Avmapki-Fakzynja (avutometinib potassium/defactinib hydrochloride)

Dosage of avutometinib potassium is expressed in terms of avutometinib. Dosage of defactinib hydrochloride is expressed in terms of defactinib.

Clinicians should reduce the dosage of avutometinib and defactinib in patients who develop adverse effects (see Table 1).

Table 1. Dose Modifications for Toxicity.

Dose Level Avutometinib Capsules Defactinib Tablets Starting Dose 3.2 mg (four 0.8 mg) 200 mg (1 tablet) twice capsules twice weekly daily for the first 3 for the first 3 weeks of weeks of each 4-week each 4-week cycle cycle Dose Reduction 2.4 mg (three 0.8 mg) 200 mg (1 tablet) once capsules twice weekly daily for the first 3 for the first 3 weeks of weeks of each 4-week each 4-week cycle cycle

Permanently discontinue both avutometinib and defactinib if patients are unable to tolerate the agents after one dose reduction of both products. Table 2 summarizes dose modifications for specific adverse events.

Table 2. Specific Adverse Events Requiring Dose Modifications

Adverse Event Severity Dose Modification Keratitis Confluent superficial Withhold combination keratitis, a cornea therapy epithelial defect, or (avutometinib/defactinib >=3-line loss in Best ) until resolved to Corrected Distance nonconfluent superficial Visual Acuity (BCDVA) keratitis, then resume at the same dose Corneal ulcer or stromal Withhold combination opacity or BCDVA 20/200 therapy or worse (avutometinib/defactinib ) until resolved to nonconfluent superficial keratitis, then resume at the reduced dose Corneal perforation Permanently discontinue combination therapy (avutometinib/defactinib ) Blurred vision Best Correct Visual Withhold combination Acuity (BCVA) worse than therapy baseline but no worse (avutometinib/defactinib than 20/200 ) until resolution to baseline or 20/40, whichever is worse, then restart treatment at the same dose BCVA 20/200 or worse Withhold combination therapy (avutometinib/defactinib ) until resolution to baseline or 20/40, whichever is worse, then restart at reduced dose Conjunctivitis Confluent superficial Withhold combination punctate staining, therapy moderate to severe (avutometinib/defactinib vasodilation ) until resolution to nonconfluent superficial keratitis, then resume at the same dose Conjunctival ulcer or Withhold combination neovascularization therapy (avutometinib/defactinib ) until resolution to nonconfluent superficial keratitis, then resume at reduced dose Retinal pigment Not applicable First occurrence: repeat epithelial (RPE) optical coherence detachment tomography (OCT) examination in 2 weeks If at the first follow-up OCT examination, RPE is present: reduce the dose of combination therapy (avutometinib/defactinib ); repeat OCT examination in 2 weeks If at the sec ond follow-up OCT examination, RPE is present and/or there is loss of 1 line in BCVA: withhold combination therapy (avutometinib/ defactinib) and repeat OCT examination in 2 weeks If at the third follow-up OCT examination, RPE is resolving/resolved: resum e at reduced dose If there is no resolution, permanently discontinue combination therapy (avutometinib/defactinib ) Rash Grade <=2 If the rash does not respond to supportive care or recurs after resolution to Grade <=1: consider withholding combination therapy (avutometinib/defactinib ) If intolerable Grade 2 rash: reduce dose of combination therapy (avutometinib/defactinib ) Grade 3 Withhold combination therapy (avutometinib/defactinib ) until resolution to Grade 2 then resume at reduced dose; resume at same dose if resolved to Grade <=1 If recurrent Grade 3 rash despite dose reduction: permanently discontinue combination therapy (avut ometinib/defactinib) Grade 4 Permanently discontinue combination therapy (avutometinib/defactinib ) Hepatotoxicity Grade 2 Withhold combination therapy (avutometinib/defactinib ) if: Grade 2 hyperbilirubinemia (without Gilbert's syndrome) with Grade <=1 increase in AST and/or ALT until hyperbilirubinemia Grade <=1, then resume at same dose Grade 2 hyperbilirubinemia with Grade 2 increase in AST and/or ALT until hyperbilirubinemia Grade <=1 or baseline, the resume at same dose Permanently discontinue combination therapy (avutometinib/defactinib ) for Grade 2 hyperbilirubinemia associated with Grade >2 increase in AST and/or ALT Grade 3 Withhold combination therapy (avutometinib /defactinib) if: Grade 3 hyperbilirubinemia is associated with Grade <=1 increase in AST and/or ALT until hyperbilirubinemia is Grade <=1 or returns to baseline; restart at same dose Recurrent Grade 3 hyperbilirubi nemia is associated with a Grade <=1 increase in AST and/or ALT until hyperbilirubinemia is Grade <=2 or returns to baseline; resume at decreased dose Grade 3 increased AST and/or ALT is not associated with hyperbilirubinemia until Grade <=2 or returns to ba seline; resume at decreased dose Permanently discontinue combination therapy (avutometinib/defactinib ) for Grade 3 hyperbilirubinemia associated with Grade >=2 increase in AST and/or ALT Grade 4 Withhold combination therapy (avutometinib/defactinib ) if: Grade 4 hyperbilirubinemia associated with Grade <=1 increase in AST and/or ALT and if resolves within 1 week, restart at decreased dose Permanently discontinue combination therapy (avutometinib/de factinib) for a Grade 4 increase in AST and/or ALT; Grade 4 hyperbilirubinemia associated with Grade <=1 elevation in AST and/or ALT that doesn't resolve within 1 week; Grade 4 hyperbilirubinemia associated with Grade >=2 increase in AST and/or ALT Increased blood creatine Grade 3 Withhold combination phosphokinase (CPK) therapy (avutometinib/defactinib ) if CPK improves to Grade <=1 within 3 weeks; resume at same dose Grade 4 Withhold combination therapy (avutometinib/defactinib ); if CPK improves to Grade <=1 within 3 weeks, restart at decreased dose. Permanently discontinue combination regimen if CPK remains increased for >3 weeks Any grade CPK elevation Permanently discontinue with rhabdomyolysis or combination regimen other event related to (avutometinib/defactinib CPK elevation ) Other adverse events Grade 2 If the adverse event does not respond to supportive care or if it recurs after resolving to a Grade <=1 reaction, consider withholding the combination (avutometinib/defactinib ) Grade 3 First occurrence: Withhold combination therapy (avutometinib/defactinib ) until reaction resolves to baseline or to Grade <=1; resume at same dose Second occurrence: Withhold combination therapy until reaction resolves to baseline or to Grade <=1; resume at reduced dose Permanently discontinue combination regimen for recurrent Grade 3 reaction despite dose reduction Grade 4 Permanently discontinue combination therapy (avutometinib/defactinib )

