COSENTYX

Secukinumab is a fully human monoclonal

IgG1/κ antibody against interleukin-17A (IL-17A), a proinflammatory cytokine implicated in various chronic immune-mediated inflammatory disorders, such as plaque psoriasis.

By blocking the actions of

IL-17A, secukinumab works to inhibit the pro-inflammatory pathways that drive immune-mediated inflammatory disorders.

Following its first global approval in Japan in December 2014, secukinumab was approved by the European Commission on January 15, 2015, and by the FDA a few days after (January 21, 2015).

It is currently approved to treat a number of chronic inflammatory conditions, such as plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and hidradenitis suppurativa. 6, 7, 10.

Secukinumab is indicated the treatment of moderate to severe plaque psoriasis in patients six years and older who are candidates for systemic therapy or phototherapy.

In Europe, the drug is used in children and adolescents six to 18 years of age for this indication.

It is also indicated for the treatment of active psoriatic arthritis (PsA).

In the

US, it is approved for patients two years of age and older 6 while in Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy.

Secukinumab is also indicated in the treatment of active enthesitis-related arthritis (ERA).

US, it is approved for patients four year of age and older.

In Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy.

US, secukinumab is indicated for the treatment of adults with active ankylosing spondylitis, non-radiographic axial spondyloarthritis with objective signs of inflammation, and adult and pediatric patients 12 years of age and older with moderate to severe hidradenitis suppurativa.

Secukinumab works to ameliorate inflammation in chronic inflammatory disorders by attenuating the release of proinflammatory cytokines and chemokines.

Total serum

IL-17A levels, representing free IL-17A and secukinumab-IL-17A complex, were increased to a plateau during drug treatment, then gradually decreased at the end of the treatment as the secukinumab-IL-17A complex was cleared from the body.

In patients with plaque psoriasis, secukinumab reduced erythema, induration, and desquamation in plaque psoriasis lesions.

Secukinumab also reduced acanthosis, parakeratosis, keratinocyte proliferation, and decrease in keratinocyte markers.

• all clinical manifestations of psoriasis.

As the formation of

CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation, secukinumab can potentially alter the concentrations of CYP substrate drugs with a narrow therapeutic index.

Following a single subcutaneous dose of either 150 mg.

• which is one-half the recommended dose.

• in patients with plaque psoriasis, the mean C max and serum trough concentrations were 13.7 ± 4.8 mcg/mL and 22.8 ± 10.2 mcg/mL, respectively.

Following administration of 300 mg, the mean C max and serum trough concentrations were 27.3 ± 9.5 mcg/mL and 45.4 ± 21.2 mcg/mL, respectively.

Following subcutaneous injection, the C max is reached in five to six days.

Steady-state concentrations were achieved by week 24 following the every 4-week dosing regimens.

In healthy subjects and subjects with plaque psoriasis, bioavailability ranged from 55% to 77% following subcutaneous administration.

The mean volume of distribution during the terminal phase (V z ) ranged from 7.10-8.60 L in plaque psoriasis subjects who received secukinumab Intravenous.

These values suggest that secukinumab undergoes limited distribution to peripheral compartments.

The volume of distribution increases with body weight.

Following subcutaneous administration of a single 300 mg dose, drug concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis subjects ranged from 27% to 40% of those in serum at one and two weeks.

Secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

The half-life ranged from 22-31 days in plaque psoriasis subjects following intravenous and subcutaneous administration across all psoriasis trials.

The mean elimination half-life was 27 days.

The mean systemic clearance (CL) ranged from 0.14 L/day to 0.22 L/day.

Clearance of secukinumab is dose.

• and time-independent, 3, 7 and is expected to increase with body weight.

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There is no information available regarding the LD50 of secukinumab.

In clinical trials, doses up to 30 mg/kg Intravenous have been administered without dose-limiting toxicity.

In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients in COSENTYX.

Cases of anaphylaxis and angioedema have been reported during treatment with COSENTYX.

Serious hypersensitivity to secukinumab or any excipients in COSENTYX.

Prior to

COSENTYX initiation, complete all age-appropriate vaccinations, evaluate patients for tuberculosis (TB).

Information for instructions on preparation and administration of COSENTYX.

COSENTYX for intravenous use must be diluted prior to administration.

Administer as an intravenous infusion after dilution over a period of 30 minutes.

Subcutaneous Dosage in Adults: Recommended dosage is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For some patients, a dose of 150 mg may be acceptable.

