CLASSES

Dermatitis Monoclonal Antibodies
Immunotherapies for Reactive and Obstructive Airway Diseases
Interleukin-4 (IL-4) Inhibitors

DEA CLASS

Rx

DESCRIPTION

Human monoclonal antibody and interleukin-4 receptor antagonist; administered subcutaneously
Used for moderate-to-severe atopic dermatitis in pediatric patients 6 months and older, allergic asthma in patients 6 years and older, eosinophilic esophagitis in patients 12 years and older, chronic rhinosinusitis with nasal polyposis (CRSwNP) in adults, and prurigo nodularis in adults
Do not use for acute bronchospasm

COMMON BRAND NAMES

DUPIXENT

HOW SUPPLIED

DUPIXENT Subcutaneous Inj Sol: 1mL, 150mg, 175mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

600 mg subcutaneously initially, then 300 mg subcutaneously every other week for atopic dermatitis, asthma, or prurigo nodularis; 300 mg subcutaneously every other week for chronic rhinosinusitis with nasal polyposis; 300 mg subcutaneously once weekly for eosinophilic esophagitis.

600 mg subcutaneously initially, then 300 mg subcutaneously every other week for atopic dermatitis, asthma, or prurigo nodularis; 300 mg subcutaneously every other week for chronic rhinosinusitis with nasal polyposis; 300 mg subcutaneously once weekly for eosinophilic esophagitis.

weighing 60 kg or more: 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for atopic dermatitis or asthma; 300 mg subcutaneously once weekly for eosinophilic esophagitis.
weighing 40 to 59 kg: 400 mg subcutaneously initially, then 200 mg subcutaneously every other week for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma; 300 mg subcutaneously once weekly for eosinophilic esophagitis.
weighing 30 to 39 kg: 400 mg subcutaneously initially, then 200 mg subcutaneously every other week for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma.
weighing 15 to 29 kg: 600 mg subcutaneously initially, then 300 mg subcutaneously every 4 weeks for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma.

12 years:
weighing 60 kg or more: 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for atopic dermatitis or asthma; 300 mg subcutaneously once weekly for eosinophilic esophagitis.
weighing 40 to 59 kg: 400 mg subcutaneously initially, then 200 mg subcutaneously every other week for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma; 300 mg subcutaneously once weekly for eosinophilic esophagitis.
weighing 30 to 39 kg: 400 mg subcutaneously initially, then 200 mg subcutaneously every other week for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma.
weighing 15 to 29 kg: 600 mg subcutaneously initially, then 300 mg subcutaneously every 4 weeks for atopic dermatitis; 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for asthma.
 
6 to 11 years:
weighing 60 kg or more: 600 mg subcutaneously initially, then 300 mg subcutaneously every other week for atopic dermatitis or asthma and co-morbid atopic dermatitis; 200 mg subcutaneously every other week for asthma.
weighing 30 to 59 kg: 400 mg subcutaneously initially, then 200 mg subcutaneously every other week for atopic dermatitis or asthma and co-morbid atopic dermatitis; 200 mg subcutaneously every other week for asthma.
weighing 15 to 29 kg: 600 mg subcutaneously initially, then 300 mg subcutaneously every 4 weeks for atopic dermatitis or asthma and co-morbid atopic dermatitis; 300 mg subcutaneously every 4 weeks for asthma.
 
1 to 5 years:
weighing 15 to 29 kg: 300 mg subcutaneously every 4 weeks for atopic dermatitis.
weighing 5 to 14 kg: 200 mg subcutaneously every 4 weeks for atopic dermatitis.

6 to 11 months:
weighing 15 to 29 kg: 300 mg subcutaneously every 4 weeks for atopic dermatitis.
weighing 5 to 14 kg: 200 mg subcutaneously every 4 weeks for atopic dermatitis.
 