Avutometinib is available as capsules and defactinib is available as tablets. The drugs are commercially available as a co-pack.

If a dose of avutometinib is missed by >24 hours, skip the missed dose and take the next dose at the regularly scheduled time. Do not take 2 doses at the same time. If a dose is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.

If a dose of defactinib is missed by >6 hours, skip the missed dose and take the next dose at the regularly scheduled time. Do not take 2 doses at the same time. If a dose is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.

No dosing information is available for this tab.

No dosing information is available for this tab.

Avutometinib is primarily metabolized by cytochrome (CYP) 3A4 and nonezymatic degradation. Defactinib is metabolized primarily by CYP3A4 and CYP2C9.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Avutometinib-Defactinib/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Avutometinib and defactinib are both CYP3A4 substrates. Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib. Avutometinib also undergoes non-enzymatic degradation is not affected by CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of defactinib and toxicity from avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular toxicities, and skin toxicities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of avutometinib-defactinib and moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. Defactinib maximum concentration (Cmax) increased by 2.2-fold and area-under-curve (AUC) by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax decreased by 6.8%.(1) No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Avutometinib-Defactinib/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Avutometinib and defactinib are CYP3A4 substrates. Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib. Avutometinib also undergoes non-enzymatic degradation is not affected by CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of defactinib and toxicity from avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular toxicities, and skin toxicities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of avutometinib-defactinib and strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Defactinib maximum concentration (Cmax) increased by 2.2-fold and area-under-curve (AUC) by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax decreased by 6.8%.(1) No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Defactinib/H2 Antagonists; Proton Pump Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer defactinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