Patients 6 Years and Older: Recommended weight-based dosage is administered by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For patients < 50 kg, the dose is 75 mg. For patients ≥ 50 kg, the dose is 150 mg. Psoriatic Arthritis: Adult Patients Subcutaneous Dosage: For PsA patients with coexistent moderate to severe PsO, use the dosage and administration for PsO.

For other

PsA patients, administer with or without a loading dosage.

With a loading dosage: 150 mg at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter Without a loading dosage: 150 mg every 4 weeks If a patient continues to have active PsA, consider a dosage of 300 mg every 4 weeks.

The recommended intravenous dosages are: With a loading dosage: 6 mg/kg given at Week as a loading dose, followed by 1.75 mg/kg every 4 weeks thereafter (max. maintenance dose 300 mg per infusion).

Without a loading dosage: 1.75 mg/kg every 4 weeks (max. maintenance dose 300 mg per infusion).

Patients 2 Years and Older Subcutaneous Dosages: Administer by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter: For patients ≥ 15 kg and < 50 kg the dose is 75 mg. For patients ≥ 50 kg the dose is 150 mg. Ankylosing Spondylitis: Adult Patients Subcutaneous Dosage: Administer with or without a loading dosage.

The recommended dosages are

With a loading dosage: 150 mg at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

Without a loading dosage: 150 mg every 4 weeks.

If a patient continues to have active ankylosing spondylitis, consider a dosage of 300 mg every 4 weeks.

Patients 12 Years and Older Subcutaneous Dosage: Administer by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For patients < 50 kg, the dose is 75 mg. For patients ≥ 50 kg, the dose is 150 mg. Non-Radiographic Axial Spondyloarthritis: Subcutaneous Dosage: Administer with or without a loading dosage.

The recommended dosage is

Recommended weight-based dosage is administered by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For patients ≥ 15 kg and < 50 kg the dose is 75 mg. For patients ≥ 50 kg the dose is 150 mg. Hidradenitis Suppurativa: Subcutaneous Dosage in Adults: Recommended dosage is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

If a patient does not adequately respond, consider increasing the dosage to 300 mg every 2 weeks.

Patients 12 Years and Older: Recommended weight-based dosage is administered by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For patients ≥ 30 kg and < 90 kg, the dose is 150 mg. For patients ≥ 90 kg, the dose is 300 mg. 2.1 Testing and Procedures Prior to Treatment Initiation Perform the following evaluations prior to COSENTYX initiation: Evaluate for active or latent tuberculosis (TB).

COSENTYX initiation is not recommended in patients with active TB infection.

Initiate treatment of latent TB prior to initiation of COSENTYX.

Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with COSENTYX. 2.2 Important Administration Instructions COSENTYX is for use under the guidance and supervision of a healthcare provider.

UnoReady pen, Sensoready pen, and prefilled syringes are for subcutaneous use only.

Solution in vials is for intravenous use in adult patients only.

Important Subcutaneous Administration Instructions

Adult patients may self-administer COSENTYX or be injected by a caregiver after proper training in subcutaneous injection technique.

Pediatric patients should not self-administer

An adult caregiver should prepare and inject COSENTYX after proper training in subcutaneous injection technique.

Administer each subcutaneous injection at a different anatomic location (such as upper arms, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis.

Administration of subcutaneous

COSENTYX in the upper, outer arm may be performed by a caregiver or healthcare provider.

COSENTYX “Instructions for Use” for each presentation and strength contains more detailed instructions on the preparation and administration of COSENTYX for patients and caregivers.

Intravenous infusion is only for use by a healthcare professional in a healthcare setting.

Prepare COSENTYX intravenous infusion by diluting

COSENTYX injection in vial(s) and administering based on patient body weight.

Intravenous infusion may be administered only in adults with PsA, AS, and nr-axSpA. 2.3 Recommended Dosage in Plaque Psoriasis Recommended Subcutaneous Dosage in Adults The recommended dosage in adults with PsO is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

Each 300 mg dosage is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. For some patients, a dosage of 150 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter may be acceptable.

Patients 6 Years of Age and Older The recommended weight-based dosage in pediatric patients 6 years of age and older with PsO is administered by subcutaneous injection at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

For patients < 50 kg, the recommended dose is 75 mg. For patients ≥ 50 kg, the recommended dose is 150 mg. 2.4 Recommended Dosage in Adults with Psoriatic Arthritis COSENTYX may be administered with or without methotrexate.

Recommended Subcutaneous Dosage For adult patients with PsA and with coexistent moderate to severe PsO, use the dosage and administration recommendations for adults with PsO.

For other adult patients with

PsA, administer COSENTYX with or without a loading dosage by subcutaneous injection.

The recommended dosage in adults with PsA: With a loading dosage is 150 mg at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

Without a loading dosage is 150 mg every 4 weeks.

