Delgocitinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Overview
Delgocitinib is a Janus kinase (JAK) inhibitor that is FDA approved for the treatment of moderate to severe chronic hand eczema (CHE) in adults who have had an inadequate response to, or for whom topical corticosteroids are not advisable.. Common adverse reactions include application site pain, paresthesia, pruritus, erythema, and bacterial skin infections including finger cellulitis, paronychia, other skin infections, leukopenia, and neutropenia. (<1%)..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
FDA-labeled Indications
- ANZUPGO is indicated for the topical treatment of moderate to severe chronic hand eczema (CHE) in adults who have had an inadequate response to, or for whom topical corticosteroids are not advisable.
Limitations of Use Use of ANZUPGO in combination with other JAK inhibitors or potent immunosuppressants is not recommended.
Recommended Dosage and Administration
- Do not use more than 30 grams per 2 weeks or 60 grams per month.
- Prior to applying ANZUPGO, clean and dry affected areas.
- Apply a thin layer of ANZUPGO, twice daily, to the affected areas only on the hands and wrists.
- ANZUPGO is for topical use only. Not for oral, ophthalmic, or intravaginal use.
- Avoid contact with eyes, mouth, or other mucous membranes. If contact with mucous membranes occurs, rinse thoroughly with water.
Recommended Immunizations Prior to Treatment Initiation
Complete any necessary immunizations, including herpes zoster vaccinations, according to current immunization guidelines prior to ANZUPGO treatment.
Dosage Forms and Strengths
Cream, 2%: Each gram of ANZUPGO cream contains 20 mg of delgocitinib in a white to slightly brown cream.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Delgocitinib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Delgocitinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Delgocitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Delgocitinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Delgocitinib in pediatric patients.
Contraindications
None.
Warnings
Serious Infections
- ANZUPGO may increase the risk of infections. Eczema herpeticum was observed in a subject treated with ANZUPGO.
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving oral or topical JAK inhibitors.
- Avoid use of ANZUPGO in patients with an active or serious infection.
- Consider the risks and benefits of treatment prior to initiating ANZUPGO in patients:
with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection with underlying conditions that may predispose them to infection.
- Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ANZUPGO.
- A patient who develops a new infection during treatment with ANZUPGO should undergo prompt and complete diagnostic testing; appropriate antimicrobial therapy should be initiated; and the patient should be closely monitored.
- Interrupt treatment with ANZUPGO if a patient develops a serious infection. Do not resume ANZUPGO until the infection resolves or is adequately treated.
Viral Reactivation
- Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical trials with ANZUPGO.
- If a patient develops herpes zoster, consider interrupting ANZUPGO treatment until the episode resolves.
- The impact of ANZUPGO on chronic viral hepatitis reactivation is unknown. Patients with active hepatitis B or C infection were excluded from clinical trials with ANZUPGO.
- Consider viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with ANZUPGO.
- If signs of reactivation occur, consult a hepatitis specialist.
- ANZUPGO is not recommended for use in patients with active hepatitis B or hepatitis C.
Non-melanoma Skin Cancers
- Non-melanoma skin cancers including basal cell carcinoma have been reported in subjects treated with ANZUPGO.
- Periodic skin examinations of the application sites are recommended for all patients, particularly those with risk factors for skin cancer.
- Advise patients to avoid sunlamps and minimize exposure to sunlight by wearing sun-protective clothing or using broad-spectrum sunscreen.
Immunizations
- Prior to ANZUPGO treatment, complete all age-appropriate vaccinations as recommended by current immunization guidelines, including herpes zoster vaccinations.
- Avoid vaccination with live vaccines immediately prior to, during, and immediately after ANZUPGO treatment.
Potential Risks Related to JAK Inhibition
- It is not known whether ANZUPGO may be associated with the observed or potential adverse reactions of JAK inhibition.
- In a large, randomized, postmarketing safety trial of an oral JAK inhibitor in combination with methotrexate in rheumatoid arthritis (RA), patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of all-cause mortality, including sudden cardiovascular death, major adverse cardiovascular events (MACE), overall thrombosis, deep venous thrombosis (DVT), pulmonary embolism (PE), and malignancies (excluding non-melanoma skin cancer) were observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. ANZUPGO is not indicated for use in RA.
- Treatment with oral and topical JAK inhibitors has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides.
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of ANZUPGO was evaluated in two randomized, double-blind, multicenter, vehicle-controlled clinical trials (TRIAL 1 and TRIAL 2), in which 959 adults with moderate to severe CHE received ANZUPGO or vehicle cream topically twice daily for 16 weeks. A total of 638 subjects were treated with ANZUPGO.