Defactinib/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Moderate CYP3A4 inducers may accelerate the metabolism of defactinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of defactinib and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of defactinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of defactinib states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. In a study, defactinib maximum concentration (Cmax) decreased by 83% and area-under-curve (AUC) by 87% following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day 14. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 79% and 70%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Defactinib/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of defactinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of defactinib and strong CYP3A4 inducers may result in decreased levels and effectiveness of defactinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of defactinib states that the concurrent use of strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study, defactinib maximum concentration (Cmax) decreased by 83% and area-under-curve (AUC) by 87% following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day 14. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 79% and 70%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2)

Defactinib/Warfarin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism is unknown. Defactinib may inhibit the metabolism of warfarin by CYP2C9 or CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of defactinib may result in increased INR and risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent administration with warfarin should be avoided. If concurrent use cannot be avoided, monitor INR frequently during treatment with defactinib.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical trials, cases of bleeding and increased INR occurred in patients taking defactinib concomitantly with warfarin.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Increase Cpk/Aumolertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Defactinib/Antacids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration with antacids may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that patients requiring acid-lowering therapy should separate defactinib from antacid administration by 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of defactinib has not been investigated in clinical studies. In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

*None.

• Lactation

• Pregnancy

There are no moderate contraindications for this drug.

The most common adverse reactions reported in >=25% of patients receiving avutometinib in combination with defactinib, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased AST, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased ALT, 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.

Less Frequent

• Hydronephrosis
• Intestinal obstruction
• Pyelonephritis
• Sepsis

More Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Anemia
• Constipation
• Cough
• Diarrhea
• Dry skin
• Dyspepsia
• Dyspnea
• Edema
• Fatigue
• Hyperbilirubinemia
• Hypertriglyceridemia
• Increased creatine kinase level
• Lymphopenia
• Musculoskeletal pain
• Nausea
• Neutropenic disorder
• Pruritus of skin
• Skin rash
• Stomatitis
• Thrombocytopenic disorder
• Urinary tract infection
• Visual changes
• Vomiting

Less Frequent

• Alopecia
• Anorexia
• Dizziness
• Dry eye
• Dysgeusia
• Headache disorder
• Hemorrhage
• Hypertension
• Hypoalbuminemia
• Hypokalemia
• Paronychia
• Periorbital edema
• Peripheral neuropathy
• Proteinuria
• Retinal detachment
• Skin photosensitivity
• Upper respiratory infection
• Venous thrombosis
• Vitreous floater
• Weight loss
• Xerostomia

No enhanced messaging available.

The safety and efficacy of avutometinib/defactinib have not been established in pediatric patients.

Based on its mechanism of action, the combination regimen (avutometinib/defactinib) may cause fetal harm if administered to pregnant women. Reproductive and developmental toxicity studies have not been conducted in animals. Confirm pregnancy status prior to initiation of therapy in females of reproductive potential. Apprise pregnant women and females of reproductive potential of the drug-associated risk to the fetus.

It is not known whether avutometinib, defactinib, or their metabolites are distributed into human milk; the effects of the drug on breastfed infants or on milk production are also unknown. Lactating women should not breastfeed during treatment and for 2 weeks following the last dose because of the potential risk of serious harm to the breastfed child.

There are no specific dosage recommendations for geriatric patients.

Of the 136 patients in clinical trials of avutometinib/defactinib, 29% were >=65 years of age. No overall differences in the safety of avutometinib/defactinib were observed between geriatric and younger patients; however there was an insufficient number of patients >=65 years of age to determine if these patients respond differently to therapy from younger patients.