15/18. Baricitinib- (OLUMIANT)- (May 2018)- to treat moderately to severely active rheumatoid arthiritis
Drug Name:15/18. Baricitinib- (OLUMIANT)- (May 2018)- to treat moderately to severely active rheumatoid arthiritis
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-(summary)
In patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors (e.g., probenecid) the recommended dosage should be reduced.
DRUG INTERACTIONS-(details)
1 Strong OAT3 Inhibitors Baricitinib exposure is increased when OLUMIANT is co-administered with strong OAT3 inhibitors (such as probenecid), hence the dosage of baricitinib should be reduced by half the recommended dose.
2 Other JAK Inhibitors or Biologic DMARDs OLUMIANT has not been studied in combination with other JAK inhibitors or with biologic DMARDs
Indication:
BRIEF SUMMARY
BARICITINIB-(May 2018)
Indn- To treat modertely to severe active rheumatoi arthiritis
Comp- Tablets: 4 mg, 2 mg, Recommended Dosage: Rheumatoid Arthritis: • 2 mg once daily.
ADR- Adverse reactions reported in clinical trials (=1%) are: • Rheumatoid Arthritis: upper respiratory tract infections (URTIs), nausea, herpes simplex, and herpes zoster.
Pat Infrm-
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 ].
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U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 15
Adverse Reaction:
ADVERSE REACTIONS-
Adverse reactions reported in clinical trials (=1%) are: • Rheumatoid Arthritis: upper respiratory tract infections (URTIs), nausea, herpes simplex, and herpes zoster.
• COVID-19: increases of liver enzymes, thrombocytosis, creatine phosphokinase increases, neutropenia, deep vein thrombosis, pulmonary embolism, and urinary tract infection (UTI)
• Alopecia Areata: URTIs, headache, acne, hyperlipidemia, creatine phosphokinase increase, UTI, liver enzyme elevations, folliculitis, fatigue, lower respiratory tract infections, nausea, genital Candida infections, anemia, neutropenia, abdominal pain, herpes zoster, and weight increase
Contra-Indications:
CONTRAINDICATIONS-
None.
WARNINGS AND PRECAUTIONS-
• Hypersensitivity: Serious reactions have been reported. Discontinue OLUMIANT if a serious hypersensitivity reaction occurs.
• Gastrointestinal Perforations: Monitor patients who may be at increased risk and evaluate promptly new onset of abdominal symptoms.
• Laboratory Abnormalities: Monitor for changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids.
• Vaccinations: Avoid use with live vaccines.
Dosages/ Overdosage Etc:
Recommended Dosage: Rheumatoid Arthritis: • 2 mg once daily.
• OLUMIANT may be used as monotherapy or in combination with methotrexate or other non-biologic DMARDs.
COVID-19: • 4 mg once daily for up to 14 days.
Alopecia Areata: • 2 mg once daily. Increase to 4 mg once daily, if the response to treatment is not adequate.
• For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider treating with 4 mg once daily.
• Reduce the dose to 2 mg once daily when an adequate response has been achieved.
Dosage Modifications in Patients with Renal or Hepatic Impairment, or Cytopenias • See the full prescribing information for dosage modifications by indication.-
Recommended Dosage: Rheumatoid Arthritis:
• 2 mg once daily. • OLUMIANT may be used as monotherapy or in combination with methotrexate or other non-biologic DMARDs.
COVID-19: • 4 mg once daily for up to 14 days.
Alopecia Areata: • 2 mg once daily. Increase to 4 mg once daily, if the response to treatment is not adequate.
• For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider treating with 4 mg once daily.
• Reduce the dose to 2 mg once daily when an adequate response has been achieved.
Dosage Modifications in Patients with Renal or Hepatic Impairment, or Cytopenias • See the full prescribing information for dosage modifications by indication. -
DOSAGE FORMS AND STRENGTHS-
Tablets: 4 mg, 2 mg,
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling
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 developing lymphomas and other malignancies, including of the skin and that periodic skin examinations should be performed while using OLUMIANT.
Instruct patients to inform their healthcare provider if they have ever had any type of cancer ].
