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

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.

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, 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.

Table 3 summarizes the adverse reactions in RAMP-201.

Clinically relevant adverse reactions in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included urticaria and decreased ejection fraction.

Table 4 summarizes the laboratory abnormalities in RAMP-201.

Clinically relevant laboratory abnormalities in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included increased INR and prolonged activated partial thromboplastin time.

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)].

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.

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.

Risk Summary

There are no data on the presence of avutometinib, defactinib, or their metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with AVMAPKI FAKZYNJA CO-PACK and for 2 weeks after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with AVMAPKI FAKZYNJA CO-PACK.

Contraception

Infertility

Based on animal studies, AVMAPKI FAKZYNJA CO-PACK may impair fertility in females and males of reproductive potential. The effects on fertility were not reversible in animals [see Nonclinical Toxicology (13.1)].

Avutometinib

Avutometinib is a MEK1 inhibitor. Avutometinib induces the formation of inactive RAF/MEK complexes and prevents phosphorylation of MEK1/2 by RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. Avutometinib inhibited MEK1/2 and ERK1/2 phosphorylation and proliferation of tumor cell lines harboring KRAS mutations. Treatment of cancer cells with avutometinib increased the level of phosphorylated focal adhesion kinase (FAK).

Defactinib

Defactinib is an inhibitor of FAK and proline-rich tyrosine kinase-2 (Pyk2), the two members of the FAK family of nonreceptor tyrosine kinases. Defactinib inhibited FAK autophosphorylation in cancer cells in vitro and in mouse xenograft models.

Avutometinib in combination with defactinib enhanced inhibition of cell proliferation in vitro and anti-tumor activity in mouse tumor models including LGSOC.

Cardiac Electrophysiology

At the recommended doses for AVMAPKI FAKZYNJA CO-PACK, a mean increase in the QTc interval >20 msec was not observed. For the 88 patients with PR interval measured in RAMP-201, the mean PR interval increased by 16 msec from baseline to Cycle 1 Day 15 4-hours post dose.

Avutometinib

Avutometinib exhibits dose proportional increases peak plasma concentrations (Cmax) and area under the concentration time curve (AUC) with a single dose ranging from 0.1 mg to 5 mg (0.03 to 1.6 times the approved recommended dose). No significant accumulation of avutometinib was observed at the recommended dosage.

Defactinib

Defactinib exhibits dose proportional increases in Cmax and AUC with twice daily dosing ranging from 12.5 mg to 450 mg (0.06 to 2.25 times the approved recommended dosage). Defactinib steady-state plasma concentrations are reached in approximately 15 days. Defactinib accumulation is approximately 1.5-fold at the approved recommended dosage.

Absorption

The median time to avutometinib peak plasma concentration (Tmax) under fasted conditions is approximately 2 hours.

The median time to defactinib Tmax under fed conditions is approximately 4 hours.

Distribution

Avutometinib steady state apparent volume of distribution (Vd) is 25 L (19%). Avutometinib human plasma protein binding is 99% in vitro.

Defactinib steady state apparent Vd is 1,560 L (59%). Defactinib human plasma protein binding is 90% in vitro.

Elimination

Avutometinib estimated elimination half-life is 51 hours (28%) and the apparent oral clearance (CL/F) is 0.3 L/h (30%).

Defactinib estimated elimination half-life is 9 hours (171%) and the CL/F is 69 L/h (173%).

Specific Populations

No clinically significant differences in the pharmacokinetics of avutometinib were observed based on age (21 to 87 years), sex, race (84% White, 3% Black and 2% Asian), body weight (40 to 169 kg), mild and moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), or mild hepatic impairment (AST > ULN or total bilirubin >1 × ULN to 1.5 × ULN). The effect of severe renal impairment (CLcr < 30 mL/min) or moderate to severe hepatic impairment (AST or ALT ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN) on avutometinib pharmacokinetics is unknown.

No clinically meaningful differences in the pharmacokinetics of defactinib were observed based on age (21 to 87 years), sex, race (82% White, 3% Black and 2% Asian), body weight (40 to 169 kg), mild and moderate renal impairment (CLcr 30 to 89 mL/min), or mild hepatic impairment (AST > ULN or total bilirubin >1 × ULN to 1.5 × ULN). The effect of severe renal impairment (CLcr < 30 mL/min) or moderate to severe hepatic impairment (AST or ALT ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN) on defactinib pharmacokinetics is unknown.

Drug Interaction Studies

Avutometinib

Defactinib

Avutometinib

In repeat-dose toxicity studies up to 13-weeks duration in rats and monkeys, tissue mineralization in multiple organs was observed at doses ≥ 0.01 mg/kg/day and 0.03 mg/kg/day, respectively (≥ 0.06 and 1.4 times the human exposure at the recommended dose based on AUC, respectively) as well as increased inorganic phosphorus in rats.

In a cardiovascular telemetry study in monkeys, a single oral dose of avutometinib increased systolic, diastolic, and mean blood pressure at 1 mg/kg (approximately 15 times the human Cmax at the recommended dose). In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC).

Defactinib

In a cardiovascular telemetry study in dogs, a single oral dose of defactinib decreased myocardial contractility at doses ≥ 5 mg/kg (approximately the human exposure at the recommended dose based on AUC) and increased ventricular systolic, diastolic and mean blood pressure at doses ≥ 25 mg/kg/day (≥ 2.7 times the human exposure at the recommended dose based on AUC). In the 13-week repeat-dose toxicology study in dogs, myocardium hypertrophy was observed at doses ≥ 1 mg/kg/day (below the human exposure at the recommended dose based on AUC) at the end of the dosing and recovery periods.