Sarilumab
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Boxed warning
WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ]. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before KEVZARA use and during therapy.
Treatment for latent infection should be initiated prior to KEVZARA use. Invasive fungal infections, such as candidiasis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral and other infections due to opportunistic pathogens. Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection.
WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning . Serious infections leading to hospitalization or death including bacterial, viral, invasive fungal, and other opportunistic infections have occurred in patients receiving KEVZARA. ( 5.1 ) If a serious infection develops, interrupt KEVZARA until the infection is controlled. ( 5.1 ) Cases of tuberculosis (TB) have been reported. Prior to starting KEVZARA, test for latent TB; if positive, start treatment for TB. ( 5.1 ) Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. ( 5.1 )
Interleukin-6 Receptor Antagonist
Dosing in kidney impairment
Renal Impairment No dose adjustment is required in patients with mild to moderate renal impairment. KEVZARA has not been studied in patients with severe renal impairment [see Clinical Pharmacology ] .
Dosing in liver impairment
Dosage Modifications for Cytopenias, Abnormal Liver Enzymes, or Infections Dosage Modifications for Patients with Rheumatoid Arthritis Laboratory Abnormalities : Modify dosage in case of neutropenia, thrombocytopenia, or liver enzyme elevations as shown in Table 1 [see Warnings and Precautions and Clinical Pharmacology ] .
For treatment initiation criteria, refer to the dosage recommendations for RA [see Dosage and Administration (2.1 , 2.2) ] . [See table below.] Low Platelet Count Lab Value (cells/mm 3 ) Recommendation 50,000 to 100,000 Hold treatment with KEVZARA until platelets greater than 100,000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate.
Less than 50,000 If confirmed by repeat testing, discontinue KEVZARA. Liver Enzyme Abnormalities Lab Value Recommendation ALT or AST greater than ULN to 3 times ULN Consider dosage modification of concomitant DMARDs as clinically appropriate. ALT or AST greater than 3 times ULN to 5 times ULN Hold treatment with KEVZARA until ALT or AST less than 3 times ULN.
KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate. ALT or AST greater than 5 times ULN Discontinue KEVZARA. Infections: If a patient with RA develops a serious infection or an opportunistic infection, hold treatment with KEVZARA until the infection is controlled [see Warnings and Precautions ].
Dosage Modifications for Patients with Polymyalgia Rheumatica Laboratory Abnormalities : Discontinue KEVZARA in patients with PMR who develop the following laboratory abnormalities [see Warnings and Precautions and Clinical Pharmacology ] : neutropenia (ANC below 1,000 per mm 3 at the end of the dosing interval) thrombocytopenia (platelet count below 100,000 per mm 3 ) AST or ALT elevations 3 times above the ULN Dosage modifications have not been studied in patients with PMR with these conditions.
For treatment initiation criteria, refer to the dosage recommendations for PMR [see Dosage and Administration (2.1 , 2.3) ] . Infections : If a patient with PMR develops a serious infection or an opportunistic infection, hold treatment with KEVZARA until the infection is controlled [see Warnings and Precautions ]. Dosage Modification for Patients with Polyarticular Juvenile Idiopathic Arthritis Dose reduction of KEVZARA has not been studied in the pJIA population.
Discontinue KEVZARA if ALT >5 ULN, platelet count ≤50,000 cells/mm 3 , neutrophil count <500 cells/mm 3 associated with infection. Hold KEVZARA dosing for ALT >3 to ≤5 ULN, platelet count >50,000 to ≤100,000 cells/mm 3 , and neutrophil count ≥500 to <1000 cells/mm 3 , and until the clinical condition has been evaluated.
The decision to discontinue KEVZARA should be based upon the medical assessment of the individual patient. If appropriate, the dose of concomitant methotrexate and/or other medications should be modified or discontinued.