1 to 5 months:
Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Administer by subcutaneous injection only.
Available in a prefilled syringe and prefilled pen for ease of patient administration. The prefilled pen is for use in adults and pediatric patients 2 years and older. The prefilled syringe is for use in adult and pediatric patients aged 6 months and older. Adults and pediatric patients 12 years and older who are properly trained in the injection technique may self-inject using the prefilled pen or prefilled syringe if the prescriber deems the action appropriate. For patients 12 to 17 years, it is recommended that the injection be given by or under the supervision of an adult. For patients 6 months to 11 years, the injection should only be given by a caregiver. The patient should not inject themselves, nor should a caregiver inject someone else, until proper training in subcutaneous injection is complete. A health care professional can show the patient or the caregiver how to prepare and inject a dose before they try to do it for the first time.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear to slightly opalescent or colorless to pale yellow. Do not use if the solution contains visible particulate matter or is discolored or cloudy (other than acceptable coloration).
Do not use the syringe if it has been damaged or the needle cap is not securely attached. Do not use the pen if it has been damaged, if the cap is not securely attached, or if the window is yellow.

STORAGE

DUPIXENT:
- Avoid direct heat and sunlight
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not expose product to temperatures above 77 degrees F
- Do not freeze syringe
- Do not shake syringe
- Protect from moisture
- See package insert for detailed storage information
- Store in a dry, well ventilated place
- Store syringe in refrigerator between 36 to 46 degrees F (2 to 8 degrees C)
- Syringe can be stored at room temperature up to 77 degrees F (25 degrees C) up to 14 days
- Throw away (dispose of) any syringe that has been left at room temperature for longer than 14 days
- To protect from light, store syringe in original carton until time of use

CONTRAINDICATIONS / PRECAUTIONS

Dupilumab is contraindicated in patients with a history of hypersensitivity to dupilumab or any of the product excipients. Use with caution in patients with hamster protein hypersensitivity, as dupilumab is produced in Chinese hamster ovary cells. Hypersensitivity reactions (e.g., rash and allergic conjunctivitis) have occurred after dupilumab administration. Such reactions generally occur within hours of administration, but may have a delayed onset (i.e., days). If a hypersensitivity reaction occurs, discontinue the drug and institute appropriate treatment.

Patients with comorbid asthma who start dupilumab therapy for atopic dermatitis or chronic rhinosinusitis with nasal polyposis (CRSwNP) should be advised not to adjust or stop their asthma treatments without consultation with a healthcare provider. While dupilumab is approved for use as add-on therapy to treat eosinophilic phenotype and oral corticosteroid-dependent moderate-to-severe asthma, it should not be used to treat acute asthma symptoms or exacerbations (i.e., acute bronchospasm or status asthmaticus). Do not discontinue use of systemic, topical, or inhaled corticosteroids abruptly upon initiation of dupilumab therapy. To avoid corticosteroid withdrawal, the dose should be reduced gradually under the direct supervision of a physician. Instruct patients to seek medical advice if asthma remains uncontrolled or worsens after starting dupilumab.[61836]

Treat patients with a preexisting helminth infection with anti-helminth therapy before starting dupilumab. If a patient becomes infected while receiving dupilumab and fails to respond to anti-helminth treatment, discontinue dupilumab until the infection resolves.[61836]

Although a causal association has not been established, cases of eosinophilic pneumonia and vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported in asthmatic recipients of dupilumab. Healthcare providers are advised to monitor asthmatic patients who present with eosinophilia for vasculitic rash, worsening pulmonary symptoms, cardiac complications, and neuropathy.[61836]

Avoid vaccination of dupilumab recipients with live virus vaccines. No data are available on the ability of live vaccines to elicit an immune response in patients being treated with dupilumab. Consider completing all age appropriate immunizations prior to initiating treatment. Limited data are available regarding coadministration of non-live vaccines with dupilumab. In a clinical study, adult patients with atopic dermatitis receiving 300 mg subcutaneously once weekly (twice the recommended dosing frequency) for 16 weeks received a Tdap vaccine and a meningococcal polysaccharide vaccine after 12 weeks of therapy. Antibody responses were assessed 4 weeks after administration of the vaccines and the response to both tetanus toxoid and serogroup C meningococcal polysaccharide were similar in dupilumab-treated and placebo-treated patients. Antibody responses to other active components of the vaccines were not assessed nor were responses to other non-live vaccines assessed.[61836]

