axitinib (Rx)

Brand and Other Names:Inlyta
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 1mg
  • 5mg

Renal Cell Carcinoma

Monotherapy

  • Indicated for advanced renal cell carcinoma (RCC) in patients who failed 1 prior systemic therapy
  • 5 mg PO BID initially

Combination therapy with avelumab

  • Indicated in combination with avelumab for first-line treatment of advanced RCC
  • Axitinib 5 mg PO BID, plus
  • Avelumab 800 mg IV q2Weeks
  • Continue until disease progression or unacceptable toxicity
  • During combination therapy with avelumab, consider escalating dose of axitinib above 5 mg/dose in 2-week intervals or longer
  • Refer the prescribing information of avelumab for dosing information

Combination therapy with pembrolizumab

  • Indicated in combination with pembrolizumab for first-line treatment of advanced RCC
  • Axitinib 5 mg PO BID, plus
  • Pembrolizumab 200 mg IV q3Weeks or 400 mg IV q6Weeks
  • Continue until disease progression or unacceptable toxicity
  • During combination therapy with pembrolizumab, consider escalating dose of axitinib above 5 mg/dose in 6-week intervals or longer
  • Refer the prescribing information of pembrolizumab for dosing information

Dosage Modifications

Dose increase or reduction based on individual safety and tolerability

Dose escalation

  • Criteria: Tolerated for at least 2 consecutive weeks with no Grade >2 adverse reactions and are normotensive and not receiving antihypertension medications
  • First dose increase: 7 mg PO BID
  • Second dose increase: Using the same criteria, may further increase to 10 mg PO BID

Dose reduction

  • Management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of therapy
  • Current dose is 5 mg PO BID: Reduce 3 mg PO BID
  • If additional dose reduction is required, reduce to 2 mg PO BID

Strong CYP3A4/5 inhibitors

  • Avoid coadministration
  • Use an alternative with no CYP3A4/5 inhibition potential
  • Although dose adjustment has not been studied, if a strong CYP3A4/5 inhibitor must be coadministered, decrease dose of axitinib by ~50%
  • Subsequent doses can be increased or decreased based on individual safety and tolerability
  • If strong inhibitor is discontinued, resume axitinib dose (after 3-5 half-lives of the inhibitor) to before initiating the strong CYP3A4/5 inhibitor

Hepatotoxicity (combination with avelumab)

  • Refer prescribing information for avelumab for dosage modifications
  • ALT or AST ≥3x to <5x ULN or total bilirubin ≥1.5x ULN but <3x ULN
    • Withhold both axitinib and avelumab until these adverse reactions recover to Grade ≤1
    • If persistent (>5 days), consider corticosteroid therapy (initial dose of 0.5-1 mg/kg/day) prednisone or equivalent followed by a taper
    • Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery
    • If rechallenging axitinib, consider dose reduction as listed above
  • ALT or AST ≥5x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN or total bilirubin ≥3x ULN
    • Permanently discontinue both axitinib and avelumab
    • Consider corticosteroid therapy (initial dose 1-2 mg/kg/day prednisone or equivalent followed by a taper)
  • Hepatotoxicity (combination with pembrolizumab)

  • Refer prescribing information for pembrolizumab for dosage modifications
  • ALT or AST ≥3x to <10x ULN without concurrent total bilirubin ≥2x ULN
    • Withhold both axitinib and pembrolizumab until these adverse reactions recover to Grade ≤1
    • Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery
    • If rechallenging axitinib, consider dose reduction as listed above
  • ALT or AST ≥10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN
    • Permanently discontinue both axitinib and pembrolizumab
    • Consider corticosteroid therapy

Renal & Hepatic Impairment

Renal impairment

  • No dedicated renal impairment trial has been conducted
  • Based on population pharmacokinetic analyses, no significant difference in clearance observed in patients with pre-existing mild-to-severe renal impairment

Hepatic impairment

  • Mild (Child-Pugh A): No adjustment of initial dose is required
  • Moderate (Child-Pugh B): Decrease initial dose by ~50%; subsequent doses can be increased or decreased based on individual safety and tolerability
  • Severe (Child-Pugh C): Has not been studied

<18 years: Safety and efficacy not established

In clinical trials, 34% of participants 65 years or older

No overall differences were observed in the safety or efficacy between elderly and younger patients

No dosage adjustment required in elderly patients

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Interactions

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and axitinib

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            Adverse Effects

            >10%

            Diarrhea (55%)

            Hypertension (40%)

            Fatigue (39%)

            Decreased appetite (34%)

            Nausea (32%)

            Dysphonia (31%)

            Palmar-plantar erythrodysesthesia syndrome (27%)

            Weight decreased (25%)

            Vomiting (24%)

            Asthenia (21%)

            Constipation (20%)

            Hypothyroidism (19%)

            Cough (15%)

            Mucosal inflammation (15%)

            Arthralgia (15%)

            Stomatitis (15%)

            Dyspnea (15%)

            Abdominal pain (14%)

            Headache (14%)

            Extremity pain (13%)

            Rash (13%)

            Proteinuria (11%)

            Dysgeusia (11%)

            1-10%

            Dry skin (10%)

            Dyspepsia (10%)

            Dizziness (9%)

            Upper abdominal pain (8%)

            Myalgia (7%)

            Pruritus (7%)

