weight loss

Patient weight was measured routinely in clinical studies. The mean observed weight loss in adult 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 adult BD patients treated with apremilast for 52 weeks was 0.52 kg. A total of 11.8% of patients receving 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.

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.

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.

Paediatric patients

The safety of apremilast was assessed in a 52-week clinical trial in paediatric patients 6 to 17 years of age with moderate to severe plaque psoriasis (SPROUT study). The safety profile of apremilast observed during the study was consistent with the safety profile previously established in adult patients with moderate to severe plaque psoriasis.