Limited data from case reports and case series with dupilumab use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus. Animal data from monkeys in an enhanced pre- and post-natal developmental study showed no adverse developmental effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development in offspring from birth to 6 months of age after subcutaneous administration of a homologous IL-4R alpha antibody up to 10-times the maximum recommended human dose (on a mg/kg basis of 100 mg/kg/week). There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to dupilumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/dupixent or by calling 1-877-311-8972.[61836]

There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk; however, the effects of gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. Weigh the benefits of breast-feeding along with the mother's clinical need for dupilumab and any potential adverse effects on the breastfed infant or from the underlying maternal condition prior to using dupilumab.

ADVERSE REACTIONS

keratitis / Delayed / 0-4.0
erythema nodosum / Delayed / 0-1.0
erythema multiforme / Delayed / 0-1.0
serum sickness / Delayed / 0-1.0
exfoliative dermatitis / Delayed / 0-1.0
thromboembolism / Delayed / 0-0.9
stroke / Early / 0-0.9
myocardial infarction / Delayed / 0-0.9
angioedema / Rapid / Incidence not known

conjunctivitis / Delayed / 2.0-20.0
antibody formation / Delayed / 1.0-16.0
eosinophilia / Delayed / 0-8.0
blepharitis / Early / 0-5.0
gastritis / Delayed / 0-2.0
blurred vision / Early / Incidence not known

injection site reaction / Rapid / 6.0-38.0
infection / Delayed / 1.0-18.0
pharyngitis / Delayed / 5.0-5.0
arthralgia / Delayed / 2.0-3.0
diarrhea / Early / 3.0-3.0
myalgia / Early / 3.0-3.0
dizziness / Early / 3.0-3.0
musculoskeletal pain / Early / 3.0-3.0
vertigo / Early / 3.0-3.0
ocular pruritus / Rapid / 1.0-2.0
xerophthalmia / Early / 0-2.0
throat irritation / Early / 2.0-2.0
rash / Early / 0-1.0
urticaria / Rapid / 0-1.0
dental pain / Delayed / 1.0-1.0
insomnia / Early / 0-1.0

