Abrocitinib

Chemical formula: C₁₄H₂₁N₅O₂S  Molecular mass: 323.42 g/mol  PubChem compound: 78323835

Interactions

Abrocitinib interacts in the following cases:

CYP2C19 inducers, CYP2C9 inducers

Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9 enzymes.

Administration of 200 mg abrocitinib after multiple doses with rifampicin, a strong inducer of CYP enzymes, resulted in reduction of abrocitinib active moiety exposures by approximately 56%.

CYP2C19 inhibitors, CYP2C9 inhibitors

Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9 enzymes.

When 100 mg abrocitinib was administered concomitantly with fluvoxamine (a strong CYP2C19 and moderate CYP3A inhibitor) or fluconazole (a strong CYP2C19, moderate CYP2C9 and CYP3A inhibitor), the extent of exposure of abrocitinib active moiety increased by 91% and 155%, respectively, compared with administration alone.

CYP2B6 substrates, CYP1A2 substrates, CYP2C19 substrates

In vitro, abrocitinib is an inducer of CYP2B6 and CYP1A2, and an inducer and inhibitor of CYP2C19 enzymes. Pharmacokinetic interaction studies have not been performed with substrates of CYP2B6, CYP1A2 and CYP2C19. The exposures of medicinal products metabolised by CYP2B6 (e.g., bupropion, efavirenz) and CYP1A2 (e.g., alosetron, duloxetine, ramelteon, tizanidine) may be decreased and of those metabolised by CYP2C19 (e.g., S-mephenytoin) may be increased initially and then decreased, when used concomitantly with abrocitinib.

P-gp substrates

In vitro, abrocitinib is an inhibitor of P glycoprotein (P-gp). Co-administration of dabigatran etexilate (a P-gp substrate), with a single dose of abrocitinib 200 mg increased dabigatran AUCinf and Cmax by approximately 53% and 40%, respectively, compared with administration alone. Caution should be exercised for concomitant use of abrocitinib with dabigatran. The effect of abrocitinib on the pharmacokinetics of other P-gp substrates has not been evaluated. Caution should be exercised as the levels of P-gp substrates with a narrow therapeutic index, such as digoxin, may increase.

OAT3 inhibitors

Abrocitinib is metabolised predominantly by CYP2C19 and CYP2C9 enzymes, and to a lesser extent by CYP3A4 and CYP2B6 enzymes, and its active metabolites are renally excreted and are substrates of the organic anion transporter 3 (OAT3).

When abrocitinib 200 mg was administered concomitantly with probenecid, an OAT3 inhibitor, abrocitinib active moiety exposures increased by approximately 66%. This is not clinically significant, and a dose adjustment is not needed.

Antacids, H2-receptor antagonists, proton pump inhibitors

The effect of elevating gastric pH with antacids, H2-receptor antagonists (famotidine), or proton pump inhibitors (omeprazole) on the pharmacokinetics of abrocitinib has not been studied and may reduce the absorption of abrocitinib due to the low solubility of abrocitinib at pH above 4.

Vaccines

No data are available on the response to vaccination in patients receiving abrocitinib. Use of live, attenuated vaccines should be avoided during or immediately prior to treatment. Prior to initiating treatment with this medicinal product, it is recommended that patients be brought up to date with all immunisations, including prophylactic herpes zoster vaccinations, in agreement with current immunisation guidelines.

Biologic immunomodulators, immunosuppressants

Combination with biologic immunomodulators, potent immunosuppressants such as ciclosporin or other Janus kinase (JAK) inhibitors has not been studied. Their concomitant use with abrocitinib is not recommended as a risk of additive immunosuppression cannot be excluded.

Immunodeficiency

Patients with immunodeficiency disorders or a first-degree relative with a hereditary immunodeficiency were excluded from clinical studies and no information on these patients is available.

Fertility

Based on the findings in rats, oral administration of abrocitinib may result in temporary reduced fertility in females of reproductive potential. The effects on female rat fertility were reversible 1 month after cessation of abrocitinib oral administration.

