apremilast: prescribing information – dosing, contraindications, interactions, side effects

Psoriatic arthritis

Otezla, 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

Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis (PSOR) 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).

Paediatric psoriasis

Otezla is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years and weighing at least 20 kg who are candidates for systemic therapy.

Behçet’s disease

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

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

Posology

Adult patients with psoriatic arthritis, psoriasis, or Behçet’s disease
The recommended dose of apremilast for adult patients is 30 mg taken orally twice daily. An initial titration schedule is required as shown below in table 1.

Table 1. Dose titration schedule for adult patients

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

Paediatric patients with moderate to severe plaque psoriasis
The recommended dose of apremilast for paediatric patients 6 years of age and older with moderate to severe plaque psoriasis is based on body weight. The recommended dose of apremilast is 20 mg taken orally twice daily for paediatric patients who weigh from 20 kg to less than 50 kg, and 30 mg taken orally twice daily for paediatric patients who weigh at least 50 kg, following the initial titration schedule shown below in table 2.

Table 2. Dose titration schedule for paediatric patients

Body weight
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
& thereafter
AM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
20 kg to less than
50 kg
10 mg
10 mg
10 mg
10 mg
20 mg
20 mg
20 mg
20 mg
20 mg
20 mg
20 mg
50 kg or more
10 mg
10 mg
10 mg
10 mg
20 mg
20 mg
20 mg
20 mg
30 mg
30 mg
30 mg

All indications (psoriasis in adults and children, psoriatic arthritis, Behçet’s disease) No re-titration is required after initial titration.

The recommended twice daily apremilast dose should be taken approximately 12 hours apart (morning and evening), with no food restrictions.

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

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 listed in table 1 and the PM doses be skipped (see section 5.2).

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 listed in table 2 above for the appropriate body weight category and the PM doses be skipped.

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 have not been established in children with moderate to severe plaque psoriasis below the age of 6 years or with a body weight less than 20 kg, or in other paediatric indications. No data are available.

Method of administration

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

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

Pregnancy (see section 4.6).

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 (see section 4.3).

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 table 3.

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 3. 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*

System Organ Class
Frequency
Adverse reaction
Psychiatric disorders
Common
Insomnia
Depression
Uncommon
Suicidal ideation and behaviour
Anxiety
Mood altered
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 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.

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.

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.

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.

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, anxiety, altered mood, 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

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

In paediatric patients 6 years of age and older with severe renal impairment, the 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 (see sections 4.2 and 5.2).

Underweight patients

Patients who are underweight and paediatric patients who have a borderline to low body mass index 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.

Lactose content

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

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.

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.

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code:
L04AA32

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 psoriatic arthritis and psoriasis.

Pharmacodynamic effects

In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL-23, and an increase in IL-10. In clinical studies in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8. In clinical studies in patients with Behçet Disease treated with apremilast, there was a significant positive association between the change in plasma TNF-alpha and clinical efficacy as measured by the number of oral ulcers.

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

Clinical efficacy and safety

Psoriatic Arthritis
The safety and efficacy of apremilast were evaluated in 3 multi-centre, randomised, double-blind, placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design in adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with small molecule or biologic DMARDs. A total of 1 493 patients were randomised and treated with either placebo, apremilast 20 mg or apremilast 30 mg given orally twice daily.

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. Apremilast was used as a monotherapy (34.8%) or in combination with stable doses of small molecule DMARDs (65.2%).
Patients received apremilast in combination with one or more of the following: methotrexate (MTX, ≤ 25 mg/week, 54.5%), sulfasalazine (SSZ, ≤ 2 g/day, 9.0%), and leflunomide (LEF; ≤ 20 mg/day, 7.4%). Concomitant treatment with biologic DMARDs, including TNF blockers, was not allowed.

Absorption

Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are 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%. The mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular 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 parent compound recovered in urine and faeces, respectively. The major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast (M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased when administered concomitantly with rifampicin, a strong inducer of CYP3A4.

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 active substances that are metabolised by CYP enzymes.