DRUG INTERACTIONS(summary)

1 Effect of Other Drugs on FOTIVDA Strong CYP3A Inducers-                              Concomitant use of FOTIVDA with a strong CYP3A inducer decreases tivozanib exposure , which may reduce FOTIVDA anti-tumor activity.

Avoid concomitant use of strong CYP3A inducers with FOTIVDA.

BRIEF SUMMARY

 TIVOZANIB-(Mar 2021)

Indn-    To treat patients with renal cell carcinoma 

Comp-   Capsules: 1.34 mg and 0.89 mg                                                          Recommended Dose: 1.34 mg once daily with or without food for 21 days on treatment followed by 7 days off treatment until disease progression or unacceptable toxicity

ADR- The most common adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis,

CI- None.

 WARNINGS-

 • Hypertension and Hypertensive Crisis: Control blood pressure prior to initiating the drug.. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the  dose.

Pat Inform-

Hypertension and Hypertensive Crisis-                                                                        Inform patients that hypertension or hypertensive crisis may occur during treatment.

Advise patients to undergo routine blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 12

Name of the Drug-    FOTIVDA

Active Ingredient -   Tivozanib

Pharmacological Classification-    To treat patients with renal cell carcinoma                                                                                                                                                         

Date of Approval-          3/10/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                       FOTIVDA safely and effectively.                                                                                    See full prescribing information for FOTIVDA. FOTIVDA® (tivozanib) capsules, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 FOTIVDA is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies.

ADVERSE REACTIONS

 The most common (=20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis, and the most common Grade 3 or 4 laboratory abnormalities (=5%) were sodium decreased, lipase increased, and phosphate decreased.

CONTRAINDICATIONS

 None.

 WARNINGS AND PRECAUTIONS

 • Hypertension and Hypertensive Crisis: Control blood pressure prior to initiating FOTIVDA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the FOTIVDA dose.

 • Cardiac Failure: Monitor for signs or symptoms of cardiac failure throughout treatment with FOTIVDA.

 • Cardiac Ischemia and Arterial Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe arterial thromboembolic events, such as myocardial infarction and stroke.

 • Venous Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe venous thromboembolic events. 

• Hemorrhagic Events: Closely monitor patients who are at risk for or who have a history of bleeding.

• Proteinuria: Monitor throughout treatment with FOTIVDA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with FOTIVDA.

 • Thyroid Dysfunction: Monitor before initiation and throughout treatment with FOTIVDA.

• Risk of Impaired Wound Healing: Withhold FOTIVDA for at least 24 days before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of FOTIVDA after resolution of wound healing complications has not been established.

 • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue FOTIVDA if signs or symptoms of RPLS occur.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.

 • Allergic Reactions to Tartrazine: The 0.89 mg capsule of FOTIVDA contains FD&C Yellow No.5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients.

DOSAGE AND ADMINISTRATION

• Recommended Dose: 1.34 mg once daily with or without food for 21 days on treatment followed by 7 days off treatment (28-day cycle) until disease progression or unacceptable toxicity.

 • Dose interruptions and/or dose reduction may be needed to manage adverse reactions.

 • For patients with moderate hepatic impairment, reduce the dose to 0.89 mg for 21 days on treatment followed by 7 days off treatment (28-day cycle). (2.3)

DOSAGE FORMS AND STRENGTHS

 Capsules: 1.34 mg and 0.89 mg 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypertension and Hypertensive Crisis-                                                                        Inform patients that hypertension or hypertensive crisis may occur during FOTIVDA treatment.

Advise patients to undergo routine blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated.

Advise patients that if they experience signs or symptoms of hypertension to immediately contact their healthcare provider 

Cardiac Failure -                                                                                                        Advise patients to immediately contact their healthcare provider if they develop symptoms of cardiac failure 

Cardiac Ischemia and Arterial Thromboembolic Events-                                            Inform patients that arterial thromboembolic events (including fatal outcomes) may occur during FOTIVDA treatment.

