DRUG INTERACTIONS

 

 P-gp inhibitors increase the blood levels of betrixaban. Reduce

 BEVYXXA dose. 

 

 Anticoagulants: Avoid concomitant use. 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  21

  

Name of the  Drug-        Kevzara

 

Active Ingredient-          Sarilumab                                                                                                                                                                                                                                   Pharmacological Classification- 

 

                       To treat adult rheumatoid arthritis                   

                                                                                                                                                             

Date of Approval-          05-22-2017

 

 (Ref- FDA approved List 2017)

 

 HIGHLIGHTS OF PRESCRIBING INFORMATION

 

These highlights do not include all the information needed to use 

KEVZARA® safely and effectively. See full prescribing information for KEVZARA.

 

 KEVZARA (sarilumab) injection, for subcutaneous use 

 Initial U.S. Approval: 2017

 

 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. 

 

 If a serious infection develops, interrupt KEVZARA until the infection 

 is controlled. 

 

 Cases of tuberculosis (TB) have been reported. Prior to starting 

 KEVZARA, test for latent TB; if positive, start treatment for TB.

 

 Closely monitor patients for signs and symptoms of infection during 

 treatment with KEVZARA.                                                                                                                                                                                                                                                   INDICATIONS AND USAGE

 

 KEVZARA® is an interleukin-6 (IL-6) receptor antagonist 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).                                                                                                     

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

 

 

 ADVERSE REACTIONS 

 

 Most common adverse reaction (incidence >5%) is bleeding. 

 

 CONTRAINDICATIONS

 

 Active pathological bleeding. 

 Severe hypersensitivity reaction to betrixaban BEVYXXA. 

 

 WARNINGS AND PRECAUTIONS

 

 Risk of Bleeding: Can cause serious, potentially fatal bleeding.

Promptly evaluate signs and symptoms of blood loss. 

 

 Severe Renal Impairment: Increased risk of bleeding events; reduce

 BEVYXXA dose 

 

 Concomitant P-gp Inhibitors: Increased risk of bleeding events; reduce

 BEVYXXA dose 

INDICATIONS AND USAGE

 

 KEVZARA® is an interleukin-6 (IL-6) receptor antagonist 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). 

 

 DOSAGE AND ADMINISTRATION

 

 KEVZARA may be used as monotherapy or in combination with 

 methotrexate (MTX) or other conventional DMARDs. 

 

The recommended dosage of KEVZARA is 200 mg once every two weeks, 

 administered as a subcutaneous injection. 

 

 General Considerations for Administration

 KEVZARA initiation is not recommended in patients with ANC less 

 than 2000/mm3, platelets less than150,000/mm3 or liver transaminases

 above 1.5 times ULN. 

 

 Dosage Modifications

 Modify dosage to manage neutropenia, thrombocytopenia, 

 and/or elevated liver transaminases. 

 

DOSAGE AND ADMINISTRATION

 

The recommended dose of BEVYXXA is an initial single dose of 160 mg,

 

 followed by 80 mg once daily, taken at the same time each day with food.

 

 The recommended duration of treatment is 35 to 42 days. 

 

 Reduce dose for patients with severe renal impairment. 

 Reduce dose for patients on P-glycoprotein (P-gp) inhibitors. 

 

DOSAGE FORMS AND STRENGTHS

 Capsules: 40 mg and 80 mg 

 

 PATIENT COUNSELING INFORMATION

 

 Advise the patients to read the FDA-approved patient labeling 

(Medication Guide and Instructions for Use).

 

 Infections

 Inform patients that KEVZARA may lower their resistance to infections.

 Instruct patients to contact their physician immediately when symptoms 

 suggesting infection appear, to ensure rapid evaluation and appropriate

 treatment.

 

Gastrointestinal Perforation

 Inform patients that some patients, particularly those also taking NSAIDS,

 and/or steroids, have had tears (perforations) of the stomach or intestines. 

 

Inform patients that gastrointestinal perforations have been reported in

 KEVZARA-treated patients in clinical studies, primarily as a complication 

 of diverticulitis. 

 

 Instruct patients to contact their physician immediately when symptoms

  of severe, persistent abdominal pain appear to ensure rapid evaluation 

 and appropriate treatment.

 

 Hypersensitivity and Serious Allergic Reaction

 Assess patient suitability for home use for SC injection. 

 

 Inform patients that some patients who have been treated with 

 KEVZARA have developed serious allergic reactions. 

 

 Advise patients to seek immediate medical attention if they experience

 any symptom of serious allergic reactions.

 

 Pregnancy Registry

 There is a pregnancy exposure registry that monitors pregnancy outcomes

  in women exposed to KEVZARA during pregnancy.

  Encourage participation in the registry 

 

 Instruction on Injection Technique

 Instruct patients and caregivers to read the Instructions for Use before

  the patient starts using KEVZARA, and each time the patient gets 

 a refill as there may be new information they need to know.

 

 Provide guidance to patients and caregivers on proper subcutaneous 

 injection technique, including aseptic technique, and how to use the 

 pre-filled syringe correctly 

 

 The pre-filled syringe should be left at room temperature for 30 minutes

 prior to use. The syringe should be used within 14 days after being taken 

 out of the refrigerator. A puncture-resistant container for disposal of syringes

 should be used and should be kept out of the reach of children. 

 

Instruct patients or caregivers in the technique as well as proper 

pre-filled syringe disposal, and caution against reuse of these items.

