Explore safety and patient management guidance
Important Warnings and Precautions When Treating Your Patients1
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%). The most common ocular event was blurred vision1,2
These events typically occurred within the first week,* were mild to moderate, and resolved without discontinuation of treatment
- 35 patients (26%) experienced vitreoretinal disorders, including retinal detachment (9%) and retinal vein occlusion (0.7%). 18 patients (13%) experienced an ocular adverse reaction that resulted in dose interruption and one patient experienced an ocular adverse reaction that resulted in dose reduction
- 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 3 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 treatment based on severity and persistence of ocular reactions
*The median time to onset of symptomatic ocular adverse events was 5 days (range 1 to 943 days) and to onset of asymptomatic ocular adverse reactions was 112 days (range 23 to 943 days).
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 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 treatment, administered during at least the first 2 cycles, and recommended as needed thereafter to mitigate dermatologic toxicities1,2
- Limit unnecessary exposure to sunlight and apply daily sunscreen SPF ≥30
Monitor for skin toxicity and withhold, reduce dose, or permanently discontinue treatment based on severity and persistence
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 were 3%, AST were 3%, bilirubin were 2.3%, and alkaline phosphatase were 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
Monitor liver-related laboratory values prior to the start of each cycle, on day 15 of the first 4 cycles, and as clinically indicated
- Withhold, reduce dose, or permanently discontinue treatment based on severity and duration of these adverse reactions
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 4 cycles, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes
- Withhold, reduce, or permanently discontinue treatment based on severity and duration of the adverse reactions
EMBRYO-FETAL TOXICITY
- Based on the mechanisms of action, Avmapki Fakzynja Co‑Pack can cause fetal harm when administered to a pregnant woman. 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 and for 1 month after the last dose
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose
Adverse events were manageable, mainly with dose holds or reductions, which allowed most patients to stay on therapy2
Serious adverse reactions occurred in 32% of patients who received Avmapki Fakzynja Co‑Pack. The most common (≥2%) serious adverse reactions were1:
- sepsis (9%)
- intestinal obstruction (3.6%)
- pyelonephritis (3.6%)
- 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%).1
The most common (≥25%) adverse reactions, including laboratory abnormalities, were1
- 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
- decreased neutrophil count
Most non-laboratory adverse events were Grade 1 or 22
Adverse Reactions (≥10%) in Patients in KRAS-Mutated Recurrent LGSOC Who Received Avmapki Fakzynja Co‑Pack in RAMP-2011*
| Adverse Reaction | Avmapki Fakzynja Co-Pack N = 57 |
|
|---|---|---|
| All Grades (%) | Grade 3 or 4† (%) | |
| Gastrointestinal disorders | ||
| Nausea | 74 | 1.8 |
| Diarrhea | 68 | 7 |
| Vomiting | 49 | 3.5 |
| Abdominal pain‡ | 39 | 1.8 |
| Dyspepsia‡ | 37 | 0 |
| Stomatitis‡ | 35 | 3.5 |
| Constipation | 30 | 0 |
| Dry mouth | 18 | 0 |
| Decreased weight | 11 | 0 |
| General disorders and administration site condition | ||
| Fatigue‡ | 72 | 3.5 |
| Edema‡ | 67 | 1.8 |
| Skin and subcutaneous tissue disorders | ||
| Rash§ | 72 | 3.5 |
| Dermatitis acneiformII | 37 | 5.3 |
| Pruritus‡ | 35 | 1.8 |
| Dry skin‡ | 30 | 0 |
| Alopecia‡ | 23 | 0 |
| Photosensitivity‡ | 16 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain1 | 68 | 1.8 |
| Joint swelling | 11 | 0 |
| Eye disorders | ||
| Vitreoretinal disorders¶ | 37 | 3.5 |
| Visual impairment# | 35 | 0 |
| Dry eye | 12 | 0 |
| Respiratory disorders | ||
| Dyspnea‡ | 26 | 5.3 |
| Cough | 25 | 0 |
| Nervous system disorders | ||
| Dizziness | 23 | 1.8 |
| Headache | 16 | 0 |
| Neuropathy peripheral‡ | 14 | 0 |
| Dysgeusia | 11 | 0 |
| Vascular disorders | ||
| Hemorrhage‡ | 23 | 0 |
| Hypertension | 16 | 5.3 |
