Apremilast

460.50000

460.50

UP7QBP99PN

C147044

L04AA32|L - Antineoplastic and immunomodulating agents

127.46000

3.52590

1.381

156.1

741.3±60.0

402.1±32.9 °C

1.612

In water, 225.4 mg/L at 25 deg C (est)

Store tablets below 30 deg C (86 deg F).

3.63X10-19 mm Hg at 25 deg C (est)

12.58None

Henry's Law constant = 3.99X10-22 atm-cu m/mol at 25 °C (est)

pKa1 = 12.58 (amide) (est)

P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P314, P322, P330, P363, P405, P501

H302

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including apremilast, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H302 (42.86%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P263, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P314, P322, P330, P363, P405, and P501|Aggregated GHS information provided by 7 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral LD50 in mice was greater than 2000 mg/kg in mice. In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females. Overdose information In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed. In cases of an overdose, supportive and symptomatic treatment should be administered. Contact the local poison control center for the most recent overdose management for apremilast.|IDENTIFICATION AND USE: Apremilast is a white to pale-yellow powder. Apremilast is used for the treatment of adult patients with active psoriatic arthritis. It is also used for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. HUMAN EXPOSURE AND TOXICITY: The most common adverse reactions are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache. Apremilast did not induce chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. ANIMAL STUDIES: Apremilast has low potential for acute toxicity. Apremilast was evaluated in a series of repeat-dose oral toxicity studies of up to 6 months duration in mice (dose levels of 10, 100 and 1000 mg/kg/day), 12 months duration in monkeys (dose levels of 60, 180 and 600 mg/kg/day) and 90 days duration in rats. Apremilast-related mortality was observed in mice and rats and was primarily attributed to vascular and/or perivascular inflammation. Dose-related inflammatory responses were predominantly observed in mice and rats and included neutrophilia, lymphopenia, and changes in serum proteins (decreased albumin, increased globulin, and increased hapotoglobin, C-reactive protein (CRP), and/or fibrinogen). These inflammatory responses were associated with arteritis and perivascular inflammation in various tissues and organs (e.g. mesentery, heart, lungs, thymus, liver, skeletal muscle, mammary gland, skin and pancreas) in mice and rats, but not in monkeys, even at higher systemic exposures than those achieved in mice and rats. Complete or partial reversibility of the inflammatory findings in mice and rats was observed. Other target organs of apremilast toxicity include non-adverse centrilobular hepatocellular hypertrophy in the liver (mouse) and variable lymphoid depletion in lymphoid tissues (mouse and rat). 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). In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility. In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, altered estrous cycling and increased time to mating was observed from 20 mg/kg/day. Nevertheless, all mice mated and pregnancy rates were unaffected. Apremilast did not induce mutations in an Ames assay. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg/day.

In multiple, large scale randomized controlled trials of apremilast in psoriasis and psoriatic arthritis, serum enzyme elevations were no more frequent among recipients of apremilast than placebo treatment. In these studies, serum ALT values rose above 150 U/L (3 to 4 times ULN) in 0.4% of apremilast- compared to 0.2% of placebo-recipients, and no patient developed clinically apparent liver injury with jaundice. Since approval there have been no published reports of hepatotoxicity attributed to apremilast, but it has had limited clinical use. Because apremilast is immunosuppressive, it may cause reactivation of viral infections including hepatitis B, but such cases have not been reported.

Otezla has not been evaluated and is not indicated to be used in combination with biological therapeutics for psoriasis such as TNF antagonists and anti-IL-12/23 p40 antibodies. Otezla is not recommended in combination with these biological therapeutics.|Otezla has not been evaluated and is not indicated in combination with potent immunosuppressive drugs (e.g. cyclosporine, tacrolimus). Otezla is not recommended in combination with potent immunosuppressive drugs.|Apremilast exposure (AUC) and maximal concentrations (Cmax) were decreased by 72% and 43% when co-administered with CYP3A4 inducer rifampin, and may result in reduced clinical efficacy of apremilast. Hence coadministration of rifampin or other CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin) along with Otezla is not recommended.|St John's Wort is a CYP3A4 inducer, and co-administration with Otezla may result in loss of efficacy or reduced clinical response, and is not recommended.

There have been uncommon reports of tachyarrhythmia, including atrial fibrillation, in Phase 2/3 studies. The incidence of tachyarrhythmia events was 0.2% for placebo and 0.6% for Otezla30 mg BID patients. Of these, atrial fibrillation had an incidence of 0.1% for placebo and 0.3% for Otezla patients. Use with caution in patients with a history of tachyarrhythmia or conditions that can be worsened by increases in heart rate (e.g. ischemic heart disease or congestive heart failure).|Otezla has not been studied in patients with severe immunological diseases, severe acute infectious diseases, or psoriasis patients treated with immunosuppressive medicinal products. Experience in patients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes zoster is limited. Otezla should be used with caution in these patient populations.

The plasma protein binding of apremilast is about 68%.