If a patient continues to have active PsA, consider increasing the dosage to 300 mg by subcutaneous injection every 4 weeks.

Each 300 mg dosage is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg. Recommended Intravenous Dosage COSENTYX injection for intravenous use (solution in vials) requires dilution prior to intravenous administration.

The recommended intravenous dosage regimen in adults with PsA: With a loading dosage is 6 mg/kg loading dose given at Week 0, followed by 1.75 mg/kg every 4 weeks thereafter (maintenance dosage).

Without a loading dosage is 1.75 mg/kg every 4 weeks.

Administer as an intravenous infusion over a period of 30 minutes.

Total doses exceeding 300 mg per infusion are not recommended for the 1.75 mg/kg maintenance dose in adults with PsA. 2.5 Recommended Dosage in Pediatric Patients 2 Years of Age and Older with Juvenile Psoriatic Arthritis COSENTYX may be administered with or without methotrexate.

The recommended weight-based subcutaneous dosage in pediatric patients 2 years of age and older with PsA at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter is as follows: For patients ≥ 15 kg and < 50 kg, the recommended dose is 75 mg. For patients ≥ 50 kg, the recommended dose is 150 mg. 2.6 Recommended Dosage in Adults with Ankylosing Spondylitis Recommended Subcutaneous Dosage Administer COSENTYX with or without a loading dosage by subcutaneous injection in adult patients with active AS.

The recommended dosage

With a loading dosage is 150 mg at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter.

If a patient continues to have active AS, consider increasing the dosage to 300 mg every 4 weeks by subcutaneous injection.

The recommended intravenous dosage regimen in adult patients with active AS: With a loading dosage is 6 mg/kg loading dose given at Week 0, followed by 1.75 mg/kg every 4 weeks thereafter (maintenance dosage).

Total doses exceeding 300 mg per infusion are not recommended for the 1.75 mg/kg maintenance dose in patients with AS. 2.7 Recommended Dosage in Pediatric Patients 12 Years of Age and Older with Juvenile Ankylosing Spondylitis The recommended weight-based subcutaneous dosage in pediatric patients 12 years of age and older with AS at Weeks 0, 1, 2, 3, and and every 4 weeks thereafter is as follows: For patients < 50 kg, the recommended dose is 75 mg. For patients ≥ 50 kg, the recommended dose is 150 mg. 2.8 Recommended Dosage in Adults with Non-Radiographic Axial Spondyloarthritis Recommended Subcutaneous Dosage Administer COSENTYX with or without a loading dosage by subcutaneous injection in adult patients with active nr-axSpA.

COSENTYX injection for intravenous use (solution in vials) requires dilution prior to intravenous administration.

The recommended intravenous dosage regimen in adult patients with active nr-axSpA: With a loading dosage is 6 mg/kg loading dose given at Week 0, followed by 1.75 mg/kg every 4 weeks thereafter (maintenance dosage).

Total doses exceeding 30.

COSENTYX (secukinumab) injection is a clear to opalescent, colorless to slightly yellowish solution available as follows: COSENTYX injection for subcutaneous use Strength Dosage Form Carton Contents NDC 75 mg/0.5 mL COSENTYX prefilled syringe 1 prefilled syringe 0078-1056-97 150 mg/mL COSENTYX prefilled syringe 1 prefilled syringe 0078-0639-97 2 prefilled syringes 0078-0639-98 COSENTYX Sensoready pen 1 Sensoready pen 0078-0639-68 2 Sensoready pens 0078-0639-41 300 mg/2 mL COSENTYX prefilled syringe 1 prefilled syringe 0078-1070-97 COSENTYX UnoReady pen 1 UnoReady pen 0078-1070-68 The removable cap of the COSENTYX Sensoready pen and prefilled syringes (150 mg/mL, 75 mg/0.5 mL) contains natural rubber latex.

COSENTYX pens and prefilled syringes are equipped with a needle safety guard.

COSENTYX injection for intravenous use Strength Dosage Form Carton Contents NDC 125 mg/5 mL COSENTYX vial 1 vial of solution for dilution prior to intravenous infusion 0078-1168-61 Storage and Handling Refrigerate COSENTYX at 2ºC to 8ºC (36ºF to 46ºF).

COSENTYX in the original carton to protect from light until the time of use.

Do not freeze.

To avoid foaming, do not shake.

COSENTYX does not contain a preservative; discard any unused portion.

If removed from refrigeration, COSENTYX Sensoready pen and prefilled syringes (150 mg/mL, 75 mg/0.5 mL): May be stored for up to 4 days at room temperature not to exceed 30°C (86°F).

