Apremilast

Registered South African indications:

• Psoriatic arthritis
• Psoriasis - moderate to severe

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding (South African manufacturer recommendations)

Cautions
South African manufacturer recommendations

• Severe renal impairment (CrCl<30ml/min)
• Hepatic impairment
• Galactose intolerance e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance

International manufacturer recommendations

• Women of childbearing potential
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Elderly
• History of depression
• Previous or existing psychiatric symptoms
• Underweight patients
• Coadministration with other medicinal products likely to cause psychiatric events
• Galactose intolerance
• Total lactase deficiency 
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Psoriatic arthritis (Additional agent(s) may be required)
- Active psoriatic arthritis (PsA) in patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy
Psoriasis - moderate to severe
- Chronic plaque psoriasis in patients who failed to or who have a contraindication to or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet A light (PUVA)

• Oral (fct): 30mg, 12hrly (morning and evening)
  An initial titration schedule is required as shown below. No re-titration is required after initial titration

Day 1	a.m.	Oral (fct): 10mg, in the morning
Day 2	a.m.	Oral (fct): 10mg, in the morning
	p.m.	Oral (fct): 10mg, in the evening
Day 3	a.m.	Oral (fct): 10mg, in the morning
	p.m.	Oral (fct): 20mg, in the evening
Day 4	a.m.	Oral (fct): 20mg, in the morning
	p.m.	Oral (fct): 20mg, in the evening
Day 5	a.m.	Oral (fct): 20mg, in the morning
	p.m.	Oral (fct): 30mg, in the evening
Day 6 and thereafter	a.m.	Oral (fct): 30mg, in the morning
	p.m.	Oral (fct): 30mg, in the evening

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For the indication of psoriatic arthritis: Apremilast may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs)

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Method of administration: Apremilast tablets should be swallowed whole, either with or without food. The tablets should not be crushed, split, or chewed

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As of August 2022, the apremilast titration pack is not yet registered in South Africa and is therefore available as a section 21 product

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International manufacturer recommendations

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

Psoriatic arthritis (Additional agent(s) may be required)
- Active psoriatic arthritis (PsA) in patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy
Psoriasis (PSOR) - moderate to severe
- Chronic plaque psoriasis in patients who failed to or who have a contraindication to or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet A light (PUVA)
Behçet's disease (BD)
- Patients with oral ulcers who are candidates for systemic therapy

• Oral (fct): 30mg, 12hrly (morning and evening)

 An initial titration schedule is required as shown below. No re-titration is required after initial titration

Day 1	a.m.	Oral (fct): 10mg, in the morning
Day 2	a.m.	Oral (fct): 10mg, in the morning
	p.m.	Oral (fct): 10mg, in the evening
Day 3	a.m.	Oral (fct): 10mg, in the morning
	p.m.	Oral (fct): 20mg, in the evening
Day 4	a.m.	Oral (fct): 20mg, in the morning
	p.m.	Oral (fct): 20mg, in the evening
Day 5	a.m.	Oral (fct): 20mg, in the morning
	p.m.	Oral (fct): 30mg, in the evening
Day 6 and thereafter	a.m.	Oral (fct): 30mg, in the morning
	p.m.	Oral (fct): 30mg, in the evening

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For the indication of psoriatic arthritis: Apremilast may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs)

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If a dose is missed, 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

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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

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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

Not established for use in children below 18 years

Pregnancy
South African manufacturer recommendations

• Contraindicated
• Apremilast is contraindicated during pregnancy. An effective method of contraception must be used during apremilast therapy

International manufacturer recommendations

• Contraindicated
• 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 
• 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

Breastfeeding
South African manufacturer recommendations

• Contraindicated 
• It is not known whether apremilast or its metabolites are present in human milk. Mothers taking apremilast should not breastfeed their infants

International manufacturer recommendations

• Caution; not recommended 
• 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 breastfeeding

Fertility 
South African manufacturer recommendations

• No information available

International manufacturer recommendations

• 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

Renal Impairment 

• Mild to moderate (CrCl≥30ml/min): No dose adjustment recommended 
• Severe (CrCl<30ml/min): Caution; dose adjustment recommended 
  Dose reduction recommended: Oral (fct): 30mg, dly 
  For initial dosage titration, it is recommended that apremilast be titrated using only the a.m. schedule and the p.m. doses be skipped 

Hepatic Impairment
South African manufacturer recommendations

• Caution; no dose adjustment recommended
  Dose adjustment is not required in patients with hepatic impairment. The safety of apremilast was not evaluated in active psoriatic arthritis (PsA) or psoriasis (PSOR) patients with hepatic impairment

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  No dose adjustment is necessary for patients with hepatic impairment. The safety of apremilast was not evaluated in active psoriatic arthritis (PsA), psoriasis (PSOR) or Behçet's disease (BD) patients with hepatic impairment

 Elderly 
South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• Caution; no dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Migraine
• Headache
  - Tension headache
• Fatigue
• Depression
• Suicidal ideation and behaviour

Respiratory Disorders 

• Bronchitis
• Upper respiratory tract infection
• Nasopharyngitis
• Cough

Gastrointestinal Disorders 

• Diarrhoea
• Nausea and vomiting
• Frequent bowel movements
• Upper abdominal pain
• Gastroesophageal reflux disease
• Dyspepsia
• Gastrointestinal haemorrhage

Endocrine and Metabolic Disorders 

• Decreased appetite
• Decreased weight

Musculoskeletal Disorders 

• Back pain

Skin and Subcutaneous Tissue Disorders 

• Rash
• Urticaria
• Angioedema

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity

• Strong CYP3A4 inducers
• Rifampicin
• Phenobarbitone
• Carbamazepine
• Phenytoin

Other interactions

• St. John's wort

• Renal function
• Weight 

Specific cases may require

• Pregnancy status

Additional observations

• Signs or symptoms of
  - Mood changes
  - Depression
  - Suicidal thoughts

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.

Film coated tablet 30mg

• Otezla 30mg (Amgen) originator