            Dehydration (6%)

            Epistaxis (6%)

            Hypercalcemia (6%)

            Anemia (4%)

            Alopecia (4%)

            Hemorrhoids (4%)

            Hematuria (3%)

            Tinnitus (3%)

            Increased lipase (3%)

            Glossodynia (3%)

            Pulmonary embolism (2%)

            Rectal hemorrhage (2%)

            Hemoptysis (2%)

            Erythema (2%)

            DVT (1%)

            Retinal vein occlusion/thrombosis (1%)

            Polycythemia (1%)

            TIA (1%)

            <1%

            Reversible posterior leukoencephalopathy syndrome

            Postmarketing Reports

            Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture

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            Warnings

            Contraindications

            None

            Cautions

            Hypertension and hypertensive crisis reported in clinical trials, typically within the first month of treatment; blood pressure increases may appear as early as 4 days after initiating; blood pressure should be well controlled before starting therapy; dosage modification or discontinuation of treatment may be required (see Dosage Modification)

            Although rare, arterial thromboembolic events (including deaths) reported during clinical trials

            Venous thromboembolic events (eg, DVT, PE, retinal vein occlusion, retinal vein thrombosis) reported, including deaths

            Hemorrhagic events (eg, cerebral hemorrhage, hematuria, hemoptysis, GI bleeding, melena) may occur

            Rare occurrences of GI perforation and fistula formation reported

            May cause thyroid dysfunction; monitor thyroid function before initiating and periodically throughout therapy

            Stop treatment 24 hr before scheduled surgery

            May cause proteinuria; monitor proteinuria before initiating and periodically throughout therapy

            Elevated liver enzymes reported; monitor ALT, AST, and bilirubin

            Moderate hepatic impairment requires dose reduction (see Dosage modification)

            Coadministration with strong CYP3A4/5 inhibitors or inducers should be avoided if possible (see Dosage modifications)

            Cardiac failure reported with axitinib use; monitor for signs or symptoms of cardiac failure throughout treatment; may require permanent discontinuation of axitinib

            Impaired wound healing

            • Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway
            • Therefore axitinib has the potential to adversely affect wound healing
            • Withhold for at least 2 days prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing
            • Safety of resumption after resolution of wound healing complications has not been established

            Major adverse cardiovascular events (MACE)

            • Combination therapy with avelumab may cause severe and fatal cardiovascular events
            • Consider baseline and periodic evaluations of left ejection fraction; monitor signs and symptoms of cardiovascular events
            • Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia
            • Discontinue axitinib and avelumab for Grade 3-4 cardiovascular events

            In combination with avelumab or with pembrolizumab

            • Combination with avelumab or with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation; consider more frequent monitoring of liver enzymes as compared to when drugs are used as monotherapy
            • Withhold axitinib and avelumab for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity; administer corticosteroids as needed
            • For elevated liver enzymes, interrupt axitinib and pembrolizumab and consider administering corticosteroids as needed

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            Pregnancy & Lactation

            Pregnancy

            Based on mechanism of action and findings from animal studies, drug can cause fetal harm when administered to a pregnant woman; there are no available human data to inform drug-associated risk; in developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at recommended clinical dose

            When used in combination with avelumab or pembrolizumab, refer to full prescribing information of avelumab or pembrolizumab for pregnancy information

            Animal data

            • Therapy administered twice daily to female mice prior to mating and through first week of pregnancy caused increase in post-implantation loss at all doses tested (greater than or equal 15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at recommended starting dose)
            • Based on findings in animal studies, drug can cause fetal harm when administered to a pregnant woman; females of reproductive potential should have a pregnancy test prior to starting treatment

            Contraception

            • Females: Therapy can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 1 week after last dose
            • Males: Based on findings in animal studies, advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose
            • When is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for contraception information

            Infertility

            • Based on findings in animals, therapy may impair fertility in females and males of reproductive potential

            Lactation

            There are no data on presence of drug in human milk, or effects on breastfed child or on milk production; because of potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment and for 2 weeks after final dose

            When used in combination with avelumab or pembrolizumab, refer to full prescribing information of avelumab or pembrolizumab for lactation information

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Multi-targeted tyrosine kinase inhibitor

            Inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3

            Absorption

            Bioavailability: 58%

            Peak Plasma Time: 2.5-4.1 hr

            Peak Plasma Concentration: 27.8 ng/mL

            AUC: 265 ng•h/mL

            Distribution

            Protein Bound: >99% (mostly to albumin, moderately to alpha1-acid glycoprotein)

            Vd: 160 L

            Metabolism

            Metabolized primarily by CYP3A4/5 and to a lesser degree by CYP1A2, CYP2C19, and UGT1A1

            Metabolites: Plasma levels detected the N-glucuronide metabolite (50%), sulfoxide metabolite (20%), and 20% unchanged drug

            Elimination

            Half-life: 2.5-6.1

            Total body clearance: 38 L/h

            Excretion: feces 41% (12% unchanged), urine 23% (as carboxylic acid and sulfoxide metabolites)

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            Administration

            Oral Administration

            Administer twice daily ~12 hr apart

            May be taken with or without food

            Swallow tablet whole with a glass of water; do not split, crush, or chew

            If patient vomits or misses a dose, an additional dose should not be taken; the next prescribed dose should be taken at the usual time

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.