Write the date

COSENTYX is removed from and returned to the refrigerator in the space provided on the carton.

Discard if stored outside of the refrigerator over 4 days.

May be returned to the refrigerator only one time and must be stored at 2ºC to 8ºC (36ºF to 46ºF) until used or expired.

Risk Summary Limited available human data with COSENTYX use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

In an embryo-fetal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of secukinumab during organogenesis at doses up to 30 times the maximum recommended human dose (MRHD) .

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

An embryo-fetal development study was performed in cynomolgus monkeys with secukinumab.

No malformations or embryo-fetal toxicity were observed in fetuses from pregnant monkeys that were administered secukinumab weekly by the subcutaneous route during the period of organogenesis at doses up to 30 times the MRHD (on a mg/kg basis at a maternal dose of 150 mg/kg).

A pre.

• and post-natal development toxicity study was performed in mice with a murine analog of secukinumab.

No treatment-related effects on functional, morphological, or immunological development were observed in fetuses from pregnant mice that were administered the murine analog of secukinumab on gestation days 6, 11, and and on postpartum days 4, 10, and at doses up to 150 mg/kg/dose.

Subcutaneous Administration Pediatric Plaque Psoriasis

The safety and effectiveness of COSENTYX have been established for the treatment of moderate to severe PsO in pediatric patients aged 6 years and older who are candidates for systemic therapy or phototherapy.

The safety and effectiveness of COSENTYX in pediatric patients with PsO below the age of 6 years old have not been established.

Juvenile Psoriatic Arthritis The safety and effectiveness of COSENTYX have been established for the treatment of active JPsA in pediatric patients aged 2 years and older who weigh 15 kg or more.

The safety and effectiveness of COSENTYX in pediatric patients with JPsA below the age of 2 years old or with a body weight less than 15 kg have not been established.

Juvenile Ankylosing Spondylitis The safety and effectiveness of COSENTYX have been established for treatment of JAS in pediatric patients 12 years of age and older.

Use of

COSENTYX for this indication is supported by safety and efficacy data from adequate and well-controlled trials in adult subjects with AS.

Additional evidence includes pharmacokinetic data from adult subjects with PsO, PsA, and AS and pediatric subjects with PsO, JPsA, and ERA, as well as safety data from clinical trials in pediatric subjects with PsO, JPsA, and ERA.

The pharmacokinetics are predicted to be comparable between adult AS and pediatric subjects with JAS.

The safety and effectiveness of COSENTYX in pediatric patients with JAS below the age of 12 years old have not been established.

Six pediatric patients with axial symptoms were participants in a study for JPsA and ERA (NCT03031782).

Due to the limited number of patients and uncertainty fulfilling Axial Juvenile Spondyloarthritis (AxJSpA) classification criteria, the effectiveness and safety of COSENTYX in AxJSpA has not been established.

Safety was comparable to pediatric patients treated with COSENTYX for JPsA and ERA.

Enthesitis-Related Arthritis The safety and effectiveness of COSENTYX have been established for the treatment of active ERA in pediatric patients aged 4 years and older who weigh 15 kg or more.

The safety and effectiveness of COSENTYX in pediatric patients with ERA below the age of 4 years old or with body weight less than 15 kg have not been established.

Hidradenitis Suppurativa The safety and effectiveness of COSENTYX have been established for the treatment of moderate to severe HS in pediatric patients 12 years of age and older who weigh 30 kg or more.

COSENTYX for this indication is supported by safety and efficacy data from adequate and well-controlled trials in adult subjects with moderate to severe HS.

Additional evidence includes population pharmacokinetic modeling and simulation based on data from adult subjects with PsO and HS and pediatric subjects with PsO, as well as safety data from clinical trials in pediatric subjects with PsO and JIA (JPsA and ERA) .

The safety and effectiveness of COSENTYX in pediatric patients with HS below the age of 12 years old or with a body weight less than 30 kg have not been established.

Intravenous Administration The safety and effectiveness of intravenous COSENTYX in pediatric patients have not been established.

Of the 3,430 PsO subjects exposed to subcutaneous COSENTYX in clinical trials, a total of 230 (7%) were 65 years of age and older, and 32 (1%) subjects were 75 years of age and older.

Although no differences in safety or efficacy were observed between subjects 65 years of age and older and younger adult subjects, the number of subjects 65 years of age and older was not sufficient to determine whether they respond differently from younger adult subjects.

Of the 1,060 subjects with HS exposed to COSENTYX in clinical trials, a total of 14 (1.3%) were 65 years of age and older.

Clinical trials in

HS did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.