DRUG INTERACTIONS-- (summary)--

• Organic Anion Transporting Polypeptide (OATP)1B1/B3 inhibitors: Monitor for adverse reactions.

 • Breast Cancer Resistance Protein (BCRP) substrates: Reduce rosuvastatin (BCRP substrate) dosage. Follow approved product information recommendations for other BCRP substrates.

DRUG INTERACTIONS-(details)

Effect of Other Drugs on OJJAARA Organic Anion Transporting Polypeptide (OATP)1B1/B3 Inhibitors Momelotinib is an OATP1B1/B3 substrate.

Concomitant use with an OATP1B1/B3 inhibitor increases momelotinib maximal concentrations (Cmax) and area under the concentration-time curve (AUC) , which may increase the risk of adverse reactions with OJJAARA.

Monitor patients concomitantly receiving an OATP1B1/B3 inhibitor for adverse reactions and consider OJJAARA dose modifications)]

2 Effect of OJJAARA on Other Drugs Breast Cancer Resistance Protein (BCRP) Substrates Momelotinib is a BCRP inhibitor. OJJAARA may increase exposure of BCRP substrates, which may increase the risk of BCRP substrate adverse reactions

When administered concomitantly with OJJAARA, initiate rosuvastatin (BCRP substrate) at 5 mg and do not increase to more than 10 mg once daily.

Dose adjustment of other BCRP substrates may also be needed. Follow approved product information recommendations for other BCRP substrates.

BRIEF SUMMARY

MOMETINIB-(Aug 2023)

Indn-     To  treat intermediate on high risk myelobrosis in  adults with anemia

Comp-   Tablets: 100 mg, 150 mg, 200 mg. • Recommended dosage: 200 mg orally once daily with or without food

ADR- The most common adverse reactions (=20% in either study) are thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea

CI-   None. 

 WARNINGS -

 • Risk of Infections: Do not initiate OJJAARA in patients with an active infection. Monitor for signs and symptoms of infection, including reactivation of hepatitis B, and initiate appropriate treatment promptly.

 • Thrombocytopenia and Neutropenia: Manage by dose reduction or interruption. 

Pat Inform

Thrombocytopenia and Neutropenia- Inform patients that the drug can cause thrombocytopenia and neutropenia, and of the need to monitor complete blood count, including platelet and neutrophil counts, before and during treatment

Hepatotoxicity-                                                                                                                Inform patients that the drug  can cause hepatotoxicity, and of the need to monitor liver blood tests before and during treatment 

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 37

Name-                      OiiJARA

Acive  Ingredient -  Mometinib

Pharmacological clssificiation-        To  treat intermediate on high risk myelobrosis in                                                               adults with anemia                                                       

Date  of approval                   9/15/2023         

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                              OJJAARA safely and effectively.

See full prescribing information for OJJAARA. OJJAARA (momelotinib) tablets, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE -

 OJJAARA is a kinase inhibitor indicated for the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF [post polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia.

(1) ----------------------- DOSAGE AND ADMINISTRATION ----------------------- • Recommended dosage: 200 mg orally once daily with or without food. (2.1) • Severe hepatic impairment (Child-Pugh Class C): Reduce the starting dose to 150 mg orally once daily. (2.3) ---------------------

DOSAGE FORMS AND STRENGTHS ---------------------- Tablets: 100 mg, 150 mg, 200 mg. (3)

------------------------------ CONTRAINDICATIONS ------------------------------ None. (4) ----------

------------- WARNINGS AND PRECAUTIONS ------------------------ • Risk of Infections: Do not initiate OJJAARA in patients with an active infection. Monitor for signs and symptoms of infection, including reactivation of hepatitis B, and initiate appropriate treatment promptly. (5.1) • Thrombocytopenia and Neutropenia: Manage by dose reduction or interruption. (5.2)

 ADVERSE REACTIONS

 The most common adverse reactions (=20% in either study) are thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea

 CONTRAINDICATIONS

 None. 

 WARNINGS AND PRECAUTIONS -

 • Risk of Infections: Do not initiate OJJAARA in patients with an active infection. Monitor for signs and symptoms of infection, including reactivation of hepatitis B, and initiate appropriate treatment promptly.

