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.

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 the following table and the PM doses be skipped.

Dose titration schedule:

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. 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.

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 hospitalized. 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.

There are limited data about the use of apremilast in pregnant women. Apremilast is contraindicated during pregnancy. Effects of apremilast on pregnancy included embryofetal loss in mice and monkeys, and reduced fetal 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 in Phase III 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 diarrhoea and 0.3% of nausea reported as being severe. 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%). The overall incidence of serious adverse reactions was low and did not indicate any specific system organ involvement.

Hypersensitivity reactions were uncommonly observed in apremilast clinical studies.

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. The frequencies of adverse drug reactions are those reported in the apremilast arms of the four Phase III studies in PsA (n=1945) or the two Phase III studies in PSOR (n=1184) (highest frequency from either data pool is represented in the following list). 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) and/or psoriasis (PSOR):

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, Depression

Uncommon: Suicidal ideation and behaviour#

Nervous system disorders

Common: Migraine*, Tension headache*, 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 administrative site conditions

Common: Fatigue

Investigations

Uncommon: Weight decrease

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

Description of selected adverse reactions

^# 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 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.

Special populations

Elderly patients

From post-marketing experience, elderly patients ≥65 years of age may be at a higher risk of complications of severe diarrhea, nausea and vomiting.

Patients with hepatic impairment

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

Patients with renal impairment

In the PsA or PSOR 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 or PSOR 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 the national reporting system listed in Appendix V.