Avutometinib Potassium And Defactinib Hydrochloride

FDA Drug Information • Also known as: Avmapki Fakzynja Co-Pack

Brand Names: Avmapki Fakzynja Co-Pack
Dosage Form: KIT
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION AVMAPKI FAKZYNJA CO-PACK contains AVMAPKI (avutometinib) capsules co-packaged with FAKZYNJA (defactinib) tablets. AVMAPKI capsules contain avutometinib, a kinase inhibitor. The chemical name of avutometinib is N-(3-Fluoro-4-{[4-methyl-7-(2-pyrimidinyloxy)-2H-chromen-2-on-3-yl]methyl}-2-pyridyl)-N'-methylsulfamide potassium salt. The molecular formula for avutometinib is C 21 H 17 FN 5 O 5 S (as potassium salt) and its molecular weight is 509.55. The chemical structure of avutometinib is shown below: Avutometinib potassium is a white to pale yellow powder. It is practically insoluble in the pH range of 1 to 7 in aqueous media. The pKa is 7.02. AVMAPKI capsules for oral administration contain 0.8 mg of avutometinib (equivalent to 0.864 mg as the avutometinib potassium salt) with the following inactive ingredients: magnesium stearate and mannitol in a hypromellose capsule shell (carrageenan, hypromellose, potassium chloride, purified water, and titanium oxide) printed with black ink (black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution). FAKZYNJA tablets contain defactinib, a kinase inhibitor. The chemical name of defactinib is N-methyl-4-({4-[({3-methyl(methylsulfonyl)aminopyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide hydrochloride. The molecular formula for defactinib is C 20 ClH 22 F 3 N 8 O 3 S (as hydrochloride [HCl] salt) and its molecular weight is 546.96. The chemical structure of defactinib is shown below: Defactinib hydrochloride is a white to pale yellow powder. It is very slightly soluble at pH 1 and practically insoluble in the pH range of 4.5 to 6.8 in aqueous media. The pKa is 3.81. FAKZYNJA tablets are available for oral administration. Each FAKZYNJA tablet contains 200 mg defactinib (equivalent to 214.36 mg as the defactinib hydrochloride salt) and the following inactive ingredients: lactose...

What Is Avutometinib Potassium And Defactinib Hydrochloride Used For?

1 INDICATIONS AND USAGE AVMAPKI FAKZYNJA CO-PACK is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. AVMAPKI FAKZYNJA CO-PACK, a combination of avutometinib and defactinib, each kinase inhibitors, is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ( 1 , 14 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION AVMAPKI 3.2 mg administered orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle. ( 2.3 ) FAKZYNJA 200 mg administered orally twice daily for the first 3 weeks of each 4-week cycle. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of recurrent LGSOC with AVMAPKI FAKZYNJA CO-PACK based on the presence of a KRAS mutation in tumor specimens [see Clinical Studies (14) ] . An FDA-approved test for the detection of a KRAS mutation in LGSOC for selecting patients for treatment with AVMAPKI FAKZYNJA CO-PACK is not available. 2.2 Eye Exams and Prophylactic Skin Medications Ophthalmic Exams Conduct a comprehensive ophthalmic exam at baseline, prior to cycle 2, and every three cycles thereafter regardless of baseline exam findings, and as clinically indicated [see Warnings and Precautions (5.1) ]. Prophylactic Medications for Skin Reactions With initiation of and during at least the first 2 cycles of AVMAPKI FAKZYNJA CO-PACK administer [see Warnings and Precautions (5.2) ] : Topical corticosteroid (applied to the face, scalp, neck, upper chest and upper back) Systemic oral antibiotics 2.3 Recommended Dosage and Administration AVMAPKI Capsules The recommended dosage of AVMAPKI capsules is 3.2 mg (four 0.8 mg capsules) taken orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take AVMAPKI at the same time with each dose. AVMAPKI should be taken with food [see Clinical Pharmacology (12.3) ] . Swallow capsules whole. Do not chew, break, or open the capsules. If a dose of AVMAPKI is missed by more than 24 hours, skip the missed dose and take the next scheduled dose as prescribed. Do not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking AVMAPKI, do not take an additional dose. Take the next scheduled dose as prescribed. FAKZYNJA Tablets The recommended dosage of FAKZYNJA tablets is 200 mg (one tablet) taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take each dose of FAKZYNJA with food [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not chew, break or crush the tablets. If a dose of FAKZYNJA is missed by more than 6 hours, skip the missed dose and take the next scheduled dose as prescribed. Do not take two tablets at the same time to make up for a missed dose. If vomiting occurs after taking FAKZYNJA, do not take an additional dose. Take the next scheduled dose as prescribed. 2.4 Dosage Modifications for Adverse Reactions Dose reductions due to adverse reactions due to AVMAPKI FAKZYNJA CO-PACK are summarized in Table 1. Table 1 Recommended Dose Reductions for Adverse Reactions Dose Level AVMAPKI Capsule FAKZYNJA Tablet Starting dose 3.2 mg twice weekly for first 3 weeks of each 4-week cycle 200 mg twice daily for first 3 weeks of each 4-week cycle Dose reduction 2.4 mg twice weekly...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Ocular Toxicities [see Warnings and Precautions (5.1) ] Serious Skin Toxicities [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Rhabdomyolysis [see Warnings and Precautions (5.4) ] The most common (≥ 25%) adverse reactions, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Verastem at 1-833-633-8786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in Warnings and Precautions reflect exposure to the AVMAPKI FAKZYNJA CO-PACK (combination of AVMAPKI 3.2 mg twice weekly and FAKZYNJA 200 mg twice daily) for the first 3 weeks in a 4-week cycle until disease progression or unacceptable toxicity in 136 adult patients with recurrent LGSOC treated on RAMP-201 and FRAME (NCT03875820). The median duration of treatment was 10 months (range 0 to 51 months). RAMP-201 The safety of AVMAPKI FAKZYNJA CO-PACK was evaluated in RAMP-201, a single-arm multicenter trial in 57 patients with KRAS- mutated recurrent LGSOC [see Clinical Studies (14) ] . Patients received AVMAPKI FAKZYNJA CO-PACK (AVMAPKI 3.2 mg twice weekly and FAKZYNJA 200 mg twice daily) for the first 3 weeks in a 4-week cycle until disease progression or unacceptable toxicity. The median duration of treatment was 12 months (range 0.03-40). Serious adverse reactions occurred in 32% of patients who received AVMAPKI FAKZYNJA CO-PACK. The most common (≥2%) serious adverse reactions were sepsis (9%), intestinal obstruction (3.6%), pyelonephritis (3.6%), and hydronephrosis (3.6%). Fatal adverse reactions occurred in 3.6% of patients who received AVMAPKI FAKZYNJA CO-PACK, including intestinal obstruction (1.8%) and perforation (1.8%). Permanent discontinuation of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 14% of patients. The adverse reactions leading to permanent discontinuation included elevations in creatine phosphokinase, dyspnea, malaise, decreased glomerular filtration rate, hyperbilirubinemia, increased alanine aminotransferase, and abdominal pain (1.8% each). Dosage interruptions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 84% of patients. Adverse reactions which required dosage interruptions in ≥ 5% of patients included elevations in creatine phosphokinase (25%), hyperbilirubinemia (25%), diarrhea (12%), edema (11%), fatigue (9%), vision blurred (9%), vitreoretinal disorders (7%), transaminitis (7%), paronychia (5%), nausea (5%), abdominal pain (5%), vomiting (5%), dyspnea (5%), sepsis (5%), and rash (5%). Dose reductions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in ≥ 5% of patients were elevations in creatine phosphokinase (9%), fatigue (5%), hyperbilirubinemia (5%), and dermatitis acneiform (5%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash,...