 • Thrombocytopenia and Neutropenia: Manage by dose reduction or interruption. 

 • Hepatotoxicity: Obtain liver tests before initiation of and periodically throughout treatment with OJJAARA.

 • Major Adverse Cardiovascular Events (MACE): Monitor for symptoms, evaluate and treat promptly. 

 • Thrombosis: Evaluate and treat symptoms of thrombosis promptly.

 • Malignancies: Monitor for development of secondary malignancies, particularly in current or past smokers.

 DOSAGE AND ADMINISTRATION-

• Recommended dosage: 200 mg orally once daily with or without food

 • Severe hepatic impairment (Child-Pugh Class C): Reduce the starting dose to 150 mg orally once daily. -

DOSAGE FORMS AND STRENGTHS -

 Tablets: 100 mg, 150 mg, 200 mg. 

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA approved patient labeling (Patient Information). Infections

Inform patients that OJJAARA can increase the risk of infections (including COVID-19) and instruct them to promptly report to their healthcare provider any signs and symptoms of infection..

Thrombocytopenia and Neutropenia- Inform patients that OJJAARA can cause thrombocytopenia and neutropenia, and of the need to monitor complete blood count, including platelet and neutrophil counts, before and during treatment

. Advise patients to observe for and report any bleeding to their healthcare provider .

Hepatotoxicity-                                                                                                                Inform patients that OJJAARA can cause hepatotoxicity, and of the need to monitor liver blood tests before and during treatment ].

Major Adverse Cardiovascular Events (MACE)- Advise patients that events of MACE including myocardial infarction, stroke, and cardiovascular death have been reported in clinical studies with another JAK inhibitor used to treat rheumatoid arthritis, a condition for which OJJAARA is not indicated.

Advise patients, especially current or past smokers and patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events and to report them to their healthcare provider

Thrombosis- Advise patients that events of deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which OJJAARA is not indicated.

Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE.

Malignancies- Advise patients, especially current or past smokers, that lymphoma and other malignancies (excluding non-melanoma skin cancers (NMSC) have been reported in clinical studies with another JAK inhibitor used to treat rheumatoid arthritis, a condition for which OJJAARA is not indicated.

 Pregnancy-                                                                                                                • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy

• Advise females of reproductive potential who are not pregnant to use highly effective contraception during therapy and for 1 week after the last dose of OJJAAR

Lactation -                                                                                                                     Advise patients not to breastfeed during treatment with OJJAARA and for at least 1 week after the last dose of OJJAARA .

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CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Momelotinib is an inhibitor of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.

2. Pharmacodynamics-                                                                                     Momelotinib inhibited STAT3 phosphorylation in whole blood from patients with MF. Maximal inhibition of STAT3 phosphorylation occurred 2 hours after momelotinib dosing and inhibition persisted for at least 6 hours.

Cardiac Electrophysiology- Momelotinib did not prolong the QT interval to any clinically relevant extent at 4 times the highest recommended dosage of 200 mg.

Effect of Food-                                                                                                                No clinically significant differences in momelotinib pharmacokinetics were observed following administration of either a high-fat meal (800 kcal; 50% fat) or low-fat meal (400 kcal; 20% fat) in healthy subjects.

Distribution -                                                                                                              Momelotinib steady state apparent volume of distribution is 984 L (118%). Momelotinib plasma protein binding is approximately 91% in healthy volunteers

Elimination -                                                                                                                  The elimination half-life of momelotinib and the M21 metabolite is 4 to 8 hours. Momelotinib clearance is 103 L/h (87%).

Metabolism:-                                                                                                              Momelotinib is metabolized by multiple cytochrome P450 (CYP) enzymes including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). 14 M21 is an active human metabolite that has approximately 40% of the pharmacological activity of the parent.

Excretion: -                                                                                                              Following a single oral dose of radiolabeled momelotinib, 69% (13% unchanged) of radioactivity was excreted in feces and 28% (<1% unchanged) in urine. Approximately 12% of the administered dose was excreted in urine as M21.

Specific Populations-                                                                                                     No clinically significant differences in momelotinib and M21 pharmacokinetics were observed based on age (range: 28 to 92 years), race (83% White, 6% Asian, 2% Black), sex (60% male), weight (range: 34 kg to 138 kg), renal impairment (eGFR: 16.4 mL/min/1.73 m2 to above 120 mL/min/1.73 m2), or mild or moderate hepatic impairment (Child-Pugh A or B).

The effect of end stage renal disease receiving dialysis on momelotinib pharmacokinetics is unknown.

Patients with Hepatic Impairment:-                                                                          Momelotinib Cmax increased by 13% and AUC increased by 97% in subjects with severe hepatic impairment (Child-Pugh C). The M21 metabolite Cmax decreased by 76% and AUC decreased by 48% in subjects with severe hepatic impairment (Child-Pugh C).

Drug Interaction Studies Clinical Studies OATP1B1/1B3 Inhibitors:                              Momelotinib Cmax increased by 40% and AUC increased by 57% following concomitant use with a single dose of a OATP1B1/1B3 inhibitor (rifampin).

The M21 metabolite Cmax increased by 6% and AUC increased by 12%. BCRP Substrates: A BCRP substrate (rosuvastatin) Cmax increased by 220% and AUC increased by 170% following concomitant use of a single dose of rosuvastatin at 10 mg with multiple doses of momelotinib (200 mg once daily).

Other Drugs:                                                                                                                   No clinically significant differences in momelotinib and M21metabolite pharmacokinetics were observed when used concomitantly with a strong CYP3A4 inducer (tested with multiple-dose rifampin), a strong CYP3A4 inhibitor (ritonavir), or an acid reducing agent (omeprazole, a proton pump inhibitor).

No clinically significant differences in the pharmacokinetics of a CYP3A4 substrate (midazolam) were observed when used concomitantly with momelotinib.

In Vitro Studies Cytochrome P450 (CYP) Enzymes:                                               Momelotinib is a weak, reversible, time-independent inhibitor of CYP2B6 but does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, or 3A4/5. The M21 metabolite does not inhibit any of these CYP enzymes.

USE IN SPECIFIC POPULATIONS

Pregnancy Risk

Summary Available data on the use of OJJAARA in pregnant women are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. Based on animal reproduction studies conducted in rats and rabbits, momelotinib may cause embryo-fetal toxicity at exposures lower than the expected exposure in patients receiving 200 mg once daily 

OJJAARA should only be used during pregnancy if the expected benefits to the mother outweigh the potential risks to the fetus.

The 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 miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summar-

There are no data on the presence of momelotinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether OJJAARA is excreted in human milk

 Because of the potential for serious adverse  reactions in a breastfed child, patients should not breastfeed during treatment with OJJAARA, and for at least 1 week after the last dose of OJJAARA.

3. Females and Males of Reproductive Potential-

Contraception -Advise females of reproductive potential who are not pregnant to use highly effective contraception during therapy and for at least 1 week after the last dose of OJJAARA.

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

5. Geriatric Use-                                                                                                                There were 275 patients aged 65 years and older in the clinical studies for MF [see Clinical Studies (14)]. Of the total number of OJJAARA-treated patients in these studies, 163/216 (75%) were aged 65 years and older, and 63/216 (29%) were aged 75 years and older.

No overall differences in safety or effectiveness of OJJAARA have been observed between patients aged 65 years and older and younger adult patients.

6. Hepatic Impairment -                                                                                                  The recommended starting dose of OJJAARA in patients with severe hepatic impairment (Child Pugh C) is 150 mg orally once daily.

No dose modification is recommended for patients with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). Momelotinib is extensively metabolized 

Momelotinib exposure increased with severe hepatic impairment (Child-Pugh C). No clinically significant changes in momelotinib exposure were observed in subjects with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment ].

 OVERDOSAGE-                                                                                                          There is no known antidote for overdose with OJJAARA. If overdose is suspected, the patient should be monitored for signs or symptoms of adverse reactions or effects, and appropriate supportive treatment should be instituted immediately. Further management should be as clinically indicated. Hemodialysis is not expected to enhance the elimination of momelotinib.