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  • CLASSES

    Immunotherapies for Reactive and Obstructive Airway Diseases
    Interleukin-5 (IL-5) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Subcutaneous humanized monoclonal antibody directed against interleukin (IL)-5
    Used for maintenance therapy in severe asthma (eosinophilic phenotype) in patients 6 years and older; adults with eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome; and hypereosinophilic syndrome in patients 12 years and older
    Reduces severe exacerbations of asthma and may allow more time in remission and lower frequency of relapse for EGPA, which may allow for oral corticosteroid dose reduction for both indications

    COMMON BRAND NAMES

    Nucala

    HOW SUPPLIED

    Mepolizumab Subcutaneous Inj Sol: 1mL, 100mg
    Nucala Subcutaneous Inj Pwd F/Sol: 100mg

    DOSAGE & INDICATIONS

    For asthma maintenance add-on therapy in patients with severe asthma (eosinophilic phenotype).
    Subcutaneous dosage
    Adults

    100 mg subcutaneously once every 4 weeks.

    Children and Adolescents 12 to 17 years

    100 mg subcutaneously once every 4 weeks.

    Children 6 to 11 years

    40 mg subcutaneously once every 4 weeks.

    For the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) .
    Subcutaneous dosage
    Adults

    300 mg subcutaneously every 4 weeks; administer as 3 separate 100-mg injections at least 5 cm (approximately 2 inches) apart.

    For the treatment of hypereosinophilic syndrome (HES) present for at least 6 months without an identifiable non-hematologic secondary cause.
    NOTE: Mepolizumab has been designated by the FDA as an orphan drug for the first-line treatment of HES.
    Subcutaneous dosage
    Adults

    300 mg subcutaneously every 4 weeks; administer as 3 separate 100-mg injections at least 5 cm (approximately 2 inches) apart. Significantly fewer patients who received mepolizumab experienced a HES flare during the 32-week treatment period compared with placebo (28% vs. 56%; odds ratio = 0.28; 95% CI, 0.12 to 0.64; p = 0.002) in a randomized, double-blind trial (n = 108). Patients were 12 years of age or older (mean age, 46 years), had HES for at least 6 months (mean duration, 5.55 years), and were on stable HES therapy (e.g., oral corticosteroids or immunosuppressive or cytotoxic therapy) for the 4 weeks prior to randomization. Patients with non-hematologic secondary HES (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or FIP1L1-PDGFR alpha kinase-positive HES were excluded from the trial.

    Adolescents and Children 12 years and older

    300 mg subcutaneously every 4 weeks; administer as 3 separate 100-mg injections at least 5 cm (approximately 2 inches) apart. Significantly fewer patients who received mepolizumab experienced a HES flare during the 32-week treatment period compared with placebo (28% vs. 56%; odds ratio = 0.28; 95% CI, 0.12 to 0.64; p = 0.002) in a randomized, double-blind trial (n = 108). Patients were 12 years of age or older (mean age, 46 years), had HES for at least 6 months (mean duration, 5.55 years), and were on stable HES therapy (e.g., oral corticosteroids or immunosuppressive or cytotoxic therapy) for the 4 weeks prior to randomization. Patients with non-hematologic secondary HES (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or FIP1L1-PDGFR alpha kinase-positive HES were excluded from the trial.

    MAXIMUM DOSAGE

    Adults

    100 mg subcutaneously every 4 weeks for severe asthma; 300 mg subcutaneously every 4 weeks for eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome.

    Geriatric

    100 mg subcutaneously every 4 weeks for severe asthma; 300 mg subcutaneously every 4 weeks for eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome.

    Adolescents

    100 mg subcutaneously every 4 weeks for severe asthma; 300 mg subcutaneously every 4 weeks for hypereosinophilic syndrome; safety and efficacy have not been established for eosinophilic granulomatosis with polyangiitis.

    Children

    1 to 5 years: Safety and efficacy have not been established.6 to 11 years: 40 mg subcutaneously every 4 weeks for asthma; safety and efficacy for other indications have not been established.12 years: 100 mg subcutaneously every 4 weeks for asthma; 300 mg subcutaneously every 4 weeks for hypereosinophilic syndrome; safety and efficacy have not been established for eosinophilic granulomatosis with polyangiitis.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear to opalescent and colorless to pale yellow or pale brown.
    Mepolizumab injection vial should be reconstituted and administered by a healthcare professional.
    The mepolizumab injection prefilled autoinjector and the prefilled syringe are only for use in adults and adolescents aged 12 years and older. Either may be administered by a patient or caregiver if the healthcare provider determines it is appropriate.
    For a 300 mg dose, administer as 3 separate 100-mg injections at least 5 cm (approximately 2 inches) apart.
    Monitoring of patients after administration of biologic agents is recommended.

    Subcutaneous Administration

    Mepolizumab for Injection Vial
     
    Reconstitution
    Reconstitute mepolizumab in the vial with 1.2 mL Sterile Water for Injection, preferably using a 2- or 3-mL syringe and a 21-gauge needle. The final concentration will be 100 mg/mL (144 mg/vial). There will be overfill in the vial.
    Direct the stream of Sterile Water for Injection vertically into the center of the lyophilized powder, which may have a cake-like appearance. Gently swirl the vial for 10 seconds at 15-second intervals until the powder is dissolved. Do not shake the reconstituted solution, as this may lead to foaming or precipitation. Reconstitution is usually complete within 5 minutes but may take additional time.
    If a mechanical reconstitution device (swirler) is used, swirl at 450 rpm for no longer than 10 minutes. Alternatively, swirling at 1,000 rpm for no longer than 5 minutes is acceptable.
    The solution should be clear to opalescent and colorless to pale yellow or pale brown and essentially particle-free. Small air bubbles are expected and acceptable.
    Do not mix with other medications.
    Storage: If not used immediately, store below 30 degrees C (86 degrees F), but do not freeze. Discard if not used within 8 hours of reconstitution.
     
    Subcutaneous Administration from the Vial
    Administer the dose into the upper arm, thigh, or abdomen; a 1-mL polypropylene syringe fitted with a disposable 21- to 27-gauge x 0.5-inch (13-mm) needle is preferable for subcutaneous administration.
    For 100 mg dose, remove 1 mL (100 mg) of the reconstituted solution from the vial.
    For 40 mg dose, remove 0.4 mL (40 mg) of the reconstituted solution from the vial.
    Each vial should be used for a single patient, and any remainder of the contents should be discarded.
     
    Mepolizumab Injection Prefilled Autoinjector and Prefilled Syringe
    Provide proper training in subcutaneous injection technique and on the preparation and administration of mepolizumab injection prior to use according to the "Instructions for Use".
    Do not use the prefilled autoinjector or prefilled syringe if it is dropped on a hard surface or if it looks damaged.
    Remove the prefilled autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for approximately 30 minutes prior to injection. Do NOT warm mepolizumab in any other way.
    Administer the subcutaneous injection into the thigh or abdomen, avoiding the 5 cm (2 inches) around the navel. The upper arm can also be used if a caregiver administers the subcutaneous injection. Never give injections into areas where the skin is tender, bruised, red, or hard.
    If a dose is missed, administer a dose as soon as possible. Thereafter, the patient can resume dosing on the usual day of administration. If the next dose is already due, then administer as planned.
    Do not use the prefilled syringe or autoinjector more than 1 time. Throw away the autoinjector or prefilled syringe in an FDA-cleared sharps disposal container after injection.
    Storage: Store unopened autoinjectors or prefilled syringes in the original carton in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F); do not freeze. Protect from light. Do not shake. Keep away from heat. If needed, an unopened carton can be stored outside the refrigerator at up to 30 degrees C (86 degrees F) for up to 7 days. Dispose of the injection properly if it is left out of the refrigerator in the unopened carton for more than 7 days. The prefilled autoinjector must be used within 8 hours after it is removed from the carton. Discard properly if it is not used within 8 hours.

    STORAGE

    Nucala:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard product if not administered within 8 hours after removal from carton
    - Do not freeze
    - May be stored at room temperature for up to 1 week
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Hamster protein hypersensitivity

    Mepolizumab is contraindicated in patients with a history of hypersensitivity to mepolizumab or excipients in the formulation. Use with caution in patients with hamster protein hypersensitivity, as the drug is produced in Chinese hamster ovary cells. Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) have occurred after mepolizumab 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.

    Acute bronchospasm, status asthmaticus

    Mepolizumab should not be used to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after mepolizumab initiation. Short-acting beta-agonists, such as albuterol, should be available for rescue therapy.

    Corticosteroid withdrawal

    Do not discontinue systemic or inhaled corticosteroid therapy abruptly upon mepolizumab initiation. Corticosteroid withdrawal and dosage reduction, if appropriate, should be done gradually under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

    Herpes infection

    In pre-marketing clinical trials, 2 cases of serious herpes infection (herpes zoster) occurred in patients who received mepolizumab compared to none in the placebo group. Nine hundred ninety-eight (998) subjects have received mepolizumab in ongoing open-label extension studies, during which additional cases of herpes zoster have been reported. If medically appropriate, consider varicella vaccination prior to treatment initiation.

    Helminth infection

    Treat patients with a pre-existing helminth infection prior to initiating therapy with mepolizumab. If a patient becomes infected while receiving mepolizumab therapy and does not respond to anti-helminth treatment, discontinue mepolizumab therapy until the infection resolves. Mepolizumab reduces the production and survival of eosinophils, which may be involved in the immunological response to some helminth infections. Although it is not known whether if mepolizumab will influence the body's response against parasitic infections, caution is warranted. Patients with known parasitic infections were excluded from clinical trials.

    Pregnancy

    Pregnancy exposure data is insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the second and third trimesters. In a development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV mepolizumab administration throughout pregnancy at drug exposures approximately 30 times the exposure at the maximum recommended human dose (100 mg subcutaneously). In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Asthma control should be closely monitored during pregnancy and treatment adjusted to maintain optimal control. Healthcare providers can enroll patients or encourage patients to enroll themselves in a pregnancy exposure registry (www.mothertobaby.org/asthma or 1-877-311-8972) that monitors pregnancy outcomes in women exposed to mepolizumab during pregnancy.

    Breast-feeding

    There is no information regarding the presence of mepolizumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. The FDA-approved product label recommends considering the developmental and health benefits of breast-feeding, the mother's need for mepolizumab therapy, and potential adverse effects of the drug or inadequately treated asthma on the breast-fed infant. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    antibody formation / Delayed / 0-6.0
    cystitis / Delayed / 3.0
    dyspnea / Early / 3.0
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    headache / Early / 19.0-19.0
    injection site reaction / Rapid / 7.0-15.0
    back pain / Delayed / 5.0-5.0
    fatigue / Early / 5.0-5.0
    muscle cramps / Delayed / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    influenza / Delayed / 3.0-3.0
    pruritus / Rapid / 3.0-3.0
    asthenia / Delayed / 3.0
    musculoskeletal pain / Early / 3.0
    dizziness / Early / 3.0
    nausea / Early / 3.0
    dental pain / Delayed / 3.0
    vomiting / Early / 3.0
    fever / Early / 3.0
    pharyngitis / Delayed / 3.0
    nasal congestion / Early / 3.0
    infection / Delayed / 3.0
    rhinitis / Early / 3.0
    rash / Early / 3.0
    myalgia / Early / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy exposure data is insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the second and third trimesters. In a development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV mepolizumab administration throughout pregnancy at drug exposures approximately 30 times the exposure at the maximum recommended human dose (100 mg subcutaneously). In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Asthma control should be closely monitored during pregnancy and treatment adjusted to maintain optimal control. Healthcare providers can enroll patients or encourage patients to enroll themselves in a pregnancy exposure registry (www.mothertobaby.org/asthma or 1-877-311-8972) that monitors pregnancy outcomes in women exposed to mepolizumab during pregnancy.

    There is no information regarding the presence of mepolizumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. The FDA-approved product label recommends considering the developmental and health benefits of breast-feeding, the mother's need for mepolizumab therapy, and potential adverse effects of the drug or inadequately treated asthma on the breast-fed infant. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mepolizumab is a fully-humanized monoclonal antibody (IgG1 kappa) that targets human interleukin (IL)-5. Inflammation is a major component in the pathogenesis of asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome; many cell types (e.g., eosinophils) and mediators (e.g., cytokines) are involved in inflammation. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab selectively binds to IL-5, blocking it from binding to the alpha chain of the IL-5 receptor complex located on the eosinophil cell surface. This, in turn, inhibits IL-5 signaling and reduces the production and survival of eosinophils. Other undefined mechanisms of action may also play a role.

    PHARMACOKINETICS

    Mepolizumab is administered by subcutaneous injection. The central volume of distribution (Vd) of mepolizumab in adult patients with asthma is approximately 3.6 L for a 70-kg individual. Mepolizumab is a humanized IgG1 monoclonal antibody, and degradation occurs via proteolytic enzymes that are widely distributed throughout the body and not restricted to hepatic tissue. Apparent systemic clearance in adult and adolescent patients is estimated to be 0.28 L/day for a 70-kg individual. Mean terminal half-life in adult patients ranges from 16 to 22 days.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Subcutaneous Route

    After subcutaneous administration in the upper arm, the bioavailability of mepolizumab in adult and adolescent patients with asthma was approximately 80%. After repeated subcutaneous administration once every 4 weeks, there was approximately a 2-fold accumulation at steady state.