Dosage & Administration
General Considerations for Administration
Recommended Dosage in RA
Recommended Dosage in PMR
Recommended Dosage in pJIA
Dosage Modifications for Cytopenias, Abnormal Liver Enzymes, Infections
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Kevzara Prescribing Information
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.
Rheumatoid Arthritis (RA)
KEVZARA® is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
Polymyalgia Rheumatica (PMR)
KEVZARA is indicated for treatment of adult patients with polymyalgia rheumatica who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
1.3 Polyarticular Juvenile Idiopathic Arthritis (pJIA)
KEVZARA is indicated for treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients who weigh 63 kg or greater.
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 mm3, or platelet count below 150,000 per mm3. Monitor laboratory parameters [see Warnings and Precautions (5.2)].
- 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 (2.6) and Warnings and Precautions (5.2)].
- Lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol and/or triglycerides): Assess lipid parameters at baseline. Monitor laboratory parameters [see Warnings and Precautions (5.2)].
- 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 (5.1)].
- Evaluate for infections: Avoid KEVZARA use in patients with active infections [see Warnings and Precautions (5.1)].
Recommended Dosage for Rheumatoid Arthritis
The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection [see Dosage and Administration (2.1)].
KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs.
Modify the dosage as recommended in Table 1 if the patient develops neutropenia, thrombocytopenia, or liver enzyme abnormalities [see Dosage and Administration (2.6), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Recommended Dosage for Polymyalgia Rheumatica
The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection, in combination with a tapering course of systemic corticosteroids [see Dosage and Administration (2.1)]. KEVZARA can be used as monotherapy following discontinuation of corticosteroids.
Discontinue KEVZARA if the patient develops neutropenia (using ANC results obtained at the end of the dosing interval), thrombocytopenia, or liver enzyme abnormalities [see Dosage and Administration (2.6), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis
The recommended dosage of KEVZARA for patients who weigh 63 kg and greater is 200 mg once every two weeks given as a subcutaneous injection (maximum dose 200 mg). Dosage in this patient population can be achieved by administering the 200 mg/1.14 mL pre-filled syringe. The pre-filled pen is not intended for use in pediatric patients [see Dosage and Administration (2.6), Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form.
In patients with pJIA, KEVZARA can be used alone or in combination with conventional DMARDs.
2.5 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.
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 (5.2) and Clinical Pharmacology (12.2)]. For treatment initiation criteria, refer to the dosage recommendations for RA [see Dosage and Administration (2.1, 2.2)].
| Low Absolute Neutrophil Count (ANC) | |
| Lab Value (cells/mm3) | Recommendation |
| ANC greater than 1,000 | Maintain current dosage of KEVZARA. |
| ANC 500 to 1,000 | Hold treatment with KEVZARA until ANC greater than 1,000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate. |
| ANC less than 500 | Discontinue KEVZARA. |
| Low Platelet Count | |
| Lab Value (cells/mm3) | 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 (5.1)].
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 (5.2) and Clinical Pharmacology (12.2)]:
- neutropenia (ANC below 1,000 per mm3 at the end of the dosing interval)
- thrombocytopenia (platelet count below 100,000 per mm3)
- 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 (5.1)].
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/mm3, neutrophil count <500 cells/mm3 associated with infection. Hold KEVZARA dosing for ALT >3 to ≤5 ULN, platelet count >50,000 to ≤100,000 cells/mm3, and neutrophil count ≥500 to <1000 cells/mm3, 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.
Injection: 150 mg/1.14 mL and 200 mg/1.14 mL clear and colorless to pale-yellow solution in a single-dose pre-filled syringe.
Injection: 150 mg/1.14 mL and 200 mg/1.14 mL clear and colorless to pale-yellow solution in a single-dose pre-filled pen.
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 pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta.
Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with KEVZARA.
Parturition is associated with significant increases of IL-6 in the cervix and myometrium. 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. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.
Lactation
Risk Summary
No information is available on the presence of sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of KEVZARA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KEVZARA and the potential adverse effects on the breastfed child from KEVZARA or from the underlying maternal condition.
Pediatric Use
KEVZARA is approved for active polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients who weigh 63 kg or greater. Use of KEVZARA in this patient population is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with pJIA 2 years of age and older. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form [see Adverse Reactions (6.1), Pharmacokinetics (12.3), and Clinical Studies (14.1, 14.3)].
The safety and effectiveness of KEVZARA have not been established in pediatric patients with pJIA below the age of 2 years.
Geriatric Use
Of the total number of patients with RA exposed to KEVZARA in clinical studies [see Clinical Studies (14.1)], 450 patients (15%) were 65 years of age and over, while 48 patients (1.6%) were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infections among KEVZARA and placebo-treated patients 65 years of age and older was higher than those under the age of 65.
Of the total number of patients with PMR exposed to KEVZARA in the clinical study (Study 3) [see Clinical Studies (14.2)], 16 patients (27.1%) were under 65 years of age, 33 patients (55.9%) were 65 to 75 years of age, and 10 patients (17.0%) were 75 years and over. The median age in the PMR study was 69.0 years and all patients were on baseline corticosteroid. There were no differences in the incidence of serious infections between the KEVZARA group and placebo group. In Study 3, no overall differences in safety were observed between older and younger patients.
As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Hepatic Impairment
The safety and efficacy of KEVZARA have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology [see Warnings and Precautions (5.6)].
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 (12.3)].
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)].