Drug Safety-related Labeling Changes (SrLC)

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VOTRIENT (NDA-022465)

(PAZOPANIB HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/25/2024 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.18 Increased Toxicity in Developing Organs

Additions and/or revisions underlined:

The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation in patients younger than 2 years of age [see Use in Specific Populations (8.4)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of VOTRIENT in pediatric patients have not been established.

VOTRIENT is not indicated for use in pediatric patients [see Warnings and Precautions (5.18)]. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development. Administration of pazopanib to juvenile rats < 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals (see Juvenile Animal Toxicity Data).

The safety and efficacy of VOTRIENT or an unapproved pazopanib formulation were investigated but not established in two open-label studies: a study in 37 pediatric patients 2 to < 17 years with recurrent or refractory solid tumors [NCT00929903] and a study in 46 pediatric patients 1 year to < 17 years with refractory solid tumors, including sarcoma [NCT01956669]. Meaningful anti-tumor activity was not observed in these studies.

09/22/2021 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Other Clinically Relevant Adverse Reactions

Lipase Elevations

In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data. Elevated lipase as an adverse reaction were reported for 4% of 225 patients, including 2.7% (6/225) with Grade 3 and 0.4% (1/225) with Grade 4. In the RCC trials, clinical pancreatitis was observed in less than 1% of 586 patients.

…

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Polycythemia Eye Disorders: Retinal detachment/tear Gastrointestinal Disorders: Pancreatitis

Metabolic and Nutrition Disorder: Tumor lysis syndrome (including fatal cases)

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture (including fatal cases)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Based on animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no available data on VOTRIENT use in pregnant women to evaluate for a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the MRHD of 800 mg/day (based on AUC) (see Data). Advise pregnant women 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 in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

• Lactation: Advise women not to breastfeed during treatment with VOTRIENT and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

• Infertility: Advise males and females of reproductive potential that VOTRIENT may impair fertility [see Use in Specific Populations (8.3)].

…

09/22/2021 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Other Clinically Relevant Adverse Reactions

Lipase Elevations

In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data. Elevated lipase as an adverse reaction were reported for 4% of 225 patients, including 2.7% (6/225) with Grade 3 and 0.4% (1/225) with Grade 4. In the RCC trials, clinical pancreatitis was observed in less than 1% of 586 patients.

…

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Polycythemia Eye Disorders: Retinal detachment/tear Gastrointestinal Disorders: Pancreatitis

Metabolic and Nutrition Disorder: Tumor lysis syndrome (including fatal cases)

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture (including fatal cases)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Based on animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no available data on VOTRIENT use in pregnant women to evaluate for a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the MRHD of 800 mg/day (based on AUC) (see Data). Advise pregnant women 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 in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

• Lactation: Advise women not to breastfeed during treatment with VOTRIENT and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

• Infertility: Advise males and females of reproductive potential that VOTRIENT may impair fertility [see Use in Specific Populations (8.3)].

…

08/17/2020 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

The following subsections underwent extensive changes; please refer to the label for complete information:

5.1 Hepatic Toxicity

5.2 QT Prolongation and Torsades de Pointes

5.3 Cardiac Dysfunction

5.4 Hemorrhagic Events

5.5 Arterial Thromboembolic Events

5.6 Venous Thromboembolic Events

5.7 Thrombotic Microangiopathy

5.8 Gastrointestinal Perforation and Fistula

5.9 Interstitial Lung Disease/Pneumonitis

5.10 Posterior Reversible Encephalopathy Syndrome

5.11 Hypertension

5.12 Risk of Impaired Wound Healing

5.13 Hypothyroidism

5.14 Proteinuria

Additions and/or revisions underlined in the below subsection:

5.19 Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VOTRIENT and for at least 2 weeks following the final dose. Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)]. 

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are elsewhere in the labeling:

• Arterial Thromboembolic Events [see Warnings and Precautions (5.5,)]

• Thrombotic Microangiopathy (TMA) [see Warnings and Precautions (5.7)]

• Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.9)]

• Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Extensive Changes; please refer to label for complete information

7 Drug Interactions

The following subsections underwent extensive changes; please refer to the label for complete information:

7.1 Effect of Other Drugs on VOTRIENT

7.2 Effects of VOTRIENT on Other Drugs

7.3 Concomitant Use with Simvastatin

7.4 Concomitant Use with Gastric Acid-Reducing Agents

The following subsection is newly added:

7.5 Drugs That Prolong the QT Interval

VOTRIENT is associated with QTc interval prolongation [see Warnings and Precautions (5.2), Clinical Pharmacology (12.2)]. Avoid coadministration of VOTRIENT with drugs known to prolong the QT/QTc interval.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

… 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 in clinically recognized pregnancies and miscarriage is 2 to 4% and 15% to 20%, respectively …

8.4 Pediatric Patients

Additions and/or revisions underlined:

The safety and effectiveness of VOTRIENT in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years …

8.5 Geriatric Use

Additions and/or revisions underlined:

In pooled clinical trials with VOTRIENT, 30% of 2080 patients were aged greater than or equal to 65 years. More patients greater than or equal to 65 years had ALT elevations > 3 × ULN compared to patients < 65 years (23% versus 18%) [see Warnings and Precautions (5.1)].

In the RCC trials, 33% of 586 patients were aged greater than or equal to 65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients.

In the STS trials, 24% of 382 patients were aged greater than or equal to 65 years. Patients aged greater than or equal to 65 years had a higher incidence of Grade 3 or 4 fatigue (19% versus 12% for patients aged <65 years), hypertension (10% versus 6%), decreased appetite (11% versus 2%), ALT elevations (3% versus 2%) and AST elevations (4% versus 1%). In the randomized STS trial (VEG110727), no overall differences in effectiveness of VOTRIENT were observed between patients aged greater than or equal to 65 years and younger patients.