EXPERIMENTAL: The lacteal excretion of apremilast was evaluated following oral administration of apremilast to lactating CD-1 mice. In this study, female mice approximately 13 days postpartum received a single oral dose of apremilast at 10 mg/kg, administered by oral gavage in a volume of 10 mL/kg. Milk and blood samples from 5 animals per time point were obtained at 1, 6, and 24 hr postdose and apremilast concentrations determined in plasma and milk using LC-MS/MS analysis. The mean apremilast plasma concentrations at 1 and 6 hr post-dose were 984 and 138 ng/mL, while concentrations in milk were 1441 and 186 ng/mL, respectively. The resulting mean milk-to-plasma ratios ranged from 1.46 to 1.62, indicating transfer of apremilast into milk in mice. Plasma and milk concentrations were below the detection limit of 3 ng/mL in the 24-hr samples.|EXPERIMENTAL: It is not known whether Otezla or its metabolites are present in human milk; however apremilast was detected in milk of lactating mice.

Apremilast is indicated for the treating of active psoriatic arthritis in adults, for the treating of active moderate to severe psoriatic arthritis in patients who are eligible for phototherapy and systemic treatment. In addition, apremilast is now indicated for the treatment of oral ulcers associated with Behcet's disease in adults.|Psoriatic arthritisOtezla, 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.PsoriasisOtezla 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 of Behcet disease|Treatment of chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis)|Treatment of psoriasis

Apremilast is an orally available, small molecule inhibitor of phosphodiesterase-4 (PDE-4) and an immunomodulating agent that is used for treatment of refractory psoriatic arthritis. Apremilast has been linked to a low rate of serum enzyme elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury.

Dermatologic Agents, Psoriasis Agents

Anti-Inflammatory Agents, Non-Steroidal; Phosphodiesterase Inhibitors|Otezla is indicated for the treatment of adult patients with active psoriatic arthritis. /Included in US product label/|Otezla is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. /Included in US product label/|EXPL THER /The purpose of this study is/ to evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor, apremilast, in treatment of ankylosing spondylitis (AS) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of PDE4 inhibition on blood biomarkers of bone biology. In this double-blind, placebo-controlled, single-centre, Phase II study, patients with symptomatic AS with active disease on MRI were randomized to apremilast 30 mg BID or placebo over 12 weeks. Bath Indices were monitored serially. Patients were followed for 4 weeks after stopping medication. Bone biomarkers were assessed at baseline and day 85. 38 subjects were randomised and 36 subjects completed the study. Although the primary end-point (change in BASDAI at week 12) was not met, apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI (-1.59 + or - 1.48 vs -0.77 + or - 1.47), BASFI (-1.74 + or - 1.91 vs -0.28 + or - 1.61) and BASMI (-0.51 + or - 1.02 vs -0.21 + or - 0.67); however, differences did not achieve statistical significance. The clinical indices returned to baseline values by 4 weeks after cessation of apremilast. Six apremilast patients (35.3%) vs 3 placebo (15.8%) achieved ASAS20 responses (p=0.25). There were statistically significant decreases in serum RANKL and RANKL:osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK-1, bone alkaline phosphatase, TRAP5b, MMP3, osteoprotegrin, or osteocalcin. Although a small pilot study, these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology. These data support further research of apremilast in axial inflammation.|EXPL THER Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder mediated by Th1 cells. Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis. Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus. The adverse events related to the drug were mild and transient. This is the first open label study to use apremilast as a treatment modality for discoid lupus. Our observations indicate that apremilast may constitute a safe and effective therapeutic option for DLE.

Treatment with Otezla is associated with an increase in adverse reactions of depression. Before using Otezla in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with Otezla in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Otezla if such events occur.|The safety and effectiveness of Otezla in pediatric patients less than 18 years of age have not been established.|It is not known whether Otezla or its metabolites are present in human milk; however apremilast was detected in milk of lactating mice. Because many drugs are present in human milk, caution should be exercised when Otezla is administered to a nursing woman.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|For more Drug Warnings (Complete) data for Apremilast (11 total), please visit the HSDB record page.

Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. A note on depression and weight loss Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast.

Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions.They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. (See all compounds classified as Anti-Inflammatory Agents, Non-Steroidal.)|Compounds that specifically inhibit PHOSPHODIESTERASE 4. (See all compounds classified as Phosphodiesterase 4 Inhibitors.)

