Ensacove (ensartinib hydrochloride)

Dosage of ensartinib hydrochloride is expressed in terms of ensartinib.

If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of ensartinib may be necessary. If dosage reduction is necessary, an initial reduction to 200 mg once daily is recommended. If further dosage reduction is necessary, the dosage should be reduced to 150 mg once daily. Once the dosage has been reduced for adverse reactions, do not subsequently increase the dose of ensartinib. If a dosage of 150 mg is not tolerated, ensartinib should be permanently discontinued.

Administer ensartinib orally once daily, at the same time each day, with or without food.

The capsules should be swallowed whole and should not be crushed, chewed, or opened; the contents should not be dissolved.

If a dose of ensartinib is missed, take the missed dose as soon as it is remembered, unless the next dose is due within 12 hours.

If vomiting occurs after administration of ensartinib, do not take an additional dose, and take the next dose at its scheduled time.

Store capsules at 20-25degreesC (excursions permitted to 15-30degreesC). Store in the original container with dessicant to protect from moisture.

No dosing information is available for this tab.

Ensartinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.

In vitro studies indicate that ensartinib is a substrate of P-glycoprotein (P-gp), but is not a substrate of breast cancer resistance protein (BCRP), organic anion protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, or OCT 2.

In vitro studies indicate that ensartinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.

In vitro studies indicate that ensartinib also does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, or OCT3.

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

Ensartinib/Dual Moderate Cyp3a4 & P-Gp 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: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1)

CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and moderate CYP3A4 inhibitors linked to this monograph include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, Schisandra, and verapamil.(2,3)

Ensartinib/Dual Moderate Cyp3a4 Inducers & P-Gp 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: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inducers of CYP3A4 may induce the metabolism of ensartinib while inhibitors of P-gp may increase the absorption of ensartinib.(1)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of ensartinib with CYP3A4 inducers may result in decreased levels and effectiveness of ensartinib while concurrent use of P-gp inhibitors may result in elevated systemic levels and toxicity from ensartinib.(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 ensartinib states concurrent use with both P-gp inhibitors and moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual moderate CYP3A4 inducers and P-gp inhibitors linked to this monograph include: elagolix and sotorasib.(2,3)

Ensartinib/Dual Strong Cyp3a4 & P-Gp 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: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1)

CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and strong CYP3A4 inhibitors linked to this monograph include: boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib.(2,3)

Ensartinib/Dual Strong Cyp3a4 Inducers & P-Gp 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: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inducers of CYP3A4 may induce the metabolism of ensartinib while inhibitors of P-gp may increase the absorption of ensartinib.(1)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of ensartinib with CYP3A4 inducers may result in decreased levels and effectiveness of ensartinib while concurrent use of P-gp inhibitors may result in elevated systemic levels and toxicity from ensartinib.(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 ensartinib states concurrent use with both P-gp inhibitors and strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual strong CYP3A4 inducers and P-gp inhibitors linked to this monograph include: enzalutamide, lumacaftor-ivacaftor, and St. John's wort.(2,3)

Ensartinib/Selected 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 inducers of CYP3A4 may induce the metabolism of ensartinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1)

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

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

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)

Ensartinib/Selected 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: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by moderate CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)

Ensartinib/Selected P-Glycoprotein (P-Gp) 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: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1)

CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, vilazodone, vimseltinib, and voclosporin.(2,3)

Ensartinib/Selected 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 inducers of CYP3A4 may induce the metabolism of ensartinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1)

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

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

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3)

Ensartinib/Selected 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: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by strong CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, ensitrelvir, grapefruit, idelalisib, relacorilant, ribociclib, troleandomycin, and voriconazole.(2,3)

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

Selected Strong Cyp3a4 Inhibitors/Atorvastatin

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

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may 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.

PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially with higher atorvastatin doses. Patients should be instructed to report any signs of myopathy.(1) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving strong CYP3A4 inhibitors.

DISCUSSION: Atorvastatin is a CYP3A4 substrate.(1) In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) Concurrent administration of atorvastatin (40 mg for 4 days) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: ceritinib, ensartinib, idelalisib, josamycin, mifepristone, relacorilant, troleandomycin, and tucatinib.(2,3)

There are no moderate interactions for this drug.

*Hypersensitivity reaction to ensartinib hydrochloride, FD&C Yellow No. 5 (tartrazine), or to any of its components.

• Lactation

• Pregnancy

• Bradycardia
• Diabetes mellitus
• Hyperuricemia
• Interstitial lung disease

The most common adverse reactions (incidence >=20%) reported with ensartinib in clinical studies were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia.

Less Frequent

• Hemorrhage
• Pneumonia

Rare or Very Rare

• Cellulitis
• DRESS syndrome
• Drug-induced hepatitis

More Frequent

• Abnormal hepatic function tests
• Anemia
• Constipation
• Cough
• Edema
• Elevated serum amylase
• Fatigue
• Fever
• Gamma-glutamyl transferase raised
• Hyperbilirubinemia
• Hyperglycemia
• Hypermagnesemia
• Hyperuricemia
• Hypoalbuminemia
• Hypocalcemia
• Hypokalemia
• Hyponatremia
• Hypophosphatemia
• Increased creatine kinase level
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lymphopenia
• Musculoskeletal pain
• Nausea
• Pruritus of skin
• Skin rash
• Vomiting

Less Frequent

• Alopecia
• Anorexia
• Bradycardia
• Dizziness
• Dry skin
• Dysgeusia
• Interstitial pneumonitis
• Skin photosensitivity
• Upper respiratory infection
• Visual changes

No enhanced messaging available.

Safety and efficacy of ensartinib have not been established in pediatric patients <18 years of age.

There are no available human data on ensartinib use in pregnant women. However, based on animal studies, ensartinib can cause fetal harm when administered during pregnancy. When administered to pregnant rats, embryo-fetal mortality, alterations to growth, and structural abnormalities occurred at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg per day.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Verify the pregnancy status of females of reproductive potential prior to initiating ensartinib.

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with ensartinib and for 1 week after the last dose.

It is not known whether ensartinib is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. However, because of the potential for adverse effects in breastfed children, advise women not to breastfeed during treatment with ensartinib and for 1 week after the last dose.

The manufacturer makes no specific dosage recommendations for patients with renal impairment.

In clinical studies, 16% of 458 patients were >=65 years of age. Exploratory analysis suggests that geriatric patients (>=65 years of age) experience a higher incidence of serious adverse events (43% vs 27%), more frequent adverse events leading to treatment discontinuations (18% vs 10%), and dose modifications (34% vs 16%) when compared to patients <65 years of age.