BRIEF SUMMARY

BARICITINIB- (May 2018)

Indn-   To treat moderately to severe active rheumatoid  arthiritis    

Comp-  Tablets (not scored): 2 mg   The recommended dose is 2 mg once daily.  May be used as monotherapy or in combination with methotrexate or other DMARDs. 

ADR-    Adverse reactions (greater than or equal to 1%) include: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster. 

CI-   None.

WARNINGS-                                                                                                                        • Serious Infections: Avoid use  in patients with active, serious infection, including localized infections. If a serious infection develops, interrupt  therapy until the infection is controlled. Do not give  to patients with active tuberculosis.

• Thrombosis: Use with caution in patients who may be at increased risk.

Pat Inform-                                                                                                                Advise patients of the potential benefits and risks of  Infections Inform patients that they may be more likely to develop infections when taking the drug.                               

Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection 

Advise patients that the risk of herpes zoster is increased in patients treated with the drug and some cases can be serious 

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  15

DOSAGE FORMS AND STRENGTHS-

ADVERSE REACTIONS

 Adverse reactions (greater than or equal to 1%) include: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster. 

CONTRAINDICATIONS

 None.

WARNINGS AND PRECAUTIONS

 • Serious Infections: Avoid use of OLUMIANT in patients with active, serious infection, including localized infections. If a serious infection develops, interrupt OLUMIANT therapy until the infection is controlled. Do not give OLUMIANT to patients with active tuberculosis.

• Thrombosis: Use with caution in patients who may be at increased risk.

 • Gastrointestinal Perforations: Use with caution in patients who may be at increased risk.

 • Laboratory Assessment: Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. 

• Vaccinations: Avoid use of OLUMIANT with live vaccines.

DOSAGE FORMS AND STRENGTHS-

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Patient Counseling

Advise patients of the potential benefits and risks of OLUMIANT. Infections Inform patients that they may be more likely to develop infections when taking OLUMIANT.

Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection 

Advise patients that the risk of herpes zoster is increased in patients treated with OLUMIANT and some cases can be serious 

Malignancies and Lymphoproliferative Disorders-                                                Inform patients that OLUMIANT may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking OLUMIANT.

Instruct patients to inform their healthcare provider if they have ever had any type of cancer 

Thrombosis-                                                                                                              Advise patients that events of DVT and PE have been reported in clinical studies with OLUMIANT. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE 

Laboratory Abnormalities-                                                                                       Inform patients that OLUMIANT may affect certain lab tests, and that blood tests are required before and during OLUMIANT treatment 

Lactation-                                                                                                                       Advise a woman not to breastfeed during treatment with OLUMIANT

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Lilly USA, LLC, Indianapolis, IN 46285, USA www.olumiant.com Copyright © yyyy, Eli Lilly and Company. All rights reserved. BAR-A10.0-NL0000-USPI-YYYYMMDD

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function.

2. Pharmacodynamics-                                                                                        Baricitinib inhibition of IL-6 induced STAT3 phosphorylation – Baricitinib administration resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 1 hour after dosing, which returned to near baseline by 24 hours.

Similar levels of inhibition were observed using either IL-6 or TPO as the stimulus. Immunoglobulins – Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with OLUMIANT, and remained stable through at least 52 weeks.

For most patients, changes in immunoglobulins occurred within the normal reference range. C-reactive protein – In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as one week after starting treatment with OLUMIANT and were maintained throughout dosing.

Cardiac Electrophysiology-                                                                                             At a dose 10 times the maximum recommended dose, baricitinib does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                               Following oral administration of OLUMIANT, peak plasma concentrations are reached approximately at 1 hour. A dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of baricitinib do not change over time.

Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation after once-daily administration.

Absorption -                                                                                                                   The absolute bioavailability of baricitinib is approximately 80%. An assessment of food effects in healthy subjects showed that a high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delayed the tmax by 0.5 hours.   

 Administration with meals is not associated with a clinically relevant effect on exposure. In clinical studies, OLUMIANT was administered without regard to meals.

Distribution-                                                                                                                  After intravenous administration, the volume of distribution is 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution.

Elimination-                                                                                                                         The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. 

 Metabolism-                                                                                                                        Approximately 6% of the orally administered baricitinib dose is identified as metabolites (three from urine and one from feces), with CYP3A4 identified as the main metabolizing enzyme. No metabolites of baricitinib were quantifiable in plasma.

Excretion-                                                                                                                    Renal elimination is the principal clearance mechanism for baricitinib through filtration and active secretion as baricitinib is identified as a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies.

In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the feces. Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%).

Specific Populations-                                                                                                        Effects of Body Weight, Gender, Race, and Age Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of baricitinib

 The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of baricitinib are approximately 41% and 22%, respectively. 

Renal Impairment-                                                                                                Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate, severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal function.

The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (Figure 1) 

Hepatic Impairment-                                                                                              Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment group, respectively, compared to subjects with normal hepatic function 

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                        The limited human data on use of OLUMIANT in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are 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 miscarriage in clinically recognized pregnancies is 2-4% and 15­ 20%, respectively.

2. Lactation Risk Summary-                                                                                           No information is available on the presence of OLUMIANT in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing infants, advise an OLUMIANT-treated woman not to breastfeed.

3. Pediatric Use-                                                                                                            The safety and effectiveness of OLUMIANT in pediatric patients have not been established.

4. Geriatric Use-                                                                                                                   Of the 3100 patients treated in the four phase 3 studies, a total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out 

OLUMIANT is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

5.Hepatic Impairment-                                                                                                    No dose adjustment is necessary in patients with mild or moderate hepatic impairment.

The use of OLUMIANT has not been studied in patients with severe hepatic impairment and is therefore not recommended 

6.Renal Impairment-                                                                                                   Renal function was found to significantly affect baricitinib exposure. OLUMIANT is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2 

 OVERDOSAGE

Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without dose-limiting toxicity.

Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours.

In case of an overdose, it is recommended that the patient should be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.