Inlyta (axitinib)

Adjustment of axitinib dosage is recommended based on individual safety and tolerability. Recommended dosage reductions for adverse reactions are provided in Table 1.

Table 1: Recommended Dosage Reductions for Axitinib Toxicity.

Dosage Reduction Level Recommended Dosage First dose reduction 3 mg twice daily Second dose reduction 2 mg twice daily

Axitinib is administered orally twice daily (in doses given approximately 12 hours apart). The drug may be given without regard to meals. Axitinib tablets should be swallowed whole with a full glass of water; the tablets should not be crushed or split.

If a dose of axitinib is missed or vomited, patients should not double the dosage or take extra doses. The next dose should be taken at the regularly scheduled time.

For patients unable to swallow tablets in clinical trials, axitinib tablets have been dissolved (without crushing) in 15 mL of USP-grade water in an amber-colored syringe and administered through a nasogastric tube; use of tap or bottled water was avoided. The nasogastric tube should be flushed with 15 mL of USP-grade water prior to and following administration of the dose. The prepared dose should not be exposed to direct light and should be prepared just prior to administration.

Procedures for proper handling of antineoplastic drugs should be followed when preparing doses of axitinib for nasogastric administration.

Store axitinib tablets at 20-25oC; excursions permitted between 15-30oC.

No dosing information is available for this tab.

Axitinib is metabolized principally by the cytochrome P-450 (CYP) isoenzyme 3A4/5 and, to a lesser extent, by CYP1A2, CYP2C19, and uridine diphosphate-glucurosyltransferase (UGT) 1A1 in vitro.

In vitro studies demonstrate that axitinib has the potential to inhibit CYP isoenzymes 1A2 and 2C8.

In vitro studies indicate that axitinib does not inhibit CYP2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or UGT1A1 at therapeutic plasma concentrations.

Axitinib inhibits P-glycoprotein (P-gp) in vitro; however, the drug is not expected to inhibit P-gp at therapeutic plasma concentrations.

Axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5 in human hepatocytes in vitro.

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

Axitinib/Strong & 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: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of axitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of axitinib.(1)

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with axitinib.(1) Consider the use of alternatives with little to no induction potential.(1)

DISCUSSION: Rifampin (600 mg daily for 9 days), a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of axitinib to less than half and less than 25% of levels seen without concurrent rifampin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(1-3)

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

Axitinib/Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of axitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from axitinib, including hypertension, thromboembolic events, or hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with axitinib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use with axitinib is warranted, consider decreasing the dose of axitinib by one-half (e.g. start with an initial dose of 2 mg twice daily). Subsequent doses may be increased or decreased based on patient response. When the CYP3A4 inhibitor has been discontinued, allow a washout period equal to 3-5 half-lives of the inhibitor before increasing the dose of axitinib.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: Ketoconazole (400 mg twice daily, a strong inhibitor of CYP3A4) increased the maximum concentration (Cmax) and area-under-curve (AUC) of axitinib (5 mg) by approximately 1.5-fold and 2-fold, respectively. Recommended dosage adjustments are expected to produce AUC levels comparable to axitinib administered without a strong CYP3A4 inhibitor; however, no data is available.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

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

Anti-Angiogenic Agents/Erlotinib

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

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of anti-angiogenic agents may increase the risk of gastrointestinal perforation in patients receiving erlotinib. Fatalities have been reported.(1)

PREDISPOSING FACTORS: Patients with a history of peptic ulceration or diverticular disease or who are receiving concomitant corticosteroids, NSAIDs, and/or taxane-based chemotherapy may be an increased risk of gastrointestinal perforation.(1)

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(1)

DISCUSSION: In a phase II trial of concurrent bevacizumab plus erlotinib, 2 of 13 patients suffered fatal gastrointestinal perforations.(2) In another phase II trial of concurrent bevacizumab with erlotinib, 1 of 104 patients died of gastrointestinal perforation.(3)

None.