Advise patients to immediately contact their healthcare provider if new onset of chest discomfort, sudden weakness, or other events suggestive of a thrombotic event occurs 

Venous Thromboembolic Events -                                                                                Advise patients to immediately contact their healthcare provider if they develop symptoms of dyspnea or localized limb edema

Hemorrhagic Events -                                                                                             Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage

 Risk of Impaired Wound Healing-                                                                                    Inform patients that FOTIVDA may impair wound healing. Advise patients that temporary interruption of FOTIVDA is recommended prior to elective surgery. Advise patients to contact their healthcare provider before any planned surgeries, including dental surgery

 Reverse Posterior Leukoencephalopathy Syndrome-                                                    Inform patients that RPLS may occur during FOTIVDA treatment.                          Advise patients to immediately contact their healthcare provider in the event of seizures, headaches, visual disturbances, confusion or difficulty thinking.

Overdosage -                                                                                                                  Instruct patients to contact their healthcare provider immediately if they inadvertently take too much FOTIVDA 

Embryo-Fetal Toxicity-                                                                                                  Advise females of reproductive potential of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy

Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose

 Lactation-                                                                                                                     Advise women not to breastfeed during treatment with FOTIVDA and for one month after the last dose

Infertility-                                                                                                                          Advise males and females of reproductive potential that FOTIVDA can impair fertility

Allergic Reactions to Tartrazine (FD&C Yellow No.5)-                                                 FOTIVDA 0.89 mg capsule contains FD&C Yellow No.5 (tartrazine) as an imprint ink which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients.

Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity

 Other Common Events -                                                                                         Advise patients that other adverse reactions with FOTIVDA treatment may include diarrhea, vomiting, dysphonia (hoarseness of voice), fatigue, asthenia and stomatitis (sores in the mouth), and cough

Important Administration Information-                                                                 Instruct patient if a dose of FOTIVDA is missed, the next dose should be taken at the regularly scheduled time. Do not take two doses in the same day

Drug Interactions -                                                                                                     Advise patients to inform their healthcare provider of all concomitant medications, vitamins, or dietary and herbal supplements 

Manufactured for: AVEO Pharmaceuticals, Inc. Boston, MA 02108 Manufactured by: Catalent CTS, Inc. Kansas City, MO 641347

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Tivozanib is a tyrosine kinase inhibitor. In vitro cellular kinase assays demonstrated that tivozanib inhibits phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases including c-kit and PDGFR ß at clinically relevant concentrations.

2. Pharmacodynamics-                                                                                     Exposure-Response Relationship Tivozanib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology At the recommended dose of FOTIVDA, no large mean increases (i.e., 20 msec) in QTc interval were observed.

3. Pharmacokinetics The pharmacokinetics of tivozanib were evaluated in patients with solid tumors administered 1.34 mg once daily unless otherwise specified.

Steady-state tivozanib AUC and Cmax increased in a dose-proportional manner over the dose range of 0.89 to 1.78 mg once daily (0.67 to 1.3 times the recommended dose).

Absorption-                                                                                                                   The median Tmax of tivozanib is 10 hours with a range of 3 to 24 hours.

Effect of Food-                                                                                                                No clinically significant differences in tivozanib AUC or Cmax were observed following administration of a high fat meal (approximately 500-600 fat calories, 250 carbohydrate calories and 150 protein calories) in healthy subjects.

Distribution-                                                                                                                    The apparent volume of distribution (V/F) of tivozanib is 123 L. Protein binding of tivozanib is = 99%, primarily to albumin in vitro and is independent of concentration. The mean blood-to-plasma concentration ratios ranged from 0.495 to 0.615 in healthy subjects.

Elimination-                                                                                                                   The apparent clearance (CL/F) of tivozanib is 0.75 L/h and the half-life is 111 hours. Metabolism Tivozanib is metabolized predominantly by CYP3A4.

Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, unchanged tivozanib constituted 90% of the radioactive drug components in serum.

Excretion-                                                                                                                     Following oral administration of a single radiolabeled 1.34 mg dose of tivozanib to healthy subjects, 79% of the administered dose was recovered in feces (26% unchanged) and 12% in urine (unchanged tivozanib not detected).

Specific Populations-                                                                                                    No clinically significant differences in the pharmacokinetics of tivozanib were observed based on age (18 years to 88 years), sex, race (93% Caucasian, 3% African American, 2% Asian, 2% others), body weight (39 kg to 158 kg), mild to severe renal impairment (CLcr 15-89 mL/min as estimated by Cockcroft-Gault) or mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).

The effect of end-stage renal disease or severe hepatic impairment on tivozanib pharmacokinetics is unknown.

Patients with Hepatic Impairment- Compared to subjects with normal hepatic function, tivozanib AUCtau increased by 1% in patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) hepatic impairment.

Compared to subjects with normal hepatic function, tivozanib AUCtau increased by 62% in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN with any AST) hepatic impairment.

Drug Interaction Studies -                                                                                               Clinical Studies Strong CYP3A Inducers: Concomitant use of multiple doses of rifampin (strong CYP3A inducer) did not change tivozanib Cmax but decreased tivozanib AUC0-INF by 52%.

Strong CYP3A Inhibitors: No clinically significant differences in the pharmacokinetics of tivozanib were observed when multiple doses of ketoconazole (strong CYP3A inhibitor) was coadministered with tivozanib.

In Vitro Studies-                                                                                                    Cytochrome P450 (CYP) Enzymes: Tivozanib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations. Tivozanib does not induce CYP1A, CYP2B6, CYP2C9, CYP2C19, or CYP3A at clinically relevant concentrations.

Uridine Diphosphate (UDP)-glucuronosyl Transferase (UGT) Enzymes: Tivozanib does not inhibit UGT at clinically relevant concentrations.

Transporter Systems: Tivozanib inhibits BCRP but does not inhibit P-gp, OCT1, OATP1B1, OATP1B3, BSEP, OAT1, OAT3, OCT2, MATE1 or MATE2-K at clinically relevant concentrations.

Tivozanib is not a substrate for P-gp, MRP2, BCRP, OCT1, OATP1B1, OATP1B3, or BSEP.

  USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary-

 Based on findings in animal studies and its mechanism of action, FOTIVDA can cause fetal harm when administered to a pregnant woman

There are no available data on FOTIVDA use in pregnant woman to inform the drug-associated risk.

In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryofetal death at doses below the maximum recommended clinical dose on a mg/m2 basis 

Advise pregnant woman of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20% respectively.

2 Lactation Risk Summary -                                                                                              There are no data on the presence of tivozanib in human milk, or the effects of tivozanib on the breastfed child, or on milk production.

Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with FOTIVDA and for one month after the last dose.

3. Females and Males of Reproductive Potential                                                                FOTIVDA can cause fetal harm when administered to a pregnant woman

Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to starting treatment with FOTIVDA.

Contraception Females- Advise females of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose.

Males- Advise males with female partners of reproductive potential to use effective contraception during treatment with FOTIVDA and for one month after the last dose

 Infertility Females and Males Based on findings in animal studies, FOTIVDA can impair fertility in females and males of reproductive potential

4. Pediatric Use-                                                                                                           The safety and effectiveness of FOTIVDA in pediatric patients have not been established.

5. Geriatric Use -                                                                                                                Of the 1008 patients with advanced RCC treated with FOTIVDA, 29% were = 65 years of age and 4% were = 75 of age. No overall differences in safety were observed between patients = 65 versus < 65 years of age.

Of the 175 patients with advanced RCC following two or more prior systemic therapies randomized to FOTIVDA, 44% were = 65 years of age and 9% were = 75 of age. No overall differences in effectiveness were observed between patients = 65 versus < 65 years of age.

6. Renal Impairment-                                                                                                      No dosage modification is recommended for patients with mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min, estimated by Cockcroft-Gault). The recommended dosage for patients with end-stage renal disease has not been established 

7. Hepatic Impairment-                                                                                                       Reduce the dosage when administering FOTIVDA in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN with any AST) hepatic impairment

 No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) hepatic impairment.

The recommended dosage of FOTIVDA in patients with severe (total bilirubin greater than 3 to 10 times ULN with any AST) hepatic impairment has not been established

 OVERDOSAGE

Overdosage with FOTIVDA can cause severe hypertension and hypertensive crisis that may result in death.

During clinical studies, three patients inadvertently received doses = 2.68 mg (= 2 times the recommended dose) of FOTIVDA.

One patient who received two daily doses of 8.9 mg of FOTIVDA experienced hypertensive crisis with severe hypertensive retinopathy; a second patient who received three doses of 1.34 mg in one day experienced fatal uncontrolled hypertension; and a third patient who received two doses of 1.34 mg FOTIVDA in one day experienced persistent hypertension lasting over 5 days.

There is no specific treatment or antidote for FOTIVDA overdose.

In cases of suspected overdose, withhold FOTIVDA, closely monitor patients for hypertension and hypertensive crisis and other potential adverse reactions.

Immediately manage signs or symptoms of hypertension and provide other supportive care as clinically indicated.