Preparation and administration
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General Considerations Prior to Administration Not Recommended for Concomitant Use with Biological DMARDS The concurrent use of KEVZARA with biological DMARDs such as tumor necrosis factor (TNF) antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators has not been studied. Avoid using KEVZARA with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection.
Recommended Evaluations Prior to Treatment Complete blood count (CBC): Treatment initiation with KEVZARA is not recommended in patients with an absolute neutrophil count (ANC) below 2000 per mm 3 , or platelet count below 150,000 per mm 3 . Monitor laboratory parameters [see Warnings and Precautions ]. Liver function tests (LFT): Treatment initiation with KEVZARA is not recommended in patients with or who have alanine transaminase (ALT) or aspartate aminotransferase (AST) above 1.5 times the upper limit of normal (ULN).
Monitor laboratory parameters [see Dosage and Administration and Warnings and Precautions ] . Lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol and/or triglycerides): Assess lipid parameters at baseline. Monitor laboratory parameters [see Warnings and Precautions ]. Active and latent tuberculosis infection evaluation: Prior to initiating KEVZARA, test patients for active and latent tuberculosis (TB).
KEVZARA should not be administered to patients with active TB. If positive for latent infection, consider treating for TB prior to KEVZARA use [see Warnings and Precautions ]. Evaluate for infections: Avoid KEVZARA use in patients with active infections [see Warnings and Precautions ] .
Preparation and Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. KEVZARA 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 pre-filled syringe or pre-filled pen appears to be damaged.
Rotate injection sites with each injection. Do not inject into skin that is tender, damaged, or has bruises or scars. Pre-filled Pen and Pre-filled Syringe KEVZARA is intended for use under the guidance of a healthcare professional. A patient may self-inject KEVZARA or the patient's caregiver may administer KEVZARA. Provide proper training to patients and/or caregivers on the preparation and administration of KEVZARA prior to use according to the Instructions for Use (IFU).
Allow the pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way. If using a pre-filled pen, allow the pre-filled pen to sit at room temperature for 60 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way. Instruct patients to inject the full amount in the syringe or pen (1.14 mL), which provides 200 mg or 150 mg of KEVZARA, according to the directions provided in the IFU.
The ability of pediatric patients to self-inject with the pre-filled pen has not been tested.
Drug interactions
Check sarilumab against a medication listLabel text (6 paragraphs)
7 DRUG INTERACTIONS
7.1 Use with Other Drugs Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on sarilumab clearance. KEVZARA has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2) ] .
7.2 Interactions with CYP450 Substrates Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA.
Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations. The modulation of IL-6 effect on CYP enzymes by KEVZARA may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of KEVZARA, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed.
Exercise caution when co-administering KEVZARA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of KEVZARA on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3) ].
7.3 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA [see Warnings and Precautions (5.7) ] .
Contraindications
4 CONTRAINDICATIONS KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
E*Likelihood score E*: Unproven but suspected cause of clinically apparent liver injury.
Sarilumab is a human monoclonal IgG1 antibody to the interleukin-6 (IL-6) receptor which is used in the therapy of rheumatoid arthritis and other autoinflammatory conditions. Sarilumab commonly causes mild serum aminotransferase elevations which are usually short lived and asymptomatic and has also been linked to rare instances of clinically apparent liver injury with jaundice.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary The limited human data with KEVZARA in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . From 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 (see Clinical Considerations and Data ) .
In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD) (see Data ) . The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions 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 to KEVZARA in utero [see Warnings and Precautions (5.7) ]. 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 (see Data ) .
Data Animal Data In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of…
Breastfeeding (LactMed)
Because sarilumab is a large protein molecule with a molecular weight of about 150,000 Da, the amount in milk is likely to be very low. It is also likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. One infant was safely breastfed for 6 months after maternal sarilumab was resumed at 28 days postpartum. If sarilumab is required by the mother, it is not a reason to discontinue breastfeeding. Until more data become available, sarilumab should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Waiting for at least 2 weeks postpartum to resume therapy may minimize transfer to the infant.
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