Defactinib

Defactinib is a prescription medication indicated in combination with avutometinib for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) in adults who have received prior systemic therapy.

Defactinib is available under the following different brand names: Fakzynja

Common side effects of Defactinib include:

• nausea 
• decreased hemoglobin
• abdominal pain 
• cough
• tiredness
• increased alanine aminotransferase
• acid reflux
• urinary tract infection
• increased aspartate aminotransferase
• vomiting
• increased alkaline phosphatase
• decreased lymphocytes
• increased blood bilirubin
• decreased neutrophils
• diarrhea
• increased triglycerides
• decreased platelets
• proteinuria
• edema
• constipation
• shortness of breath

Serious side effects of Defactinib include:

• eye problems may cause symptoms like changes in vision, such as blurred vision, double vision, or vision loss, eye pain, dry eye(s), new or increased floaters (small dark spots or squiggly lines that float across your vision), eye and eyelid inflammation, including redness, swelling, and itching, light hurting eyes or seeing flashes of light
• symptoms of severe skin reactions may include skin rash or acne, skin blistering or peeling, blisters or sores in the mouth, dry skin, redness or swelling of the face, hands, soles of the feet, itching, skin infection 
• liver problems may cause symptoms like yellowing of the skin and white of the eyes, nausea or vomiting, itchy skin, pain on the right side of the abdomen, feeling very tired, dark urine, flu-like symptoms, bleeding or bruising more than normal
• rhabdomyolysis may cause symptoms like weakness or difficulty moving arms and legs, muscle or bone aches or pain that does not go away, dark, red colored urine, decreased urine output

Rare side effects of Defactinib include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 200 mg
• Co-packaged with Avmapki (avutometinib)

Ovarian Cancer

Adult dosage

• 200 mg orally twice daily for the first 3 weeks of each 4-week cycle plus
• Avutometinib 3.2 mg orally twice per week (on Days 1 and 4) for the first 3 weeks of each 4-week cycle
• Continue therapy until disease progression or unacceptable toxicity

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Drug interaction overview

Defactinib is a moderately sensitive CYP3A4 substrate

• Strong or moderate CYP3A4 inhibitors
  • Avoid coadministration
  • Use together may increase defactinib and the risk of adverse effects
• Strong or moderate CYP3A4 inducers
  • Avoid coadministration
  • Using together may decrease defactinib exposure and reduce efficacy
• Gastric acid reducing agents
  • Avoid coadministration with proton pump inhibitors (PPIs) or H2 antagonists
  • Defactinib displays pH-dependent aqueous solubility
  • Using together may decrease defactinib exposure and reduce efficacy
  • Administer defactinib 2 hours before or after PPI or H2 antagonist if concomitant use cannot be avoided
• Warfarin
  • Avoid coadministration; use an alternate agent for anticoagulation
  • If concomitant use is unavoidable, monitor INR frequently during therapy
  • Bleeding and increased INR were reported in patients taking defactinib concomitantly with warfarin in clinical trials

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Defactinib?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Defactinib?”

Cautions

Ocular toxicity

• Can cause ocular adverse reactions, including visual impairment and vitreoretinal disorders
• Median time to onset of symptomatic ocular adverse reactions: 5 days (range, 1-943)
• Median time to onset of asymptomatic ocular adverse reactions: 112 days (range, 23-943)
• Median time to onset of retinal detachment: 27 days (range, 2-535)
• Monitor for ocular adverse reactions
• Perform a comprehensive ophthalmic exam at baseline, before cycle 2, 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
• Hold, reduce dosage, or permanently discontinue based on the severity and persistence of adverse reaction

Skin toxicity

• Can cause serious skin toxicities, including severe cutaneous adverse reactions (SCARs)
• Median time to onset of skin toxicity: 14 days (range, 1-500)
• Bacterial skin infections may develop
• Limit sunlight exposure and apply daily sunscreen (sun protection factor [SPF] greater than 30)
• Starting at the beginning of therapy and continuing at least the first 2 cycles
• Apply topical corticosteroids to the face, scalp, neck, upper chest, and upper back
• Give systemic oral antibiotics for the prophylaxis of skin adverse reactions
• Hold, reduce dosage, or permanently discontinue based on the severity and persistence of adverse reaction

Hepatotoxicity

• Can cause hepatotoxicity
• Hyperbilirubinemia may be caused by defactinib due to inhibition of UGT1A1 and OATP1B1/1B3
• Monitor liver function tests before starting each cycle, on day 15 of the first 4 cycles, and as clinically indicated
• Hold, reduce dosage, or permanently discontinue based on the severity and duration of the adverse reaction

Rhabdomyolysis

• Can cause increased creatinine phosphokinase (CPK) levels
• Monitor CPK before starting each cycle, on day 15 of the first 4 cycles, and as clinically indicated
• Evaluate for rhabdomyolysis or other causes in patients who develop increased CPK levels
• Hold, reduce dosage, or permanently discontinue based on the severity and duration of the adverse reaction

Embryo-fetal toxicity

• May cause fetal harm when administered during pregnancy, based on the mechanism of action
• Advise pregnant patients and females of reproductive potential of the risk to the fetus
• Effective contraception is recommended during and after therapy for females of reproductive potential and males with female partners of reproductive potential

Pregnancy and Lactation

• May cause fetal harm when administered during pregnancy, based on its mechanism of action
• No available data on use in pregnant patients to inform drug-associated risk
• Animal reproductive and developmental toxicity studies have not been conducted with defactinib
• Inhibition of the same molecular pathway has been associated with embryo-fetal anomalies and lethality in animals
• Verify the pregnancy status of females of reproductive potential before starting therapy
• Advise pregnant patients and females of reproductive potential of fetal risk
• Contraception requirements
  • Females of reproductive potential: Use effective contraception during therapy and for 1 month after the last dose
  • Male patients with female partners of reproductive potential: Use effective contraception during therapy and for 4 months after the last dose

Infertility

• May impair fertility in females and males of reproductive potential, based on data from animal studies
• Effects on fertility were not reversible in animals

Lactation

• No data on the presence of defactinib or its metabolites in human milk or on the effects on breastfed children or milk production
• Avoid breastfeeding during therapy and for 2 weeks after the last dose due to the potential for serious adverse reactions in breastfed children