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Brodalumab

Pronunciation

(broe DAL ue mab)

Index Terms

  • AMG 827
  • Siliq

Pharmacologic Category

  • Antipsoriatic Agent
  • Interleukin-17A Receptor Antagonist
  • Monoclonal Antibody

Pharmacology

Brodalumab is a human monoclonal IgG2 antibody that antagonizes the interleukin-17 receptor A (IL-17RA) pathway. Brodalumab selectively binds with high affinity to IL-17RA and blocks the activity with cytokines IL-17A, IL-17C, IL-17F, IL-17A/F heterodimer, and IL-17E (IL-25) (Papp 2012). IL-17A, IL-17C, and IL-17F are elevated in psoriatic plaques. Inhibiting IL-17RA blocks cytokine-induced responses, including release of pro-inflammatory cytokines and chemokines.

Distribution

Vd: 8.9 ± 9.4 L.

Metabolism

Degraded into small peptides in a manner similar to endogenous IgG.

Excretion

Clearance: Mean (±SD) apparent total clearance (CL/F) of a 210 mg subcutaneous dose was 3.0 ± 3.5 L/day.

Time to Peak

~3 days

Special Populations Note

Weight: Trough concentrations were lower in subjects with higher body weight.

Use: Labeled Indications

Plaque psoriasis: Treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.

Contraindications

Crohn disease

Dosing: Adult

Plaque psoriasis: SubQ: 210 mg at weeks 0, 1, and 2, followed by 210 mg once every 2 weeks. Consider discontinuing if an adequate response is not achieved after 12 to 16 weeks (continuing treatment beyond 16 weeks in patients without an adequate response is not likely to result in greater success).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

Allow prefilled syringe to reach room temperature (~30 minutes) before injecting. Do not warm in any other way. Upon visual inspection, a few proteinaceous particles may be present, however, do not use if solution is cloudy or discolored or if foreign matter is present.

Administration

Administer subcutaneously into the thigh, abdomen (except the 2 inch area around the navel), or outer upper arm. Do not inject into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. Allow prefilled syringe to reach room temperature for ~30 minutes prior to use (do not warm in any other way). Do not shake the syringe. The prefilled syringe may be self-injected in appropriate patients following proper training in subcutaneous injection technique.

Storage

Store at 2°C to 8°C (36°F to 46°F) in the original carton; do not freeze. Protect from light. Do not shake. When necessary, prefilled syringes can be stored at room temperature up to a maximum of 25°C (77°F) in the original carton for a maximum single period of 14 days with protection from light and heat sources. Once the prefilled syringe has reached room temperature, do not place back into the refrigerator. Discard after 14 days at room temperature.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%: Infection: Infection (25%; including bronchitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, urinary tract infection)

1% to 10%:

Central nervous system: Fatigue (3%)

Dermatologic: Tinea (1%; tinea cruris, tinea pedis, tinea versicolor)

Gastrointestinal: Diarrhea (2%), nausea (2%)

Hematologic & oncologic: Neutropenia (≤1%; ≥grade 3: <1%)

Immunologic: Antibody development (3%)

Infection: Fungal infection (2%), influenza (1%)

Local: Injection site reaction (2%; bleeding at injection site, bruising at injection site, erythema at injection site, injection site pruritus, pain at injection site)

Neuromuscular & skeletal: Arthralgia (5%), myalgia (2%)

Respiratory: Oropharyngeal pain (2%)

<1%, postmarketing, and/or case reports: Candidiasis (esophageal, genital, oral), conjunctivitis, Crohn's disease, exacerbation of Crohn's disease, suicidal ideation

ALERT: U.S. Boxed Warning

Suicidal ideation and behavior:

Suicidal ideation and behavior, including completed suicides, have occurred in patients treated with brodalumab. Prior to prescribing brodalumab, weigh the potential risks and benefits in patients with a history of depression and/or suicidal ideation or behavior. Patients with new or worsening suicidal ideation and behavior should be referred to a mental health professional, as appropriate. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new onset or worsening depression, anxiety, or other mood changes.

Because of the observed suicidal behavior in subjects treated with brodalumab, brodalumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SILIQ REMS Program.

Warnings/Precautions

Concerns related to adverse effects:

• Infections: Brodalumab may increase the risk of infections. In clinical trials, serious infections and fungal infections occurred at a higher rate in patients who received brodalumab, compared to those who received placebo. Cryptococcal meningitis has been reported (case report). Consider the risks versus benefits prior to treatment initiation in patients with a history of chronic or recurrent infection. Monitor for infections; patients should seek medical attention for signs/symptoms of a clinically important infection (acute or chronic). If a serious infection develops or is unresponsive to appropriate therapy for the infection, monitor closely and discontinue brodalumab until the infection resolves.

• Suicidal thinking/behavior: [US Boxed Warning]: Suicidal ideation and behavior, including completed suicides, have occurred with brodalumab treatment. Weigh the potential risks and benefits in patients with a history of depression and/or suicidal ideation or behavior prior to prescribing brodalumab. Refer patients with new or worsening suicidal ideation and behavior to a mental health professional, as appropriate. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new onset or worsening depression, anxiety, or other mood changes. Risks and benefits of continuing treatment should be evaluated in the event of suicidal behavior. Patients with a history of depression or suicidality had in increased incidence of suicidal ideation/behavior compared to those without a history. Consider discontinuing treatment if an adequate response to brodalumab therapy is not achieved within 12 to 16 weeks (due to the risk of suicidal ideation/behavior).

• Tuberculosis: Patients should be evaluated for tuberculosis (TB) infection prior to initiating therapy. Do not administer brodalumab to patients with an active TB infection. Treatment for latent TB should be administered prior to administering brodalumab. Consider anti-TB therapy prior to treatment initiation in patients with a history of latent or active TB in whom an adequate course of TB treatment cannot be confirmed. Monitor closely for signs/symptoms of active TB during and after brodalumab treatment.

Disease-related concerns:

• Crohn disease: While psoriasis studies excluded patients with active Crohn disease, Crohn disease occurred in one study participant (which led to brodalumab discontinuation). In other studies, exacerbation of Crohn disease was observed with brodalumab. Discontinue brodalumab if Crohn disease develops during treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Other warnings/precautions:

• Immunizations: Avoid the use of live vaccines in patients treated with brodalumab; there is no data on the ability to elicit an immune response with live or inactive vaccines in patients receiving brodalumab.

• REMS program: [US Boxed Warning]: Due to suicidal behavior in subjects treated with brodalumab, brodalumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SILIQ REMS Program. Prescribers and pharmacies must be certified with the program and patients must sign a patient-prescriber agreement; pharmacies can only dispense to patients who are authorized to receive brodalumab. Further information is available at http://www.SILIQREMS.com or at 855-511-6135.

Monitoring Parameters

Evaluate for tuberculosis infection (prior to treatment). Monitor for signs of suicidal ideation or behavior; signs/symptoms of infection, including active tuberculosis.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Brodalumab is a monoclonal immune globulin; immune globulins are known to cross the placenta.

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