Sarilumab

Black Box Warnings

Serious infections

• Use of sarilumab increases risk for developing serious infections that may lead to hospitalization or death
• Opportunistic infections reported
• Most patients who developed infections were taking concomitant immunosuppressants (eg, methotrexate, corticosteroids)
• Avoid use in patients with active infection
• Closely monitor for signs and symptoms of infection during treatment; if a serious infection develops, interrupt sarilumab therapy until the infection is controlled
• Consider the risks and benefits of using sarilumab before initiating in patients with chronic or recurrent infection; a history of opportunistic infections, underlying conditions, in addition to RA, that may predispose them to infection, have been exposed to tuberculosis, or lived in or traveled to areas of endemic tuberculosis or endemic mycoses
• Reported infections include
  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease; test for latent TB before and during therapy; treatment for latent infection should be initiated before sarilumab is started; closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy
  • Invasive fungal infections (eg, candidiasis, pneumocystis); patients with invasive fungal infections may present with disseminated, rather than localized, disease
  • Bacterial, viral, and other infections due to opportunistic pathogens

Contraindications

Documented hypersensitivity to drug or inactive ingredients

Cautions

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported (see Black Box Warnings)

GI perforations reported in clinical studies, primarily as complications of diverticulitis; GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids

Immunosuppression may result in an increased risk of malignancies

Hypersensitivity reactions reported

Not recommended with active hepatic disease or hepatic impairment

Laboratory abnormalities

• Neutropenia, thrombocytopenia, elevated liver enzymes, and lipid abnormalities reported (see Dosage Modifications)
• Assess platelet count prior to initiation of therapy and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter
• Assess ALT/AST levels prior to initiation of therapy and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter; when clinically indicated, consider other liver function tests such as bilirubin
• Assess lipid parameters approximately 4-8 weeks following initiation of therapy, then at approximately 6-month intervals; manage patients according to clinical guidelines for the management of hyperlipidemia

Drug interaction overview

• Live virus vaccines
  • Avoid concurrent use of live virus vaccines, owing to potentially increased risk of infections
  • The interval between live vaccinations and initiation of sarilumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents
• CYP450 substrates
  • The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (eg, IL-1, IL-6, IL-10, TNF-alpha, IFN) during chronic inflammation
  • Elevated IL-6 concentration may down-regulate CYP activity, such as in patients with RA, and, hence, increase drug levels compared with subjects without RA
  • Blockade of IL-6 signaling by IL-6 antagonists (eg, sarilumab) might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to decreased drug concentrations
  • Caution when initiating or discontinuing sarilumab if coadministered with CYP450 substrates, especially those with a narrow therapeutic index

Pregnancy

Limited human data in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester

Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed in utero

From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers

Pregnancy registry

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sarilumab during pregnancy
• Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Human monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors

IL-6 is produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes (eg, rheumatoid arthritis)

IL-6 is a pleiotropic proinflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts

IL-6 has been shown to be involved in diverse physiological processes (eg, T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute-phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation

Absorption

Peak plasma time: 2-4 days

Peak plasma concentration: 20 mg/L

Minimum plasma concentration: 6.35 mg/L

AUC: 202 mg·day/L

Steady state: Reached in 14-16 weeks

Distribution

Vd: 7.2 L

Metabolism

Expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG

Elimination

Half-life: 10 days (200 mg q2wk); 8 days (150 mg q2wk)

Excretion: Monoclonal antibodies are not eliminated via renal or hepatic pathways

SC Preparation

Allow the prefilled syringe to sit at room temperature for 30 minutes prior to SC injection; do not warm in any other way

Visually inspect syringe for particulate matter and discoloration prior to administration

Solution should be clear and colorless to pale yellow; do not use if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged

SC Administration

Patient may self-inject or the patient's caregiver may administer after properly instructed

Instruct patients to inject the full amount in the syringe (1.14 mL), which provides 200 mg or 150 mg

Rotate injection sites with each injection; do not inject into skin that is tender, damaged, or has bruises or scars

Storage

Refrigerate at 36-46°F (2-8°C) in original carton to protect from light

Do not freeze

Do not shake

If needed, may store at room temperature up to 77°F (25°C) up to 14 days in the outer carton; do not store above 77°F (25°C)

After removal from the refrigerator, use within 14 days or discard

Sarilumab may be found in some form under the following brand names:

• Kevzara

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

• If you have an allergy to sarilumab or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have liver disease or raised liver enzymes.
• If you have a low platelet count or a low white blood cell count.
• If you are taking any of these drugs: Abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, natalizumab, rituximab, or tocilizumab.
• If you are taking tofacitinib.

This is not a list of all drugs or health problems that interact with sarilumab.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Note: Do not initiate if ANC is <2,000/mm3, platelets are <150,000/mm3 or if ALT or AST are >1.5 times ULN.

Rheumatoid arthritis: SubQ: 200 mg once every 2 weeks. Note: May use as monotherapy or in combination with nonbiologic DMARDs. Do not use in combination with biologic DMARDs.

CrCl 30 to 90 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild to moderate renal impairment: No adjustment recommended.
Severe renal impairment: Data not available