Psoriatic arthritis

Wetzo^®, 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. 

Psoriasis

Wetzo^® 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). 

Treatment with Wetzo^® should be initiated by specialists experienced in the diagnosis and treatment of psoriasis and psoriatic arthritis.

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

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 

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

Diarrhea, 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

Wetzo^® 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.

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 (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. 

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.

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) and psoriasis (PSOR)

*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.

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.

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

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 conjugates 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.

In vitro, Apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50>50μM), however clinically relevant drug interactions mediated via P-gp are not expected to occur.

In vitro, Apremilast has little to no inhibitory effect (IC50>10μM) 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.

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. 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.

Elderly patients

Apremilast 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 Cmax for Apremilast than that in young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years of age in clinical trials. No dosage adjustment is necessary for elderly patients.

Renal impairment

There is no meaningful difference in the PK of Apremilast between mild or moderate renally impaired subjects and matched healthy subjects (N=8 each). The results support that no dose adjustment is needed in patients with mild and moderate renal impairment. Apremilast dose should be reduced to 30 mg once daily in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 or CLcr < 30 mL/min). In 8 subjects with severe renal impairment to whom a single dose of 30 mg Apremilast was administered, the AUC and Cmax of Apremilast increased by approximately 89% and 42%, respectively.

Hepatic impairment

The pharmacokinetics of Apremilast and its major metabolite M12 are not affected by moderate or severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment.

Long-term studies were conducted in mice and rats with Apremilast to evaluate its carcinogenic potential. No evidence of Apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively).

Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay. In a fertility study of male mice, Apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, Apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD (≥20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early post implantation losses. There was no effect of Apremilast approximately 1.0-times the MRHD (10 mg/kg/day).

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.

Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol 6000, talc, titanium dioxide, yellow iron oxide, red iron oxide, black iron oxide.

None.

Store below 30°C.

As with all medicines, keep this product out of the reach of children.

Wetzo^® Tablets 10 mg: Pink coloured, circular, biconvex, film coated tablets debossed with “U 47” on one side and plain on the other side, presented in PVC/Alu blisters, intended for oral use.

Wetzo^® Tablets 20 mg: Brown coloured, circular, biconvex, film coated tablets debossed with “U 48” on one side and plain on the other side, presented in PVC/Alu blisters, intended for oral use.

Wetzo^® Tablets 30 mg Beige coloured, circular, biconvex, film coated tablets debossed with “U 49” on one side and plain on the other side, presented in PVC/Alu blisters, intended for oral use.

Pack Size:

• The treatment starter pack contains 28 Film Coated Tablets (4 tablets of 10mg, 4 tablets of 20mg and 20 tablets of 30mg).

• The one-month standard pack contains 56 x 30mg Film Coated Tablets.

No special requirements.