Drug Interactions

7 DRUG INTERACTIONS Strong and moderate CYP3A4 inhibitors : Avoid concomitant use with AVMAPKI FAKZYNJA CO-PACK. ( 7.1 ) Strong and moderate CYP3A4 inducers : Avoid concomitant use with AVMAPKI FAKZYNJA CO-PACK. ( 7.1 ) Warfarin : Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with warfarin and use an alternative to warfarin. ( 7.2 ) Gastric acid reducing agents : Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with proton pump inhibitors (PPIs) or H2 receptor antagonists. If use of an acid-reducing agent cannot be avoided, administer FAKZYNJA 2 hours before or 2 hours after the administration of a locally acting antacid. ( 7.1 ) 7.1 Effect of Other Drugs on AVMAPKI FAKZYNJA CO-PACK Strong and Moderate CYP3A4 Inhibitors Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with strong or moderate CYP3A4 inhibitors. Defactinib is a CYP3A4 substrate. Concomitant use of defactinib with a strong CYP3A4 inhibitor increases defactinib exposure [see Clinical Pharmacology (12.3) ], which may increase the risk of AVMAPKI FAKZYNJA CO-PACK adverse reactions. Strong and Moderate CYP3A4 Inducers Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with strong or moderate CYP3A4 inducers. Defactinib is a CYP3A4 substrate. Concomitant use of defactinib with a strong CYP3A4 inducer decreases defactinib exposure, which may reduce the effectiveness of FAKZYNJA [see Clinical Pharmacology (12.3) ] . Gastric Acid Reducing Agents Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with proton pump inhibitors (PPIs) or H2 receptor antagonists. If concomitant use of an acid-reducing agent cannot be avoided, administer FAKZYNJA 2 hours before or 2 hours after the administration of a locally acting antacid. Concomitant use of FAKZYNJA with gastric acid reducing agents decreases defactinib exposure, which may reduce the effectiveness of AVMAPKI FAKZYNJA CO-PACK [see Clinical Pharmacology (12.3) ] . 7.2 Effect of AVMAPKI FAKZYNJA CO-PACK on Other Drugs Warfarin Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with warfarin. For patients requiring anticoagulation, an alternative to warfarin is recommended. If concomitant use is unavoidable, monitor INR frequently during treatment with AVMAPKI FAKZYNJA CO-PACK. Cases of bleeding and increased INR occurred in patients taking FAKZYNJA concomitantly with warfarin in clinical trials.

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of AVMAPKI FAKZYNJA CO-PACK in pregnant women to inform a drug-associated risk. Animal reproductive and developmental toxicity studies have not been conducted with avutometinib or defactinib; however, inhibition of either molecular pathway has been associated with embryo-fetal anomalies and lethality in animals. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING AVMAPKI FAKZYNJA CO-PACK is supplied in a carton that contains: AVMAPKI capsules in a 24-count bottle with child-resistant closure (NDC 71779-660-02) NDC 71779-623-01 FAKZYNJA tablets in a 42-count bottle with child-resistant closure (NDC 71779-630-01) AVMAPKI (avutometinib) 0.8 mg capsules are supplied as white capsules with "6766" printed on the cap and the strength "0.8 mg" printed on the body in black ink in a bottle containing 24 capsules. The bottle contains a desiccant that should not be discarded. FAKZYNJA (defactinib) 200 mg tablets are supplied as white to off-white, oval and debossed with "VS2" on one side of the tablet in a bottle containing 42 tablets. Store AVMAPKI capsules and FAKZYNJA tablets refrigerated at 2°C to 8°C (36°F to 46°F) in their original bottles.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.