Deep venous thrombosis (DVT), pulmonary embolism (PE)

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving abrocitinib. Abrocitinib should be used with caution in patients at high risk for DVT/PE. Risk factors that should be considered in determining the patient’s risk for DVT/PE include older age, obesity, a medical history of DVT/PE, prothrombotic disorder, use of combined hormonal contraceptives or hormone replacement therapy, patients undergoing major surgery or prolonged immobilisation. If clinical features of DVT/PE occur, treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.

Pregnancy

There are no or limited amount of data on the use of abrocitinib in pregnant women. Studies in animals have shown reproductive toxicity. Abrocitinib has been shown to cause embryo-foetal lethality in pregnant rats and rabbits, skeletal variations in the foetuses of pregnant rats and rabbits, and to affect parturition and peri/postnatal development in rats. Abrocitinib is contraindicated during pregnancy.

Nursing mothers

There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats. A risk to newborns/infants cannot be excluded and abrocitinib is contraindicated during breast-feeding.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

Women of reproductive potential should be advised to use effective contraception during treatment and for 1 month following the final dose of abrocitinib. Pregnancy planning and prevention for females of reproductive potential should be encouraged.

Fertility

Based on the findings in rats, oral administration of abrocitinib may result in temporary reduced fertility in females of reproductive potential. The effects on female rat fertility were reversible 1 month after cessation of abrocitinib oral administration.

Effects on ability to drive and use machines

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

Adverse reactions


Summary of the safety profile

The most commonly reported adverse reactions are nausea (15.1%), headache (7.9%), acne (4.8%), herpes simplex (4.2%), blood creatine phosphokinase increased (3.8%), vomiting (3.5%), dizziness (3.4%) and abdominal pain upper (2.2%). The most frequent serious adverse reactions are infections (0.3%).

Tabulated list of adverse reactions

A total of 3 128 patients were treated with abrocitinib in clinical studies in atopic dermatitis representing 2 089 patient-years of exposure. There were 994 patients with at least 48 weeks of exposure. Five placebo-controlled studies were integrated (703 patients on 100 mg once daily, 684 patients on 200 mg once daily and 438 patients on placebo) to evaluate the safety of abrocitinib in comparison to placebo for up to 16 weeks.

Listed in the following table are adverse reactions observed in atopic dermatitis clinical studies presented by system organ class and frequency, using the following categories: 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); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

System organ class Very common Common Uncommon
Infections and infestations  Herpes simplexa
Herpes zosterb
Pneumonia
Blood and lymphatic system
disorders
  Thrombocytopenia
Lymphopenia
Metabolism and nutrition
disorders
  Hyperlipidaemiac
Nervous system disorders  Headache
Dizziness
 
Vascular disorders   Thrombotic events
including pulmonary
embolismd
Gastrointestinal disorders Nausea Vomiting
Abdominal pain upper
 
Skin and subcutaneous tissue
disorders
 Acne 
Investigations  Creatine
phosphokinase
increased ˃5 × ULNe
 

a Herpes simplex includes oral herpes, ophthalmic herpes simplex, genital herpes, and herpes dermatitis.
b Herpes zoster includes ophthalmic herpes zoster.
c Hyperlipidaemia includes dyslipidaemia and hypercholesterolaemia.
d Thrombotic events include deep vein thrombosis.
e Includes changes detected during laboratory monitoring (see text below).

Description of selected adverse reactions

Infections

In placebo-controlled studies, for up to 16 weeks, infections have been reported in 27.4% of patients treated with placebo and in 34.9% and 34.8% of patients treated with abrocitinib 100 mg and 200 mg, respectively. Most infections were mild or moderate. The percentage of patients reporting infection-related adverse reactions in the 200 mg and 100 mg groups compared to placebo were: herpes simplex (4.2% and 2.8% versus 1.4%), herpes zoster (1.2% and 0.6% versus 0%), pneumonia (0.1% and 0.1% versus 0%). Herpes simplex was more frequent in patients with a history of herpes simplex or eczema herpeticum. Most of the herpes zoster events involved a single dermatome and were non-serious. All the opportunistic infections were cases of multidermatomal cutaneous herpes zoster (0.6%), most of which were non-serious. The incidence rate of herpes zoster in patients 65 years of age and older (7.40 per 100 patient-years) was higher than that of patients 18 to less than 65 years of age (3.44 per 100 patient-years) and less than 18 years of age (2.12 per 100 patient-years). The incidence rate of herpes zoster in patients with severe atopic dermatitis at baseline (4.93 per 100 patient-years) was higher than that of patients with moderate atopic dermatitis at baseline (2.49 per 100 patient-years).

In placebo-controlled studies, for up to 16 weeks, the rate of serious infections was 1.81 per 100 patient-years in patients treated with placebo, 3.32 per 100 patient-years in patients treated with 100 mg, and 1.12 per 100 patient-years in patients treated with 200 mg. Among all patients treated with abrocitinib, including the long-term extension study, the rate of serious infections was 2.18 per 100 patient-years treated with 100 mg and 2.11 per 100 patient-years treated with 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia.

Thrombotic events including pulmonary embolism

Among all patients treated with abrocitinib, including the long-term extension study, the rate of PE was 0.23 per 100 patient-years for 200 mg and 0 per 100 patient-years for 100 mg. The rate of DVT was 0.23 per 100 patient-years in the 200 mg group and 0 per 100 patient-years in the 100 mg group.

Thrombocytopenia

In placebo-controlled studies, for up to 16 weeks, treatment was associated with a dose-related decrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy. Confirmed platelet counts of <50 × 103/mm³ were reported in 0.1% of patients exposed to 200 mg, and in 0 patients treated with 100 mg or placebo. Among all patients exposed to abrocitinib, including the long-term extension study, confirmed platelet counts of <50 × 103/mm³ were reported in 0.1% of patients treated with 200 mg, occurring at Week 4. A higher proportion of patients 65 years of age and older developed a platelet count nadir <75 × 103/mm³.

Lymphopenia

In placebo-controlled studies, for up to 16 weeks, confirmed ALC <0.5 × 103/mm³ occurred in 0.3% of patients treated with 200 mg and 0% of patients treated with 100 mg or placebo. Both cases occurred in the first 4 weeks of exposure. Among all patients exposed to abrocitinib, including the long-term extension, confirmed ALC <0.5 × 103/mm³ were reported in 0.3% of patients treated with 200 mg and 0.1% of patients treated with 100 mg, most of whom were 65 years of age and older.

Lipid elevations

In placebo-controlled studies, for up to 16 weeks, there was a dose-related increase in low-density lipoprotein cholesterol (LDL-c), total cholesterol, and high-density lipoprotein cholesterol (HDL-c) relative to placebo at Week 4 which remained elevated through the final visit in the treatment period. There was no meaningful change in the LDL/HDL ratio in patients treated with abrocitinib relative to patients treated with placebo. Events related to hyperlipidaemia occurred in 0.4% of patients exposed to abrocitinib 100 mg, 0.6% of patients exposed to 200 mg and 0% of patients exposed to placebo.

Creatine phosphokinase elevations (CPK)

In placebo-controlled studies, for up to 16 weeks, significant increases in CPK values (>5 × ULN) occurred in 1.8% of patients treated with placebo, 1.8% of patients treated with 100 mg and 3.8% of patients treated with 200 mg of abrocitinib, respectively. Most elevations were transient and none led to discontinuation.

Nausea

In placebo-controlled studies, for up to 16 weeks, nausea was reported in 1.8% of patients treated with placebo and in 6.3% and 15.1% of patients treated with 100 mg and 200 mg, respectively. Discontinuation due to nausea occurred in 0.4% of patients treated with abrocitinib. Among patients with nausea, 63.5% of patients had onset of nausea in the first week of therapy. The median duration of nausea was 15 days. Most of the cases were mild to moderate in severity.

Paediatric population

A total of 635 adolescent patients (12 to less than 18 years of age) were treated with abrocitinib in clinical studies in atopic dermatitis representing 425.9 patient-years of exposure. The safety profile observed in adolescents in atopic dermatitis clinical studies was similar to that of the adult population.

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