Apremilast

Apremilast is a novel, orally available small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4). It is indicated in the treatment of active psoriatic arthritis in adults (approved by the FDA in March 2014) and moderate to severe plaque psoriasis (approved by the FDA in September 2014). PDE-4 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase that is predominantly located in inflammatory cells. By inhibiting PDE-4, Apremilast increases intracellular levels of cAMP and thereby inhibits the production of multiple proinflammatory mediators including PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase. By targeting a central component of the inflammatory signaling cascade rather than a single inflammatory marker, PDE-4 inhibition may restore the homeostatic balance between pro- and anti-inflammatory signalling.

psoriatic arthritis (treatment of active psoriatic arthritis in adults in monotherapy or in combination with HDL with insufficient response or intolerance to previous HDL therapy),

psoriasis (treatment of moderate to severe plaque psoriasis in adults with insufficient response, contraindications, or intolerance to other basic anti-inflammatory therapy, including cyclosporine, methotrexate, or drugs used together with UV-A radiation (PUVA therapy).

Inside, swallow whole, preferably with water, regardless of the time of the meal.

Treatment with Otesla can only be prescribed by a specialist who has sufficient experience in the diagnosis and treatment of psoriasis and PsA.

Doses

The recommended dose of apremilast is 30 mg orally 2 times a day, in the morning and in the evening, with an interval of about 12 hours. Initial titration of the dose is required, as shown in the table. After the initial titration, no re-titration is required.

Table

Dose titration scheme

If the patient misses taking the drug, then the next dose should be taken as soon as possible. If a missed dose is detected just before the time of taking the next dose, then the missed dose is not taken and the next dose is taken at the appropriate time. Patient SHOULD NOT take two doses of the drug at the same time.

The maximum therapeutic effect was observed in the first 24 weeks of treatment. If the effect is not achieved after 24 weeks, the treatment should be reviewed.

It is recommended to regularly evaluate the patient's response to treatment. There are no clinical data on the use of the drug for more than 52 weeks (see "Pharmacodynamics").

Special patient groups

Children and teenagers. The efficacy and safety of apremilast in children from birth to 18 years of age has not been studied.

Elderly patients. There is no need to change the dose in elderly patients (see "Side effects" and "Pharmacokinetics").

Impaired renal function. In patients with mild or moderate renal insufficiency, there is no need to change the dose. The dose of apremilast should be reduced to 30 mg once a day in patients with severe renal insufficiency (creatinine Cl <30 ml / min when evaluated by the Cockcroft-Gault formula). At the initial titration, it is recommended to take only the morning dose, as indicated in the table, and skip the evening dose.

Liver function disorders. There is no need to change the dose in patients with hepatic insufficiency (see "Pharmacokinetics").

hypersensitivity to apremilast or other components included in the composition of the drug,

rare hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (the drug contains lactose),

pregnancy,

breastfeeding period,

children under 18 years of age (not enough clinical experience).

With caution: patients with mental disorders or indications of the presence of such in the anamnesis, or in the case of planned use by the patient of other concomitant drugs that can cause mental disorders (see "Special instructions"), patients with severe renal insufficiency (see "Pharmacokinetics", "Method of administration and doses", "Special instructions"), patients with insufficient body weight (see "Special instructions").

Use Apremilast as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Apremilast by mouth with or without food.
• Swallow Apremilast whole. Do not break, crush, split, or chew before swallowing.
• If you miss a dose of Apremilast, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Apremilast.

Use: Labeled Indications

Behçet disease: Treatment of oral ulcers associated with Behçet disease.

Psoriasis: Treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Psoriatic arthritis: Treatment of patients with active psoriatic arthritis.

See also:
What other drugs will affect Apremilast?

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Apremilast. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Riociguat: Apremilast may enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

The most frequent adverse drug reactions (NLR) in phase III clinical trials were gastrointestinal disorders-diarrhea (15.7%) and nausea (13.9%). Most of these violations were mild or moderate, and only 0.3% of each of these NLRs were considered severe. These NLRs occurred mainly in the first 2 weeks of treatment and usually resolved after 4 weeks. Other common NLRs were upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%). Overall, most NLRs were mild to moderate in severity.

The most frequent NLRs that caused discontinuation of treatment in the first 16 weeks were diarrhea (1.7%) and nausea (1.5%). The overall incidence of serious NLR was low, and these reactions were not specific to any organ system.

Hypersensitivity reactions have rarely been reported in apremilast clinical trials.

NLR observed in patients with apremilast therapy is classified according to the lesion of organs and organ systems (MedDRA).

This frequency was recorded in the course of clinical studies of apremilast in PsA (1945 patients) and psoriasis (1184 patients).

These NLRs were reported in apremilast clinical trials for PsA (1945 patients) and psoriasis (1184 patients).

The frequency of NLR was determined according to the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000).

Infectious and parasitic diseases: often-bronchitis, upper respiratory tract infections, nasopharyngitis*.

On the part of the immune system: infrequently-hypersensitivity reactions.

From the side of metabolism and nutrition: often-decreased appetite*.

Mental disorders: often-insomnia, depression, infrequently-suicidal thoughts and behavior**.

From the nervous system: often-migraine*, tension headache*, headache*.

From the respiratory system, chest and mediastinal organs: often-cough.

From the gastrointestinal tract: very often-diarrhea*, nausea*, often-vomiting*, dyspepsia, frequent stools, pain in the upper abdomen*, GERD, infrequently-gastrointestinal bleeding.

From the skin and subcutaneous tissues: infrequently-rash.

From the musculoskeletal system and connective tissue: often-back pain*.

General disorders and disorders at the injection site: often-fatigue.

Laboratory and instrumental data: rarely is the reduction of body weight.

* At least one of these NLRs is considered serious.

** Infrequent cases of suicidal thoughts and behaviors have been reported in clinical trials and post-marketing use, and completed suicide attempts are known from post-marketing experience. The patient and caregivers should inform the prescribing physician of any changes in the patient's behavior or mood and suicidal thoughts (see also With caution and "Special Instructions").

The description of the individual NLR

The reduction of body weight. The patients ' body weight was regularly evaluated in clinical trials. The average weight loss on the background of taking apremilast for 52 weeks was 1.99 kg. Overall, 14.3% of patients treated with apremilast had a weight loss of 5-10%, and 5.7% had a weight loss of more than 10%. None of the patients had any clinically significant weight loss effects. In total, only 0.1% of patients stopped taking apremilast due to weight loss as an undesirable phenomenon.

At the beginning of treatment of patients with reduced body weight, it is necessary to familiarize yourself with additional precautions in the section "Special instructions" and the subsection With caution.

Special patient groups

Elderly patients. In the course of clinical studies, there were no differences in the safety profile of apremilast in elderly patients (≥65 years) and in patients under the age of 65 years.

Impaired liver function. The safety of apremilast has not been evaluated in patients with PsA or psoriasis and impaired liver function.

Impaired renal function. In clinical studies with PsA and psoriasis, the safety characteristics of the drug did not differ in patients with normal renal function and mild renal insufficiency. The safety of apremilast has not been studied in patients with PsA or psoriasis and moderate to severe renal insufficiency.

Symptoms: The use of apremilast was studied in healthy volunteers at a maximum daily dose of 100 mg (50 mg 2 times a day) for 4.5 days without signs of dose-limiting toxicity.

Treatment: monitoring the symptoms and signs of NLR. If necessary, prescribe symptomatic and supportive treatment.