- In TRIAL 1 and TRIAL 2, adverse reactions that were reported in ≤ 1% of subjects in the ANZUPGO group were application site pain, paresthesia, pruritus, erythema, and bacterial skin infections including finger cellulitis, paronychia, other skin infections, leukopenia, and neutropenia.
- In an open label extension trial (TRIAL 3), 801 subjects were treated for up to an additional 36 weeks after completing TRIAL 1 or TRIAL 2.
- A total of 198 subjects received continuous treatment with ANZUPGO for 52 weeks.
- Eczema herpeticum was observed in one subject and herpes zoster was observed in two subjects treated with ANZUPGO.
Postmarketing Experience
There is limited information regarding Delgocitinib Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Delgocitinib Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Risk Summary
- The available data on the use of topical delgocitinib during pregnancy is insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
- In animal reproduction studies, oral administration of delgocitinib to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects at doses 120 or 193 times, respectively, the maximum recommended human dose (MRHD) based on AUC comparison (see Data).
- The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data
Animal Data
- In embryofetal development studies, delgocitinib was administered orally to pregnant rats or rabbits during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day in rats, and 1, 3 and 10 mg/kg/day in rabbits, respectively.
- In rats, no significant maternal toxicity was noted at doses up to 30 mg/kg/day (1446 times the MRHD based on AUC comparison). Decreases in fetal weight and skeletal variations were observed at doses ≥10 mg/kg/day (512 times the MRHD based on AUC comparison).
- An increase in post-implantation loss was observed at 30 mg/kg/day (1446 times the MRHD based on AUC comparison).
- No embryofetal toxicity was noted at 3 mg/kg/day (120 times the MRHD based on AUC comparison).
- In rabbits, no significant maternal toxicity was noted at doses up to 10 mg/kg/day (992 times the MRHD based on AUC comparison).
- An increase in post-implantation loss, reduced number of live fetuses, and decrease in fetal weights were observed at 10 mg/kg/day (992 times the MRHD based on AUC comparison).
- No embryofetal toxicity was noted at 3 mg/kg/day (193 times the MRHD based on AUC comparison).
- In a pre- and post-natal development study in pregnant rats, delgocitinib was orally administered at doses of 3, 10 and 30 mg/kg/day from gestation day 7 to lactation day 20. No significant maternal toxicity was noted at 30 mg/kg/day (1555 times the MRHD based on AUC comparison).
- Extended gestation period, a decrease in the birth index, and an increase in the number of dead newborns were observed at 30 mg/kg/day (1555 times the MRHD based on AUC comparison). Decreased fetal viability and reduced pup weights were noted during the early postnatal period at 30 mg/kg/day (1555 times the MRHD based on AUC comparison).
- No developmental toxicity was noted at 10 mg/kg/day (378 times the MRHD based on AUC comparison).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Delgocitinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Delgocitinib during labor and delivery.
Nursing Mothers
Risk Summary
- There are no data on the presence of delgocitinib in human milk, the effects on the breastfed infant, or the effects on milk production.
- After oral administration, delgocitinib was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ANZUPGO and any potential adverse effects on the breastfed infant from ANZUPGO or from the underlying maternal condition.
Clinical Considerations To minimize potential infant exposure, advise breastfeeding women to avoid direct contact with the nipple and surrounding area immediately after applying ANZUPGO to the hands and/or wrists.
Pediatric Use
The safety and efficacy of ANZUPGO have not been established in pediatric patients.
Geriatic Use
- Of the 691 subjects exposed to ANZUPGO in clinical trials, 59 subjects (8.5%) were 65 years of age and older and 10 subjects (1.4%) were 75 years of age and older.
- No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger adult subjects.
Gender
There is no FDA guidance on the use of Delgocitinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Delgocitinib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Delgocitinib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Delgocitinib in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Delgocitinib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Delgocitinib in patients who are immunocompromised.
Administration and Monitoring
Administration
- Advise patients that ANZUPGO is for topical use only and is not for ophthalmic, oral, or intravaginal use.
- Advise patients to limit treatment to 30 grams per 2 weeks or 60 grams per month.
- Instruct patients to clean and dry affected areas prior to applying ANZUPGO.
- Instruct patients to apply ANZUPGO, twice daily, to affected areas only on the hands and wrists, and avoid contact with eyes, mouth, or other mucous membranes
Monitoring
There is limited information regarding Delgocitinib Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Delgocitinib and IV administrations.
Overdosage
There is limited information regarding Delgocitinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Delgocitinib Pharmacology in the drug label.
Mechanism of Action
- Delgocitinib, a Janus kinase (JAK) inhibitor, inhibits the activity of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).
- JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, and activation and subsequent localization of STATs to the nucleus, leading to the expression of cytokine-responsive genes to induce specific biological responses in target cells.
- The exact mechanism of action of delgocitinib in the treatment of moderate to severe CHE is currently not known.
Structure
Delgocitinib is a Janus kinase (JAK) inhibitor [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] with the chemical name 3-[(3S,4R)-3-Methyl- 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3- oxopropanenitrile.
The molecular formula is C16H18N6O and the molecular weight is 310.35 g/mol. Delgocitinib has the structural formula:
Add STRUCTURE IMAGE
Pharmacodynamics
Pharmacodynamics of delgocitinib in the treatment of CHE are unknown.
Cardiac Electrophysiology At 193 times the mean maximal concentration provided by the recommended topical dose, clinically significant QTc interval prolongation was not observed.
Pharmacokinetics
- The pharmacokinetics of ANZUPGO were evaluated in a pharmacokinetic (PK) trial involving 15 adult subjects 22 to 69 years of age with moderate to severe CHE and in 313 subjects in TRIAL 2.
- Absorption
In the PK trial, subjects applied on average 0.87 g of ANZUPGO topically to the affected areas of the hands and wrists twice a day for 8 days.
The mean ± SD maximum plasma concentration (Cmax) and area under the concentration-curve from time 0 to 12 hours (AUC0-12) on Day 1 was 1.53 ng/mL ± 2.24 and 6.1 ng*h/mL ± 8.14, respectively. The lower limit of quantification was 0.005 ng/mL in the assay. The systemic exposure (AUC and Cmax) between Day 1 and Day 8 were similar. There was no evidence of accumulation with twice daily topical application of ANZUPGO.
In TRIAL 2, a single PK sample was assessed between 2-6 hours following twice daily application of ANZUPGO. The mean plasma concentration on Weeks 1, 4, and 16 were 0.42 ng/mL, 0.50 ng/mL, and 0.35 ng/mL, respectively.
- Distribution
Plasma protein binding of delgocitinib is 22 to 29%.
- Elimination
Following repeated topical application of ANZUPGO, the average half-life of delgocitinib was estimated to be 21 hours.
- Metabolism
Delgocitinib does not undergo extensive metabolism and the main plasma component is unchanged delgocitinib. Following oral administration, four metabolites (formed via oxidation and glucuronide conjugation) were detected at < 2% of the average unchanged delgocitinib plasma concentrations. The limited metabolism of delgocitinib occurs primarily though CYP3A4/5 and to a lesser extent by CYP1A1, CYP2C9, CYP2C19, and CYP2D6.
- Excretion
Delgocitinib is primarily eliminated by renal excretion as approximately 75% of the total dose after oral administration was found unchanged in the urine.
- Drug Interaction Studies
Clinical Studies Drug interaction studies with ANZUPGO have not been conducted.
In Vitro Studies Delgocitinib does not inhibit or induce cytochrome P450 enzymes or inhibit transporter systems such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting proteins (OATP), organic anion transporters (OAT), organic cation transporters (OCT), or multidrug and toxin extrusion protein (MATE) at clinically relevant concentrations.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Delgocitinib was not carcinogenic when administered topically in a 2-year dermal carcinogenicity study in mice.
- No drug-related neoplastic findings were observed at strengths up to 5% delgocitinib ointment (approximately 600 times the MRHD based on AUC comparison).
- In a 2-year oral carcinogenicity study in rats, delgocitinib was administered at doses of 3, 10, and 30 mg/kg/day. Benign thymoma was seen in female rats at 30 mg/kg/day (2274 times the MRHD based on AUC comparison). No drug-related neoplastic findings were observed in males at doses up to 30 mg/kg/day (1869 times the MRHD based on AUC comparison) or in females at 10 mg/kg/day (580 times the MRHD based on AUC comparison).
- Delgocitinib was not mutagenic or clastogenic in a bacterial mutagenicity assay (the Ames test) or in vivo chromosomal aberration tests in rat bone marrow cells and human peripheral blood lymphocytes.
- Delgocitinib did not impair fertility in male rats at oral doses up to 30 mg/kg/day (1308 times the MRHD based on AUC comparison).
- In female rats, delgocitinib resulted in a decrease in fertility index and corpora lutea, and an increase in implantation loss at 100 mg/kg/day (5897 times the MRHD based on AUC comparison).
- An increase in post-implantation loss and a decrease in the number of live embryos were observed at 10 and 30 mg/kg/day, respectively (432 and 1087 times the MRHD based on AUC comparison).
- No adverse effects on fertility were noted at 30 mg/kg/day (1087 times the MRHD based on AUC comparison) and no adverse effects on early embryonic development were noted at 3 mg/kg/day (110 times the MRHD based on AUC comparison).