 

Manufactured by:

Reference ID:

Sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY

U.S. License # 1752 Marketed by: sanofi-aventis U.S. LLC (Bridgewater, NJ 08807)

 and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591)

 KEVZARA® is a registered trademark of Sanofi Biotechnology ©2017 

Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC 

 

Issue Date: May 2017

Reference ID:

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 Sarilumab 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 a pleiotropic pro-inflammatory 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 such 

 as T-cell activation, induction of immunoglobulin  secretion, initiation of hepatic

 acute phase protein synthesis, and stimulation  of hematopoietic precursor 

 cell proliferation and differentiation. 

 

 IL-6 is also produced by synovial and endothelial cells leading to local

 production of IL-6 in joints affected by inflammatory processes such as 

 rheumatoid arthritis.

 

2. Pharmacodynamics

 Following single-dose subcutaneous administration of sarilumab 200-mg

 and 150-mg in patients with RA, rapid reduction of CRP levels was observed.

 Levels were reduced to normal within 2 weeks after treatment initiation. 

 

 Following single-dose sarilumab administration, in patients with RA, 

  absolute neutrophil counts decreased to the nadir between 3 to 4 days and

  thereafter recovered towards baseline.

 

 Treatment with sarilumab resulted in decreases in fibrinogen and serum 

 amyloid A, and increases in hemoglobin and serum albumin.

 

 3. Pharmacokinetics

  Absorption

 The pharmacokinetics of sarilumab were characterized in 1770 patients

  with rheumatoid arthritis (RA) treated with sarilumab which included

  631 patients treated with 150 mg and 682 patients treated with 200 mg 

 doses by subcutaneous injection every two weeks for up to 52 weeks. 

 

The median tmax was observed in 2 to 4 days.

 

 At steady state, exposure over the dosing interval measured by area under

 curve (AUC) increased 2-fold with an increase in dose from 150 to 200 mg 

every two weeks. Steady state was reached in 14 to 16 weeks with

 a 2-to 3-fold accumulation compared to single dose exposure.

 

 For the 150 mg every two weeks dose regimen, the estimated mean 

 (± SD) steady-state AUC, Cmin and Cmax of sarilumab were 

 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively.

 

For the 200 mg every two weeks dose regimen, the estimated mean (± SD) 

steady-state AUC, Cmin and Cmax of sarilumab were 

395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively.

 

 Distribution

 In patients with RA, the apparent volume of distribution at steady state was 7.3 L.

 

 Elimination

 Sarilumab is eliminated by parallel linear and non-linear pathways.

 At higher concentrations, the elimination is predominantly through the linear, 

 non-saturable proteolytic pathway, while at lower concentrations, 

 non-linear saturable target-mediated elimination predominates. 

 

 The half-life of sarilumab is concentration-dependent. At 200 mg every 

 2 weeks, the concentration-dependent half-life is up to 10 days in patients 

 with RA at steady state. At 150 mg every 2 weeks, the concentration-dependent 

 half-life is up to 8 days in patients with RA at steady state.

 

 After the last steady state dose of 150 mg and 200 mg sarilumab, the median

 times to non-detectable concentration are 28 and 43 days, respectively.

 

 Population pharmacokinetic analyses in patients with RA revealed that there 

 was a trend toward higher apparent clearance of sarilumab in the presence of 

 anti-sarilumab antibodies.

 

 Metabolism

 The metabolic pathway of sarilumab has not been characterized. As a 

 monoclonal antibody sarilumab is expected to be degraded into small peptides 

 and amino acids via catabolic pathways in the same manner as endogenous IgG.

 

 Excretion

 Monoclonal antibodies, including sarilumab, are not eliminated via renal 

 or hepatic pathways.

 

 Specific Populations

 Population pharmacokinetic analyses in adult patients with rheumatoid arthritis 

 showed that age, gender and race did not meaningfully influence the 

 pharmacokinetics of sarilumab. Although body weight influenced the 

 pharmacokinetics of sarilumab, no dose adjustments are recommended 

 for any of these demographics.

 

 Hepatic impairment

 No formal study of the effect of hepatic impairment on the pharmacokinetics

 of sarilumab was conducted.

 

 Renal impairment

 No formal study of the effect of renal impairment on the pharmacokinetics

 of sarilumab was conducted. 

 

 Based on population pharmacokinetic analysis of data from 1770 patients 

 with RA, including patients with mild  (creatinine clearance (CLcr): 

 60 to 90 mL/min; N=471at baseline) or 

 moderate (CLcr: 30 to 60 mL/min; N=74 at baseline) renal impairment, 

 

 CLcr was correlated with sarilumab exposure. However, the effect of CLcr

  on exposure is not sufficient to warrant a dose adjustment.

 

 Patients with severe renal impairment were not studied.

 

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

 Pregnancy Exposure Registry

 There is a pregnancy exposure registry that monitors pregnancy outcomes

  in women exposed to KEVZARA during pregnancy. 

 Physicians are encouraged to register patients and pregnant women are 

 encouraged to register themselves by calling 1-877-311-8972.

 

 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 infants.

 

 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 

 

 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

 

 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.

 

 

2. 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.

 

3.Pediatric Use

 Safety and efficacy of KEVZARA in pediatric patients have not been established.

 

4.Geriatric Use

 Of the total number of patients in clinical studies of KEVZARA , 15% were 

 65 years of age and over, while 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 infection 

 among KEVZARA and placebo-treated patients 65 years of age and older

  was higher than those under the age of 65. 

 

 As there is a higher incidence of infections in the elderly population in general, 

 caution should be used when treating the elderly.

 

5. 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.

 

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 .