DRUG INTERACTIONS

Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Carbamazepine: (Moderate) Coadministration of dupilumab may result in altered exposure to carbamazepine. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as carbamazepine. Monitor carbamazepine concentrations if dupilumab is initiated or discontinued in a patient taking carbamazepine; carbamazepine dose adjustments may be needed.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclosporine: (Moderate) Coadministration of dupilumab may result in altered exposure to cyclosporine. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. Monitor cyclosporine concentrations if dupilumab is initiated or discontinued in a patient taking cyclosporine; cyclosporine dose adjustments may be needed.
Digoxin: (Moderate) Coadministration of dupilumab may result in altered exposure to digoxin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as digoxin. Monitor digoxin concentrations if dupilumab is initiated or discontinued in a patient taking digoxin; digoxin dose adjustments may be needed.
Ethosuximide: (Moderate) Coadministration of dupilumab may result in altered exposure to ethosuximide. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as ethosuximide. Monitor ethosuximide concentrations if dupilumab is initiated or discontinued in a patient taking ethosuximide; ethosuximide dose adjustments may be needed.
Fosphenytoin: (Moderate) Coadministration of dupilumab may result in altered exposure to fosphenytoin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as fosphenytoin. Monitor phenytoin concentrations if dupilumab is initiated or discontinued in a patient taking fosphenytoin; fosphenytoin dose adjustments may be needed.
Intranasal Influenza Vaccine: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Lithium: (Moderate) Coadministration of dupilumab may result in altered exposure to lithium. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as lithium. Monitor lithium concentrations if dupilumab is initiated or discontinued in a patient taking lithium; lithium dose adjustments may be needed.
Live Vaccines: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Phenytoin: (Moderate) Coadministration of dupilumab may result in altered exposure to phenytoin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as phenytoin. Monitor phenytoin concentrations if dupilumab is initiated or discontinued in a patient taking phenytoin; phenytoin dose adjustments may be needed.
Procainamide: (Moderate) Coadministration of dupilumab may result in altered exposure to procainamide. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as procainamide. Monitor procainamide concentrations if dupilumab is initiated or discontinued in a patient taking procainamide; procainamide dose adjustments may be needed.
Rotavirus Vaccine: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Rubella Virus Vaccine Live: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Tacrolimus: (Moderate) Coadministration of dupilumab may result in altered exposure to tacrolimus. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. Monitor tacrolimus concentrations if dupilumab is initiated or discontinued in a patient taking tacrolimus; tacrolimus dose adjustments may be needed.
Theophylline, Aminophylline: (Moderate) Coadministration of dupilumab may result in altered exposure to theophylline. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline. Monitor theophylline concentrations if dupilumab is initiated or discontinued in a patient taking theophylline; theophylline dose adjustments may be needed.
Typhoid Vaccine: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.
Warfarin: (Moderate) Coadministration of dupilumab may result in altered exposure to warfarin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. Monitor the INR if dupilumab is initiated or discontinued in a patient taking warfarin; warfarin dose adjustments may be needed.
Yellow Fever Vaccine, Live: (Major) Avoid administration of live vaccines to dupilumab recipients. Before initiation of dupilumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. No data are available on the response to live vaccines in patients receiving dupilumab therapy.

PREGNANCY AND LACTATION

Limited data from case reports and case series with dupilumab use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus. Animal data from monkeys in an enhanced pre- and post-natal developmental study showed no adverse developmental effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development in offspring from birth to 6 months of age after subcutaneous administration of a homologous IL-4R alpha antibody up to 10-times the maximum recommended human dose (on a mg/kg basis of 100 mg/kg/week). There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to dupilumab; information about the registry can be obtained at mothertobaby.org/ongoing-study/dupixent or by calling 1-877-311-8972.[61836]

There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk; however, the effects of gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. Weigh the benefits of breast-feeding along with the mother's clinical need for dupilumab and any potential adverse effects on the breastfed infant or from the underlying maternal condition prior to using dupilumab.

MECHANISM OF ACTION

Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding specifically to the IL-4R alpha subunit shared by the IL-4 and IL-13 receptor complexes. By blocking IL-4R alpha, dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory response, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE, which plays a role in the development of asthma and atopic dermatitis. Consistent with receptor blockade, serum levels of IL-4 and IL-13 are increased following dupilumab treatment.[61836]

PHARMACOKINETICS

Dupilumab is administered subcutaneously. The pharmacokinetics of dupilumab are similar in subjects with atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and prurigo nodularis. The estimated total Vd of dupilumab is approximately 4.8 +/- 1.3 L. The metabolic pathway of dupilumab is unknown; however, as a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a similar manner as endogenous IgG. In clinical trials, after the last steady-state dose of dupilumab 300 mg every 2 weeks, 300 mg weekly, 200 mg every 2 weeks, 300 mg every 4 weeks, or 200 mg every 4 weeks, the median times to non-detectable concentration (less than 78 ng/mL) ranged from 9 to 13 weeks in patients 12 years and older. Formation of anti-drug antibodies results in reduced systemic exposure of dupilumab. A few subjects who had high antibody titers also had no detectable dupilumab concentrations.[61836]
 
Affected cytochrome P450 isoenzymes: CYP2D6
No clinically significant changes in exposure were observed when dupilumab was administered concurrently with substrates of CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP1A2 (caffeine). The largest effect was observed with metoprolol (CYP2D6), with an exposure increase of 29%.[61836]