| Venous thromboembolism‡ | 14 | 5.3 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 18 | 1.8 |
| Infections and infestations | ||
| Urinary tract infection | 25 | 3.5 |
| Paronychia | 14 | 1.8 |
| Upper respiratory tract infection | 11 | 0 |
*Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
†No Grade 4 treatment-emergent adverse events occurred
‡Includes multiple terms
§Includes: butterfly rash, dermatitis, drug eruption, erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic
IIIncludes: acne, dermatitis acneiform, folliculitis, perioral dermatitis, and rash pustular
¶Includes: chorioretinopathy, detachment of retinal pigment epithelium, macular fibrosis, macular hole, maculopathy, retinal
detachment, retinal drusen, retinal vein occlusion, retinopathy, serous retinal detachment, serous retinopathy, subretinal fluid, vitreous detachment, and vitreous floaters
#Includes: asthenopia, astigmatism, halo vision, metamorphopsia, photophobia, photopsia, vision blurred, visual field defect, and visual impairment
Clinically relevant adverse reactions in <10% of patients who received Avmapki Fakzynja Co‑Pack included urticaria and decreased ejection fraction.1
No grade 4 treatment-emergent adverse events occurred1
Proactive patient monitoring and management to help mitigate select adverse reactions1
OPHTHALMIC EXAMS
Refer patients to a qualified eye care professional for a comprehensive ophthalmologic exam at baseline, prior to cycle 2 and every 3 cycles thereafter, regardless of baseline exam findings, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs or symptoms.1
SKIN PROTECTION
Administer prophylactic medications for skin reactions with initiation of and during at least the first 2 cycles of Avmapki Fakzynja Co‑Pack including1:
- Topical corticosteroid applied to the face, scalp, neck, upper chest and upper back
- Systemic antibiotics
Monitor for skin toxicity.
LIVER FUNCTION TESTING
Inform patients that they will need to undergo laboratory testing to monitor their liver function prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. Advise them to contact their healthcare provider for signs or symptoms of liver dysfunction.1
CPK LEVEL MONITORING
Inform patients that they will need to undergo laboratory testing to monitor CPK levels prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. Advise them to contact their healthcare provider for signs or symptoms of rhabdomyolysis.1
PREGNANCY STATUS
Verify the pregnancy status of females of reproductive potential prior to initiating treatment.1
Testing and monitoring schedule1
| Liver Function Tests | CPK Evaluation | Eye Exams | Pregnancy Status | |
|---|---|---|---|---|
| BASELINE: Prior to cycle 1 |
X | X | X | X |
| Cycle 1 Day 15 | X | X | ||
| Prior to cycle 2 | X | X | X | |
| Cycle 2 Day 15 | X | X | Continue every 3 cycles and as clinically indicated | |
| Prior to cycle 3 | X | X | ||
| Cycle 3 Day 15 | X | X | ||
| Prior to cycle 4 | X | X | ||
| Cycle 4 Day 15 | X | X | ||
| Cycle 5 onward >> | Prior to each cycle (no Day 15) and as clinically indicated | |||
Incidence of dose modifications due to adverse events1
- 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%).
Dosing modifications to help manage adverse events
Learn more about specific dosing modifications based on adverse event and severity.
Drug Interactions1
- For patients requiring anticoagulation, an alternative to warfarin is recommended.
- If concomitant use is unavoidable, monitor INR frequently during treatment.
- Cases of bleeding and increased INR occurred in patients taking Fakzynja concomitantly with warfarin in clinical trials.
- Avoid concomitant use with proton pump inhibitors or H2 receptor antagonists.
- If concomitant use of gastric acid reducing agent cannot be avoided, administer Fakzynja 2 hours before or 2 hours after the administration of a locally acting antacid.
| Avoid concomitant use of Avmapki Fakzynja Co-Pack with: | |||
|---|---|---|---|
| Strong and moderate CYP3A4 inhibitors | Strong and moderate CYP3A4 inducers | Warfarin | Gastric acid reducing agents |
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; SPF, sun protection factor.
References: 1. Avmapki Fakzynja Co‑Pack. Prescribing Information. Verastem Inc; 2025. 2. Banerjee SN, et al. J Clin Oncol. 2025;43(25):2782-2792.