• Arterial aneurysm
• Arterial dissection
• Lactation

• Acute myocardial infarction
• Cerebral metastases
• Cerebrovascular accident
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Deep venous thrombosis
• Disease of liver
• Gastrointestinal hemorrhage
• Hypertension
• Impaired wound healing
• Intracerebral hemorrhage
• Posterior reversible encephalopathy syndrome
• Pregnancy
• Proteinuria
• Pulmonary thromboembolism
• Retinal vascular occlusion
• Thromboembolic disorder
• Transient cerebral ischemia

• Gastrointestinal fistula
• Gastrointestinal perforation
• Hypothyroidism

Adverse effects occurring in 20% or more of patients receiving axitinib in combination with avelumab for first-line treatment of advanced renal cell carcinoma were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia (hand-foot syndrome), dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.

Adverse effects occurring in 20% or more of patients receiving axitinib in combination with pembrolizumab for first-line treatment of advanced renal cell carcinoma were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia (hand-foot syndrome), nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Adverse effects occurring in 20% or more of patients receiving axitinib for the second-line treatment of advanced renal cell carcinoma in the randomized trial were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, vomiting, asthenia, and constipation.

More Frequent

• Hemorrhage
• Hypertension
• Hypothyroidism
• Increased alanine transaminase
• Increased aspartate transaminase
• Leukopenia
• Lymphopenia
• Thrombocytopenic disorder

Less Frequent

• Acute myocardial infarction
• Anemia
• Arterial thrombosis
• Deep venous thrombosis
• Heart failure
• Hemoptysis
• Hyperbilirubinemia
• Hypercalcemia
• Hyperthyroidism
• Pulmonary thromboembolism
• Rectal bleeding
• Retinal thrombosis
• Thromboembolic disorder
• Thrombotic disorder

Rare or Very Rare

• Abnormal hepatic function tests
• Arterial aneurysm
• Arterial dissection
• Gastrointestinal fistula
• Gastrointestinal perforation
• Hepatic failure
• Hypertensive crisis
• Impaired wound healing
• Intracerebral hemorrhage
• Posterior reversible encephalopathy syndrome
• Transient cerebral ischemia

More Frequent

• Acute abdominal pain
• Anorexia
• Arthralgia
• Constipation
• Cough
• Dehydration
• Diarrhea
• Dizziness
• Dry skin
• Dysgeusia
• Dyspepsia
• Dyspnea
• Epistaxis
• Fatigue
• General weakness
• Headache disorder
• Myalgia
• Nausea
• Palmar-plantar erythrodysesthesia
• Proteinuria
• Pruritus of skin
• Skin rash
• Stomatitis
• Voice change
• Vomiting
• Weight loss

Less Frequent

• Alopecia
• Elevated serum lipase
• Erythema
• Erythrocytosis
• Hemorrhoids
• Sore tongue

No enhanced messaging available.

Safety and efficacy of axitinib have not been established in pediatric patients younger than 18 years of age. The pharmacokinetics of axitinib also have not been studied in pediatric patients.

Toxicities in bone (e.g., thickened growth plates) and teeth (e.g., abnormalities in growing incisor teeth, including dental caries, malocclusions, broken and/or missing teeth) have been observed in immature animals receiving oral axitinib for one month or longer. Other toxicities of potential concern in pediatric patients have not been evaluated to date in juvenile animal studies.

Axitinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

There are no available human data to inform the drug-associated risk.

It is not known whether axitinib is distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk are unknown. Because of the potential for adverse reactions to axitinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose.

No dosage adjustment is necessary in geriatric patients.

In controlled clinical studies evaluating axitinib in patients with renal cell carcinoma either as a single agent or in combination with avelumab or pembrolizumab, 34-40% of patients were 65 years of age or older. Although no overall differences in safety and efficacy were observed between patients 65 years of age or older and younger patients, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.