An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast absorption.|Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption.|The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment.|In healthy patients, the plasma clearance of apremilast is about 10 L/hour.|Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.|The lacteal excretion of apremilast was evaluated following oral administration of apremilast to lactating CD-1 mice. In this study, female mice approximately 13 days postpartum received a single oral dose of apremilast at 10 mg/kg, administered by oral gavage in a volume of 10 mL/kg. Milk and blood samples from 5 animals per time point were obtained at 1, 6, and 24 hr postdose and apremilast concentrations determined in plasma and milk using LC-MS/MS analysis. The mean apremilast plasma concentrations at 1 and 6 hr post-dose were 984 and 138 ng/mL, while concentrations in milk were 1441 and 186 ng/mL, respectively. The resulting mean milk-to-plasma ratios ranged from 1.46 to 1.62, indicating transfer of apremilast into milk in mice. Plasma and milk concentrations were below the detection limit of 3 ng/mL in the 24-hr samples.|In monkeys, pregnant animals were administered daily oral doses of apremilast beginning on gestation day 20 through gestation day 50, and a single oral dose on gestation day 100 at dosages of 20, 50, 200, and 1000 mg/kg/day (n = 16/group at the beginning of the study). Maternal and fetal blood was collected at 5 hr postdose on gestation Day 100. In all dosage groups, the fetal-to-maternal plasma concentration ratios were between 0.3 and 0.4, indicating apremilast crossed the placenta in monkeys.|As part of fertility and developmental toxicity study in female CD-1 mice and an embryo-fetal development study in cynomolgus monkeys, the transport of apremilast across the placenta was assessed. In mice, following daily oral administration of apremilast beginning 15 days prior to cohabitation and continuing through Day 15 of presumed gestation at doses of 10, 20, 40, and 80 mg/kg/day, blood was collected from pregnant mice (n = 3/time point) at 0.5, 2, 4, 8, and 24 hr postdose on gestation Day 15. Blood was collected from fetuses) at the time of sacrifice in the 24 hr postdose mice. Maternal plasma apremilast concentrations increased in a less than dose proportional manner. The fetal plasma concentrations at 24 hr were highly variable, with six of the ten litters evaluated being below the limit of quantification (1 ng/mL). In fetal plasma from four of the ten litters evaluated, apremilast was quantified, with concentrations ranging from 14.5 to 2813 ng/mL. The mean fetal-to-maternal plasma concentration ratios ranged from 0.3 to 1.07, indicating apremilast crossed the placenta in mice.|For more Absorption, Distribution and Excretion (Complete) data for Apremilast (13 total), please visit the HSDB record page.

Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation. About 23 metabolites are produced from its metabolism. The CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes. The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug. Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast. After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma. Minor metabolites M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast.|The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.|Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.|In /an/ oral study, concentrations of both total radioactivity (e.g., parent compound plus any metabolites) and of parent compound in plasma were greater in females than in males. In males, the total radioactivity AUC values were 25 to 96 times greater than those for parent compound, whereas in females the difference was only 2- to 3-fold, suggesting that metabolism was more extensive in male than in female rats. In the same study following six daily doses, accumulation was indicated by Cmax and AUC values in females, but not in males.|In a bile-duct cannulated male mouse study following a single 10 mg/kg oral dose of (14)C-apremilast, 54% and 16% of the radioactive dose was excreted via the biliary and urinary routes, suggesting that at least 70% of the radioactive dose was absorbed in mice, indicating apremilast is subject to moderate first pass metabolism. Toxicokinetic evaluation in mice suggests exposure increases dose-proportionally and less than dose-proportionally at doses over 100 mg/kg/day. The studies do not indicate sex-related differences or inversion of apremilast to its R enantiomer in mice.|For more Metabolism/Metabolites (Complete) data for Apremilast (6 total), please visit the HSDB record page.

The average elimination half-life of this drug ranges from 6-9 hours.|terminal elimination half-life of approximately 6-9 hours

The full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms.|Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin. Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.|Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-a (TNF-a), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-a, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals.|Apremilast, a small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. Phosphodiesterase 4 inhibition elevates intracellular cAMP levels, thereby reducing the inflammatory response by modulating the expression of tumor necrosis factor-alpha (TNF-a), interleukin-23 (IL-23), IL-17 and IL-10.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose.

/SIGNS AND SYMPTOMS/ The most common adverse reactions (> or =5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache.|/GENOTOXICITY/ Apremilast did not induce ... chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. ...|/ALTERNATIVE and IN VITRO TESTS/ Human cereblon binding was investigated due to structural similarities between apremilast and thalidomide, namely the phthalimide moiety. The aminoglutarimide moiety which is responsible for thalidomide binding to cereblon is substituted for a di-alkoxyphenyl in apremilast. As cereblon binding is considered responsible for teratogenic effects associated with thalidomide, the comparative binding of apremilast to cereblon was investigated in competition studies of CRBN binding to thalidomide-analog affinity beads. Endogenous CRBN in human U266 MM cell extracts was incubated with varying concentrations of either apremilast, CC-5013 (lenalidomide, a thalidomide analog with an aminoglutarimide moiety) as a positive control for CRBN binding to the aminoglutarimide moiety, or dimethyl sulfoxide (1%) as the control vehicle. Apremilast at concentrations up to 100 uM did not compete for CRBN binding. In contrast, the positive control agent lenalidomide, successfully competed for CRBN binding with an IC50 value of approximately 3 uM.

apremilast

Otezla tablets are supplied in 10-, 20-, and 30-mg strengths for oral administration. Each tablet contains apremilast as the active ingredient and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only).

Human drugs -> Otezla -> EMA Drug Category|Immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients