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Siliq

Generic Name: Brodalumab
Class: Skin and Mucous Membrane Agents, Miscellaneous
Chemical Name: Disulfide with human monoclonal light chain, anti-(human interleukin 17 receptor A) (human monoclonal heavy chain), immunoglobulin G dimer
Molecular Formula: C6372H9840N1712O1988S52
CAS Number: 1174395-19-7

Warning

    Suicidal Ideation and Behavior
  • Suicidal ideation and behavior, including completed suicides, reported.1 (See Suicidal Ideation and Behavior under Cautions.)

  • Weigh potential risks and benefits before initiating brodalumab therapy in patients with a history of depression and/or suicidal ideation or behavior.1

  • Refer patients with new or worsening suicidal ideation and behavior to a mental health professional, as appropriate.1

  • Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new onset or worsening of depression or anxiety, or other mood changes.1

  • Available only through a restricted distribution program under a REMS.1 5 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for brodalumab to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of brodalumab and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). Also see Restricted Distribution Program under Dosage and Administration: General.

Introduction

Recombinant human IgG2 kappa monoclonal antibody that binds specifically to interleukin-17 receptor A (IL-17RA) and inhibits its interactions with proinflammatory cytokines IL-17A, IL-17C, IL-17F, IL-17A/F heterodimer, and IL-25 (also known as IL-17E).1 2 3 4 6 7 9

Uses for Siliq

Plaque Psoriasis

Management of moderate to severe plaque psoriasis in patients who are candidates for phototherapy or systemic therapy and who have failed to respond to or have lost response to other systemic therapies.1 2 3 4

Siliq Dosage and Administration

General

  • Evaluate patients for tuberculosis infection prior to initiating brodalumab.1 (See Infectious Complications under Cautions.)

Restricted Distribution Program

  • Available only through a restricted distribution program (Siliq REMS Program).1 5 (See Boxed Warning and also see Suicidal Ideation and Behavior under Cautions.)

  • Only prescribers and pharmacies certified with the program may prescribe and dispense brodalumab; patients must sign a patient-prescriber agreement to receive the drug.1 5

  • Call 855-511-6135 or visit for additional information and to enroll in the program.1 14

Administration

Sub-Q Administration

Administer by sub-Q injection into the upper arms, thighs, or any quadrant of the abdomen; do not make abdominal injections within 2 inches of the navel.1 Administration into upper outer arm should be performed by a caregiver or clinician.1

Rotate injection sites.1

Do not make injections into areas where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis or into scars or stretch marks.1

Intended for use under the guidance and supervision of a clinician, but may be self-administered if clinician determines the patient and/or caregiver is competent to safely administer the drug after appropriate training.1

Use of Prefilled Syringe

Remove syringe from refrigerator and allow to sit at room temperature for approximately 30 minutes prior to injection.1 (See Storage under Stability.) Do not warm solution in any other way.1 Do not remove needle cap while syringe is warming to room temperature.1

Do not shake the solution.1

Inject entire contents of prefilled syringe (1.5 mL providing 210 mg).1

Dosage

Adults

Plaque Psoriasis
Sub-Q

210 mg at weeks 0, 1, and 2, followed by 210 mg every 2 weeks.1

If adequate response not obtained after 12–16 weeks, consider discontinuing the drug.1 Continued therapy beyond 16 weeks not likely to result in greater success.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Siliq

Contraindications

  • Crohn's disease.1 (See Exacerbation of Crohn's Disease under Cautions.)

Warnings/Precautions

Warnings

Suicidal Ideation and Behavior

Suicidal ideation and behavior, including completed suicides, reported.1

Because of risk of suicidality, available only through a restricted distribution program under a REMS.1 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

Weigh potential risks and benefits before initiating brodalumab therapy in patients with a history of depression and/or suicidal ideation or behavior.1

Refer patients with new or worsening symptoms of depression or suicidal ideation and behavior to a mental health professional, as appropriate, and advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new onset or worsening of depression or anxiety, or other mood changes.1 (See Advice to Patients.)

Reassess risks and benefits of continuing brodalumab therapy if such adverse effects occur; consider discontinuance if an adequate response is not attained within 12–16 weeks.1

Other Warnings and Precautions

Infectious Complications

Increased risk of infections.1 Higher rates of serious infections and fungal infections observed in patients receiving brodalumab compared with those receiving placebo.1 Most infections did not warrant drug discontinuance, and most fungal infections were not serious.1

Brodalumab-associated neutropenia (generally transient) reported; no serious neutropenia-associated infections reported.1

Consider risks and benefits prior to initiating brodalumab in patients with chronic infection or history of recurrent infection.1 Closely monitor patients who develop a serious infection or an infection that does not respond to standard therapy, and discontinue brodalumab until infection resolves.1

Evaluate patients for tuberculosis before initiating brodalumab.1 Do not administer to patients with active tuberculosis infection.1 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection before initiating brodalumab.1 Also consider antimycobacterial therapy for patients with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed.1 Closely monitor patients for active tuberculosis during and after brodalumab treatment.1

Exacerbation of Crohn's Disease

Clinical studies in psoriasis patients excluded individuals with Crohn's disease; one patient receiving brodalumab in these studies developed Crohn's disease and discontinued the drug.1 In other studies, brodalumab exacerbated Crohn's disease.1 16

Discontinue brodalumab if patient develops Crohn’s disease.1 (See Contraindications.)

Immunization

Avoid live vaccines.1 (See Vaccines under Interactions.)

Immunogenicity

Formation of antibrodalumab antibodies reported; neutralizing antibodies not detected.1

Specific Populations

Pregnancy

Data regarding use and associated risks in pregnant women not available.1 Potential for fetal exposure since human IgG crosses the placenta.1

No evidence of adverse embryofetal toxicity or malformations and no adverse effects on morphologic, functional, or immunologic development in animal studies.1

Lactation

Not known whether brodalumab distributes into human milk, affects milk production, or affects breast-fed infant.1 Brodalumab distributes into milk in cynomolgus monkeys.1

Consider benefits of breast-feeding and importance of the drug to the woman; also consider any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No apparent differences in safety or efficacy between geriatric patients and younger adults with psoriasis; however, insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

No formal studies to date.1

Renal Impairment

No formal studies to date.1

Common Adverse Effects

Arthralgia,1 2 4 headache,1 3 4 fatigue,1 diarrhea,1 oropharyngeal pain,1 nausea,1 myalgia,1 injection site reactions (pain, erythema, bruising, hemorrhage, pruritus),1 2 3 influenza,1 neutropenia,1 3 tinea infections.1

Interactions for Siliq

Drugs Metabolized by Hepatic Microsomal Enzymes

Because elevated levels of certain cytokines during chronic inflammation may alter formation of CYP isoenzymes, brodalumab-induced changes in cytokine levels may affect formation of CYP enzymes.1

CYP substrates: Upon initiation or discontinuance of brodalumab, consider monitoring therapeutic effect or drug concentration and consider dosage adjustment of the CYP substrate, especially if substrate has a narrow therapeutic index.1

Vaccines

Avoid live vaccines.1

No available data to date regarding response to live or inactivated vaccines.1

Specific Drugs

Drug

Interaction

Comments

Cyclosporine

Possible effect on cyclosporine metabolism; brodalumab-induced changes in cytokine concentrations may affect CYP enzyme formation1

Consider monitoring cyclosporine concentrations and consider cyclosporine dosage adjustment upon initiation or discontinuance of brodalumab1

Midazolam

Increased midazolam exposure1 15

Warfarin

Possible effect on warfarin metabolism; brodalumab-induced changes in cytokine concentrations may affect CYP enzyme formation1

Consider monitoring therapeutic effect of warfarin and consider warfarin dosage adjustment upon initiation or discontinuance of brodalumab1

Siliq Pharmacokinetics

Absorption

Bioavailability

Bioavailability is approximately 55% following sub-Q administration.1

Peak serum concentrations achieved by approximately 3 days following a single 210-mg sub-Q dose.1

Steady-state concentrations achieved by week 4 following sub-Q administration of brodalumab 210 mg every 2 weeks.1

Exhibits nonlinear pharmacokinetics; exposure increases in more than dose-proportional manner over a sub-Q dose range of 140–350 mg.1

Special Populations

Patients with higher body weight have lower trough concentrations.1

Distribution

Extent

Not known whether distributed into human milk.1

Elimination

Metabolism

Metabolic pathway not characterized.1

Expected to be degraded into small peptides and amino acids via catabolic pathways in a similar manner as endogenous IgG.1

Elimination is nonlinear; clearance increases with decreasing doses.1

Special Populations

Pharmacokinetics not formally studied in renal or hepatic impairment.1

Population analysis suggests age does not substantially affect clearance in adults with plaque psoriasis.1 Clearance appears to be similar in patients ≥65 years of age and younger adults.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Keep in original carton and protect from light.1 Do not freeze.1

May store in original carton at 20–25°C for a maximum single period of 14 days, with protection from light and heat.1 Following storage at room temperature, do not return to refrigerator; discard if not used within 14 days.1

Actions

  • Binds to IL-17RA and inhibits interaction with IL-17A, IL-17C, IL-17F, IL-17A/F heterodimer, and IL-25 (also known as IL-17E), thus blocking IL-17 cytokine-induced responses, including release of proinflammatory cytokines and chemokines.1 2 6 8 9

  • Elevated levels of IL-17A, IL-17C, and IL-17F found in psoriatic lesions.1 2 3 6 7 8 9

Advice to Patients

  • Provide all patients with a copy of the manufacturer's patient information (medication guide and instructions for use) with each prescription of the drug.1 Advise patient to read the medication guide prior to initiation of therapy and each time the prescription is refilled.1

  • Advise patients and their caregivers that suicidal behavior and ideation (including completed suicides) have been reported in patients receiving brodalumab.1 Advise patients and their caregivers to monitor for the emergence of suicidality and to immediately seek medical attention if the patient experiences suicidal thoughts, new or worsening depression or anxiety, or other changes in mood or behavior.1

  • Advise patients that brodalumab is available only through a restricted distribution program; instruct patients on the program requirements and how to obtain the drug.1 Advise patients to carry the wallet card that describes symptoms requiring immediate medical evaluation, to show this card to other treating clinicians, and to call the National Suicide Prevention Lifeline at 800-273-8255 if they experience suicidal thoughts.1

  • Instruct patient and/or caregiver regarding proper storage, dosage, and administration of brodalumab, including the use of aseptic technique, and proper disposal of prefilled syringes if it is determined that the patient and/or caregiver is competent to safely administer the drug.1

  • Inform patients that brodalumab may lower the ability of their immune system to fight infection.1 Advise patients to promptly inform clinician if any signs or symptoms of infection (e.g., fever, sweats, or chills; muscle aches; cough or shortness of breath; warm, red, or painful sores on the body; diarrhea or stomach pain; burning upon urination or increased urination) occur.1

  • Advise patients to inform a clinician if they experience signs and symptoms of Crohn's disease (e.g., abdominal pain, diarrhea, weight loss).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., active infection, Crohn's disease) or any history of tuberculosis, other infections, mood disorders, or suicidality.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of brodalumab is restricted.1 5 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

Brodalumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

210 mg/1.5mL

Siliq (available as single-use prefilled syringes)

Valeant

AHFS DI Essentials. © Copyright 2018, Selected Revisions January 1, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Valeant Pharmaceuticals. Siliq (brodalumab) injection prescribing information. Bridgewater, NJ; 2017 Feb.

2. Papp KA, Leonardi C, Menter A et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012; 366:1181-9. [PubMed 22455412]

3. Papp KA, Reich K, Paul C et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016; 175:273-86. [PubMed 26914406]

4. Lebwohl M, Strober B, Menter A et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med. 2015; 373:1318-28. [PubMed 26422722]

5. Valeant Pharmaceuticals North America. Siliq (brodalumab) BLA 761032 risk evaluation and mitigation strategy (REMS). Bridgewater, NJ; 2017 Jun. Available from FDA website.

6. Salinger DH, Endres CJ, Martin DA et al. A semi-mechanistic model to characterize the pharmacokinetics and pharmacodynamics of brodalumab in healthy volunteers and subjects with psoriasis in a first-in-human single ascending dose study. Clin Pharmacol Drug Dev. 2014; 3:276-83. [PubMed 27128833]

7. Endres CJ, Salinger DH, Köck K et al. Population pharmacokinetics of brodalumab in healthy adults and adults with psoriasis from single and multiple dose studies. J Clin Pharmacol. 2014; 54:1230-8. [PubMed 24846347]

8. Bauer E, Lucier J, Furst DE. Brodalumab -an IL-17RA monoclonal antibody for psoriasis and psoriatic arthritis. Expert Opin Biol Ther. 2015; 15:883-93. [PubMed 25985813]

9. Nirula A, Nilsen J, Klekotka P et al. Effect of IL-17 receptor A blockade with brodalumab in inflammatory diseases. Rheumatology (Oxford). 2016; 55:ii43-ii55. [PubMed 27856660]

12. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005; 64 Suppl 2:ii65-8; discussion ii69-73.

13. Bushnell DM, Martin ML, McCarrier K et al. Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure to assess psoriasis symptom severity. J Dermatolog Treat. 2013; 24:356-60. [PubMed 23092173]

14. Valeant Pharmaceuticals, North America. What is the Saliq REMS program. From Saliq REMS website. Accessed 2017 Aug 28.

15. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761032orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

16. Targan SR, Feagan B, Vermeire S et al. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease. Am J Gastroenterol. 2016; 111:1599-1607. [PubMed 27481309]

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