8.6 Renal Impairment

Additions and/or revisions underlined:

No dose adjustment is recommended for patients with renal impairment. VOTRIENT has not been studied in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dose adjustment is required in patients with mild hepatic impairment (either total bilirubin less than or equal to ULN and ALT > ULN or bilirubin > 1 to 1.5 × ULN and any ALT value). VOTRIENT is not recommended in patients with moderate (total bilirubin > 1.5 to 3 × ULN and any ALT value) and severe (total bilirubin > 3 × ULN and any ALT value) hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What should I tell my healthcare provider before taking VOTRIENT?

Before you take VOTRIENT, tell your healthcare provider if you:

• had recent surgery or are going to have surgery. You should stop taking VOTRIENT at least 1 week before scheduled surgery because VOTRIENT may affect healing after surgery. Do not take VOTRIENT for at least 2 weeks following major surgery and until your wound heals adequately. Your healthcare provider should tell you when you may start taking VOTRIENT again after surgery.

What are the possible side effects of VOTRIENT?

VOTRIENT may cause serious side effects including:

• Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a condition that can happen while taking VOTRIENT that may cause death.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

• Posterior Reversible Encephalopathy Syndrome: Advise patients to inform their doctor if they have worsening of neurological function consistent with PRES (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances) [see Warnings and Precautions (5.10)].

• Risk of Impaired Wound Healing: Advise patients that VOTRIENT may impair wound healing. Advise patients to inform their healthcare provider of any scheduled surgical procedure [see Warnings and Precautions (5.12)].

07/17/2020 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

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

06/02/2020 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Tumor Lysis Syndrome

(New subsection added)

Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported in RCC and STS patients treated with VOTRIENT. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated.

6 Adverse Reactions

 

(Addition of the following to the bulleted line listing, information transferred from subsection 6.1)

…

• Hypothyroidism

• Proteinuria

• Tumor Lysis Syndrome

…

6.2 Postmarketing Experience

 

(Additions underlined)

…

Metabolic and Nutrition Disorder: Tumor Lysis Syndrome (including fatal cases)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions underlined)

…

What are the possible side effects of VOTRIENT?

 VOTRIENT may cause serious side effects including:

…

• Tumor lysis syndrome (TLS). TLS is a condition that can happen during treatment with VOTRIENT that may cause death. TLS is caused by a fast breakdown of cancer cells. Your healthcare provider may do blood test to check you for TLS. Call your healthcare provider or get emergency medical help right away if you develop any of these symptoms during treatment with VOTRIENT: irregular heartbeat, seizures, confusion, muscle cramps or spasms, or a decrease in urine output.

   

  …

PATIENT COUNSELING INFORMATION

(Additions underlined)

…

Tumor Lysis Syndrome: Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS such as abnormal heart rhythm, seizure, confusion, muscle cramps or spasms, or a decrease in urine output.

 

…

05/31/2017 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.18 Embryo-Fetal Toxicity

(subsection revised, additions underlined)

Based on findings from animal studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman. Administration of VOTRIENT to pregnant rats and rabbits during the period of organogenesis resulted in maternal toxicity, teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg (based on AUC).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VOTRIENT and for at least 2 weeks following the final dose

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

Based on animal reproduction studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman.There are no available data in pregnant womento inform a drug-associated risk. In animal developmental and reproductive toxicology studiesa, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at the maximum recommended human dose of 800 mg (based on AUC) [see Data]. Advise pregnant women or women of childbearing potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

 

Data

Animal Data

In a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day). Postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day).

In embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. In rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1- fold the AUC at the MRHD of 800 mg/day) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight. In rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007 - fold the AUC at the MRHD of 800 mg/day). In addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to100 mg/kg/day (0.02-fold the AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (AUC not calculated).

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of pazopanib or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breast- fed infants from VOTRIENT, advise a lactating woman not to breastfeed during treatment with VOTRIENT and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Based on animal reproduction studies and its mechanism of action, VOTRIENT can cause fetal harm when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to starting treatment with VOTRIENT.

 

Contraception

Females

VOTRIENT can cause fetal harm when administered to a pregnant woman]. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT.

Males

To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose.

Infertility

Based on findings from animal studies, VOTRIENT may impair fertility in females and males of reproductive potential while receiving treatment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(extensive additions, please refer to label)

05/31/2017 (SUPPL-25)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during postapproval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Eye Disorders: Retinal detachment/tear. Gastrointestinal Disorders: Pancreatitis.

Blood and lymphatic system disorders: Polycythemia.

08/05/2016 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

(Addition of the following subsection following Table 4)

• Adverse Reactions in East Asian Patients: In an analysis of pooled clinical trials (N=1938) with VOTRIENT, Grade 3 and Grade 4 adverse reactions were observed more frequently in patients of East Asian descent than in patients of non-East Asian descent for neutropenia (12% vs. 2%), thrombocytopenia (6% vs. <1%) and palmar-plantar erythrodysethesia syndrome (6% vs. 2%).

05/20/2016 (SUPPL-22)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pregnancy

• If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.,,, Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - Before you take VOTRIENT, tell your healthcare provider if you:

• You should not become pregnant while you are taking VOTRIENT…You should use effective birth control during treatment with VOTRIENT and for 2 weeks after your last dose of VOTRIENT. Talk to your healthcare provider about types of birth control that may be right for you during this time.

PCI

• Advise females of reproductive potential of the potential hazard to the fetus and to use effective contraception during treatment and for at least 2 weeks after the last dose of VOTRIENT.