Clinical Studies
- The efficacy of ANZUPGO was evaluated in two randomized, double-blind, vehicle-controlled, 16-week trials (TRIAL 1 [NCT04871711] and TRIAL 2 [NCT04872101]) which enrolled a total of 960 adult subjects with moderate to severe CHE who had a history of inadequate response to, or for whom topical corticosteroids were not advisable.
- All subjects who completed TRIAL 1 and TRIAL 2 were eligible to enroll into a long-term extension trial (TRIAL 3 [NCT04949841]).
- Disease severity of enrolled subjects was defined using the Investigator's Global Assessment for chronic hand eczema (IGA-CHE) score and the Hand Eczema Symptom Diary (HESD) itch score (weekly average).
- The IGA-CHE is the investigator's overall assessment of chronic hand eczema at a given time point on a scale ranging from 0 (clear) to 4 (severe).
- The HESD itch score assesses disease severity of pruritus using a scale ranging from 0 (no symptoms) to 10 (severe symptoms).
- Subjects enrolled in these three trials had an IGA-CHE score of 3 or 4 (moderate or severe, respectively) and a HESD itch score (weekly average) of ≥ 4 points at baseline.
- Across all treatment groups in TRIAL 1 and TRIAL 2, the mean age of enrolled subjects was 44.1 years, and 8% of subjects were 65 years of age or older, 64% were female, 90% were White, 4% were Asian, and 1% were Black.
- For ethnicity, 94% of subjects identified as not Hispanic or Latino and 3% of subjects identified as Hispanic or Latino.
- The primary classifications of CHE by subtype were atopic hand eczema (35.9%), hyperkeratotic eczema (21.5%), irritant contact dermatitis (19.6%), allergic contact dermatitis (13.9%), vesicular hand eczema (9.1%), and contact urticaria/protein contact dermatitis (0.1%).
- Across all trial arms, 28% of subjects were diagnosed with two or more overlapping CHE subtypes.
- The HESD itch score is a weekly average of daily itch severity on an 11-point scale from 0-10 that assesses the maximal intensity of pruritus in the last 24 hours with 0 being no pruritus and 10 being the worst pruritus.
- The HESD pain score is a weekly average of daily pain severity on an 11-point scale from 0-10 that assesses the maximal intensity of pain in the last 24 hours with 0 being no pain and 10 being the worst pain.
- In these trials, 28% of subjects had a baseline IGA-CHE score of 4 (severe CHE). The mean baseline HESD itch and pain scores were 7.1 and 6.7, respectively.
- In both trials, subjects applied either topical ANZUPGO or vehicle twice daily to affected areas on the hands and wrists for 16 weeks.
- The primary efficacy endpoint was the proportion of subjects who achieved IGA-CHE treatment success (IGA-CHE TS) at Week 16, defined as a score of 0 (clear) or 1 (almost clear) with at least a 2-point improvement from baseline.
ADD EFFICACY TABLE AND FIG.1,2,3
How Supplied
NZUPGO is a white to slightly brown cream containing 2% delgocitinib (each gram contains 20 mg of delgocitinib) and is supplied in the following package:
30 g laminated tubes: NDC 50222-280-30
Storage
Store ANZUPGO at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze.
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Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Patient Information).
Administration Instructions
- Advise patients that ANZUPGO is for topical use only and is not for ophthalmic, oral, or intravaginal use.
- Advise patients to limit treatment to 30 grams per 2 weeks or 60 grams per month.
- Instruct patients to clean and dry affected areas prior to applying ANZUPGO.
- Instruct patients to apply ANZUPGO, twice daily, to affected areas only on the hands and wrists, and avoid contact with eyes, mouth, or other mucous membranes
Serious Infections
- Inform patients that ANZUPGO may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any signs or symptoms of infection.
Non-melanoma Skin Cancers
- Inform patients that ANZUPGO may increase the risk of developing non-melanoma skin cancers.
- Inform patients that periodic skin examinations should be performed while using ANZUPGO.
- Instruct patients to inform their healthcare provider if they have ever had any type of cancer.
- Advise patients to avoid sunlamps and minimize exposure to sunlight by wearing sun-protective clothing or using broad-spectrum sunscreen.
Immunizations
- Advise patients treated with ANZUPGO to avoid use of live vaccines immediately prior to, during, and immediately after treatment.
Lactation
- Advise breastfeeding women to avoid direct contact with the nipple and surrounding area immediately after applying ANZUPGO to the hands and/ or wrists to minimize infant exposure
Precautions with Alcohol
Alcohol-Delgocitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Anzupgo®
Look-Alike Drug Names
There is limited information regarding Delgocitinib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.