avmapki fakzynja co-pack (copackaged)

Important safety information

Ocular Toxicities: Ocular toxicities, including visual impairment and vitreoretinal disorders, occurred. Perform comprehensive ophthalmic evaluation at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated. Withhold AVMAPKI FAKZYNJA CO-PACK for ocular toxicities until improvement at the same or reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for any grade 4 toxicity. ( 2.4 , 5.1 ) Serious Skin Toxicities : Skin toxicities, including photosensitivity and severe cutaneous adverse reactions (SCARs), occurred. Adhere to concomitant medications. Monitor for skin toxicities and interrupt, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity, tolerability and duration. ( 2.4 , 5.2 ) Hepatotoxicity : Monitor liver function tests prior to each cycle, on day 15 of the first 4 cycles, and as clinically indicated. Withhold, reduce or discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence of abnormality. ( 2.4 , 5.3 ) Rhabdomyolysis: Monitor creatine phosphokinase prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of the adverse reaction. ( 2.4 , 5.4 ) Embryo-Fetal Toxicity : AVMAPKI FAKZYNJA CO-PACK can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Ocular Toxicities AVMAPKI FAKZYNJA CO-PACK can cause ocular adverse reactions, including visual impairment and vitreoretinal disorders. Ocular adverse reactions occurred in 68% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK. Common ocular adverse reactions (≥ 5%) were visual impairment (38%), dry eye (13%), orbital/periorbital edema (8%), and vitreous floaters (5%). Thirty-five patients (26%) experienced vitreoretinal disorders, including retinal detachment (9%), and retinal vein occlusion (0.7%). Eighteen patients (13%) experienced an ocular adverse reaction that resulted in dose interruption of AVMAPKI FAKZYNJA CO-PACK and one patient experienced an ocular adverse reaction that resulted in dose reduction. The median time to onset of symptomatic ocular adverse reactions was 5 days (range 1 to 943 days) and to onset of asymptomatic ocular adverse reactions was 112 days (range 23 to 943 days). The median time to onset of retinal detachment was 27 days (range 2 to 535 days). Of the patients who experienced ocular adverse reactions, 29% had ongoing ocular events at last follow-up. Refer patients to a qualified eye care professional for a comprehensive ophthalmic exam at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs or symptoms. Monitor for ocular adverse reactions and withhold, reduce, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence of ocular adverse reactions [see Dosage and Administration (2.4) ]. 5.2 Serious Skin Toxicities AVMAPKI FAKZYNJA CO-PACK can cause serious skin toxicities, including Severe Cutaneous Adverse Reactions (SCARs). Cases of acute generalized exanthematous pustulosis, erythema multiforme and drug reaction with eosinophilia and systemic symptoms have been reported in clinical trials of avutometinib (a drug in AVMAPKI FAKZYNJA CO-PACK). Skin toxicities occurred in 94% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK. The most common skin toxicities (≥ 10%) were rash (67%), dermatitis acneiform (43%), dry skin (43%), pruritus (32%), and photosensitivity (13%). Grade 3 skin reactions occurred in 12% of patients including dermatitis acneiform (7%), rash (7%), and pruritus (1.5%). Thirteen patients (10%) developed bacterial skin infections. Skin toxicity led to dose interruption of AVMAPKI FAKZYNJA CO-PACK in 10%, to dose reduction in 7%, and to permanent discontinuation in 0.7% of patients. The median time to onset of the first skin toxicity was 14 days (range 1 to 500 days). At last follow-up, 66% of patients had ongoing skin toxicity. Patients in RAMP-201 used topical corticosteroids (applied to the face, scalp, neck, upper chest and upper back) and systemic oral antibiotics for prophylaxis of skin adverse reactions. These medications were initiated at the start of AVMAPKI FAKZYNJA CO-PACK and administered during at least the first two cycles of treatment. Limit unnecessary exposure to sunlight and apply daily sunscreen (sun protection factor [SPF] ≥ 30). Monitor for skin toxicity and withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence [see Dosage and Administration (2.4) ]. 5.3 Hepatotoxicity AVMAPKI FAKZYNJA CO-PACK can cause hepatotoxicity. In patients with recurrent LGSOC who received AVMAPKI FAKZYNJA CO-PACK, increased AST (73%), bilirubin (51%), ALT (49%), and alkaline phosphatase (46%) occurred. Grade 3-4 elevations in ALT was 3%, AST was 3%, bilirubin was 2.3% and alkaline phosphatase was 0.8%. Elevations in one or more liver related laboratory values led to dose interruption for 20%, dose reduction for 2.2%, and permanent discontinuation for 0.7% of patients. Increased blood bilirubin may be attributed to defactinib (a component of AVMAPKI FAKZYNJA CO-PACK) due to the inhibition of enzymes responsible for metabolizing (uridine diphosphate-glucuronosyltransferase (UGT)1A1) and transporting (Organic Anion Transporting Polypeptides (OATP)1B1/1B3) bilirubin [see Clinical Pharmacology (12.3) ]. Monitor liver related laboratory values prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. Withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of these adverse reactions [see Dosage and Administration (2.4) ]. 5.4 Rhabdomyolysis AVMAPKI FAKZYNJA CO-PACK can cause increased creatine phosphokinase (CPK). Increased CPK occurred in 75% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK, including Grade 3-4 elevations in 18% of patients. Among the patients who experienced an elevation in CPK, concurrent increase in creatinine occurred in 19% (n=19/102) and myalgia occurred in 10% (n=10/102). Elevation of CPK >10 times the baseline value with a concurrent increase in serum creatinine of ≥1.5 times the baseline value occurred in 0.7% of patients. Increased CPK resulted in dose interruption for 22%, in dose reduction for 7%, and in discontinuation for 2.9% of patients. Rhabdomyolysis has occurred in a patient with LGSOC treated with AVMAPKI FAKZYNJA CO-PACK at the recommended dosage in a clinical trial. Monitor CPK prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of the adverse reactions [see Dose Modifications (2.4) ] . 5.5 Embryo-Fetal Toxicity 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) ] . 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. Advise females of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 4 months after the last dose [see Use in Specific Populations (8.3) ] .