Major Adverse Cardiovascular Events- Inform patients that OLUMIANT may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death
Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events
Thrombosis- Advise patients that events of DVT and PE have been reported in clinical studies with OLUMIANT.
Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE ].
Hypersensitivity Reactions- Advise patients to discontinue OLUMIANT and seek immediate medical attention if they develop any signs and symptoms of serious allergic reactions.].
Gastrointestinal Perforations- Inform patients that gastrointestinal perforations have been reported in clinical trials with OLUMIANT.
Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting].
Laboratory Abnormalities - Inform patients that OLUMIANT may affect certain lab tests, and that blood tests are required before and during OLUMIANT treatment.
Live Vaccines- Instruct patients to inform the healthcare practitioner that they are taking OLUMIANT prior to a potential vaccination since the use of live vaccine is not recommended.
Pregnancy - Advise pregnant females and females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with OLUMIANT.
Inform patients to report their pregnancy to Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) [see Use in Specific Populations (8.1, 8.3)].
Lactation- Advise a woman not to breastfeed during treatment with OLUMIANT and for four days after the last dose ,
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA www.olumiant.com Copyright © 2018, 2022, Eli Lilly and Company. All rights reserved. OLM-0007-USPI-20220
Pharmacology/ Pharmacokinetics:
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.
12.2 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.
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 doseproportional 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- Rheumatoid Arthritis and Alopecia Areata: The total body clearance of baricitinib is 8.9 L/h in patients with rheumatoid arthritis and 11 L/h in patients with alopecia areata.
Elimination half-life in patients with rheumatoid arthritis and alopecia areata is approximately 12 to 16 hours. COVID-19: The total body clearance and half-life of baricitinib is 14.2 L/h and 10.8 hours, respectively, in patients with COVID-19 who are intubated and have baricitinib administered via NG or OG tube.
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 (Figure 1).
Patients with 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) [see Use in Specific Populations (8.7)].
Patients with 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
Drug Interactions- Potential for Baricitinib to Influence the PK of Other Drugs In vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6).
In clinical pharmacology studies, there were no clinically meaningful changes in the pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with baricitinib.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on the findings from animal reproduction studies, OLUMIANT may cause fetal harm during pregnancy.
Available data from clinical trials and postmarketing case reports with OLUMIANT exposure in pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are no human data on chronic baricitinib exposure throughout pregnancy.
There are risks to the mother and the fetus associated with rheumatoid arthritis in pregnancy (see Clinical Considerations)
The background risks 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 women not to breastfeed during treatment with OLUMIAN
3. Females and Males of Reproductive Potential- Contraception- - Based on animal studies, OLUMIANT may cause fetal harm when administered during pregnancy
Consider pregnancy planning and prevention for females of reproductive potential
4. Pediatric Use- The safety and effectiveness of OLUMIANT in pediatric patients have not been established.
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 indicated..
Of the 1200 patients in the alopecia areata clinical trials, a total of 29 patients were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they respond differently from younger patients. 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 geriatric 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 rheumatoid arthritis or alopecia areata and severe hepatic impairment and is therefore not recommended.
OLUMIANT has not been studied in patients with COVID-19 and severe hepatic impairment. OLUMIANT should only be used in patients with COVID-19 and severe hepatic impairment if the potential benefit outweighs the potential risk
6. Renal Impairment- Renal function was found to significantly affect baricitinib exposure. Rheumatoid Arthritis and Alopecia Areata - The recommended dosage of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and <60 mL/min/1.73 m2) should be reduced by half the recommended dose.
OLUMIANT is not recommended for use in patients with rheumatoid arthritis or alopecia areata and severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2) [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. COVID-19
- The recommended dosage of OLUMIANT in patients with moderate renal impairment (estimated GFR between 30 and <60 mL/min/1.732) or severe renal impairment (estimated GFR between 15 and <30 mL/min/1.73 m2) is 2 mg once daily and 1 mg once daily, respectively.
OLUMIANT is not recommended for use in patients who are on dialysis, have end-stage renal disease (ESRD), or with estimated GFR of <15 mL/min/1.73 m2
10 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.
11 DESCRIPTION OLUMIANT (baricitinib) is a Janus kinase (JAK) inhibitor with the chemical name {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl
