September 3, 2015
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Votrient

"Investigators in The Cancer Genome Atlas (TCGA) Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcin"...

Votrient




Votrient Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 4/23/2015

Votrient (pazopanib) is a tyrosine kinase inhibitor used to treat kidney cancer, and it may also be used to treat certain other types of cancer (soft tissue sarcoma). Common side effects of Votrient include headache, loss of appetite, weight loss, altered sense of taste, nausea and vomiting (may be severe), diarrhea, numbness/tingling/redness in hands/feet, changes in hair or skin color, joint or muscle pain, or feeling tired/weak.

The recommended dose of Votrient is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). Votrient may interact with other drugs that can cause bleeding/bruising such as antiplatelet drugs, NSAIDs, aspirin, or blood thinners. It can also interact with azole antifungals, antidepressants, antibiotics, rifamycins, St. John's wort, seizures medications, HIV medicines, and other drugs that can affect the heart rhythm (QT prolongation), including amiodarone, dofetilide, pimozide, procainamide, quinidine, or sotalol. Tell your doctor all medications and supplements you use. Votrient is not recommended for use during pregnancy. It may harm a fetus. Discuss birth control with your doctor. If you become pregnant or think you may be pregnant, tell your doctor. It is unknown if this medication passes into breast milk. Consult your doctor before breastfeeding.

Our Votrient (pazopanib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Patient Information in Detail?

Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.

Votrient in Detail - Patient Information: Side Effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using pazopanib and call your doctor at once if you have a serious side effect such as:

  • slow healing of a wound or surgical incision;
  • dizziness, fainting, fast or pounding heartbeat;
  • fever, chills, easy bruising, flu symptoms, sores in your mouth and throat;
  • feeling short of breath (even with mild exertion), swelling, rapid weight gain;
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
  • nosebleed, bleeding gums;
  • any wound that will not heal;
  • nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • sudden numbness or weakness (especially on one side of the body), sudden severe headache, confusion, problems with vision, speech, or balance;
  • seizures (convulsions);
  • sudden cough, wheezing, rapid breathing, coughing up blood;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • pain, swelling, warmth, or redness in one or both legs; or
  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

Less serious side effects may include:

  • mild nausea or vomiting, diarrhea;
  • weight loss;
  • changes in hair or skin color;
  • joint or muscle pain;
  • tumor pain, mild headache; or
  • unusual or unpleasant taste in your mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Votrient (Pazopanib Tablets)

What is Patient Information Overview?

A concise overview of the drug for the patient or caregiver from First DataBank.

Votrient Overview - Patient Information: Side Effects

SIDE EFFECTS: See also Warning section.

Headache, loss of appetite, weight loss, altered sense of taste, numbness/tingling/redness in hands/feet, or feeling tired/weak may occur. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals or limiting activity may help lessen some of these effects.

Many people have more frequent/loose stools or diarrhea while taking this medication. Diarrhea can cause a serious loss of body water (dehydration). Drink plenty of fluids and minerals (electrolytes) to replace what is lost. Tell your doctor immediately if you develop signs of dehydration (such as extreme thirst, decreased urination, muscle cramps, weakness, fainting).

If diarrhea persists or becomes a problem, your doctor may lower the dose or have you temporarily stop this medication. Do not stop or change the dose of this medicine without talking with your doctor. Tell your doctor immediately if you develop: persistent/severe diarrhea, abdominal or stomach pain/cramping, blood in your stool.

This medication may cause high blood pressure. Your doctor will check your blood pressure regularly while you are taking this medication and may start you on a medication to lower your blood pressure.

Temporary hair loss and/or change in hair or skin color may occur. Normal hair growth should return after treatment has ended.

Many people using this medication have serious side effects and require a dosage reduction or drug discontinuation. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor right away if you have any serious side effects, including: signs of an underactive thyroid (such as unusual weight gain, cold intolerance, slow heartbeat, unusual tiredness), signs of infection (such as fever, chills, persistent sore throat), wounds that do not heal, signs of congestive heart failure (such as swelling of the ankles/feet, trouble breathing, unusual tiredness), change in the amount of urine, unusual tiredness.

This drug can cause serious (rarely fatal) bleeding. Tell your doctor immediately if you have any signs of unusual bleeding such as: bloody/black stools, easy bleeding/bruising (such as nose bleed or bloody/pinkish urine), vomit that looks like coffee grounds, severe stomach/abdominal pain, coughing up blood.

Get medical help right away if you have any very serious side effects, including: fast/irregular heartbeat, severe dizziness, fainting, symptoms of a heart attack (such as chest/jaw/left arm pain, shortness of breath, unusual sweating), signs of a stroke (such as weakness on one side of the body, slurred speech, sudden vision changes, confusion), signs of a blood clot in the arms/legs/lungs (such as pain/redness/swelling in the arm/leg/calf/groin, coughing up blood, chest pain, trouble breathing), signs of a certain brain condition (such as headache, seizure, confusion, decreased alertness, vision changes, blindness).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the entire patient information overview for Votrient (Pazopanib Tablets)

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Votrient FDA Prescribing Information: Side Effects
(Adverse Reactions)

CLINICAL PHARMACOLOGY

Mechanism Of Action

Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.

Pharmacodynamics

Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.

The QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a positive control. Pazopanib 800 mg was dosed under fasting conditions on Days 2 to 8 and 1,600 mg was dosed on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites. No large changes (i.e., > 20 msec) in QTc interval following the treatment of pazopanib were detected in this QT trial. The trial was not able to exclude small changes ( < 10 msec) in QTc interval, because assay sensitivity below this threshold ( < 10 msec) was not established in this trial [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

Pazopanib is absorbed orally with median time to achieve peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in geometric mean AUC and Cmax of 1,037 mcg•h/mL and 58.1 mcg/mL (equivalent to 132 μM), respectively. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.

Administration of a single pazopanib 400-mg crushed tablet increased AUC(0-72) by 46% and Cmax by approximately 2 fold and decreased Tmax by approximately 2 hours compared with administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets of VOTRIENT should not be crushed.

Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal [see DOSAGE AND ADMINISTRATION].

Distribution

Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP.

Metabolism

In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.

Elimination

Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for < 4% of the administered dose.

Hepatic Impairment

Mild hepatic impairment was defined as either total bilirubin WNL with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of the ALT value. The median steady-state pazopanib Cmax and AUC(0-24) after a once-daily dose of 800 mg/day in patients (N = 12) with mild impairment were 34 mcg/mL (range: 11 to 104) and 774 mcg•h/mL (range: 215 to 2,034), respectively. These were in a similar range as the median steady-state pazopanib Cma x and AUC(0-24) in patients (N = 18) with no hepatic impairment (52 mcg/mL, range: 17 to 86 and 888 mcg•h/mL, range: 346 to 1,482, respectively) [see DOSAGE AND ADMINISTRATION].

Moderate hepatic impairment was defined as total bilirubin > 1.5 X to 3 X ULN regardless of the ALT value. The maximum tolerated pazopanib dose in patients with moderate impairment was 200 mg once daily. The median (N = 11) steady-state Cmax with that regimen was 22 mcg/mL (range: 4.2 to 33), and the median AUC(0-24) was 257 mcg•h/mL (range: 66 to 488). These values were approximately 43% and 29% of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function (N = 18) [see DOSAGE AND ADMINISTRATION].

Severe hepatic impairment was defined as total bilirubin > 3 X ULN regardless of the ALT value. Median exposures in patients with severe hepatic impairment receiving 200 mg once daily (N = 14) were unexpectedly lower than those observed in patients with moderate hepatic impairment receiving 200 mg once daily. The median steady-state Cmax was 9.4 mcg/mL (range: 2.4 to 24), and the median AUC(0-24) was 131 mcg•h/mL (range: 47 to 473). These values were approximately 18% and 15% of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function. Despite the observed concentrations, the dose of 200 mg was not well tolerated in patients with severe hepatic impairment. Use of VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations].

Drug Interactions

Coadministration of multiple doses of oral pazopanib 400 mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp inhibitor) resulted in a 1.7fold increase in the AUC(0-24) and a 1.5-fold increase in the Cma x of pazopanib compared with pazopanib administered alone. Concurrent administration of a single dose of pazopanib eye drops with ketoconazole in healthy volunteers resulted in a 2-fold and 1.5-fold increase in mean AUC(0-t) and Cma x values, respectively [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

Administration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP, with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC(0-24) and Cma x compared with administration of 800 mg pazopanib alone.

In vitro studies with human liver microsomes showed that pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human pregnane X receptor (PXR) assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and Cmax of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Coadministration of pazopanib 800 mg once daily and paclitaxel 80 mg/m² (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and Cmax, respectively [see DRUG INTERACTIONS].

Pazopanib exhibits pH-dependent solubility. In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a PPI, decreased the exposure of pazopanib by approximately 40% (AUC and Cmax).

In vitro studies also showed that pazopanib inhibits UGT1A1 and organic anion-transporting polypeptide (OATP1B1) with IC50s of 1.2 and 0.79 μM, respectively. Pazopanib may increase concentrations of drugs eliminated by UGT1A1 and OATP1B1.

Pharmacogenomics

Pazopanib can increase serum total bilirubin levels [see WARNINGS AND PRECAUTIONS]. In vitro studies showed that pazopanib inhibits UGT1A1, which glucuronidates bilirubin for elimination. A pooled pharmacogenetic analysis of 236 Caucasian patients evaluated the TA-repeat polymorphism of UGT1A1 and its potential association with hyperbilirubinemia during pazopanib treatment. In this analysis, the (TA)7/(TA)7 genotype (UGT1A1*28/*28) (underlying genetic susceptibility to Gilbert's syndrome) was associated with a statistically significant increase in the incidence of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.

Clinical Studies

Renal Cell Carcinoma

The safety and efficacy of VOTRIENT in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial. Patients (N = 435) with locally advanced and/or metastatic RCC who had received either no prior therapy or one prior cytokine-based systemic therapy were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo once daily. The primary objective of the trial was to evaluate and compare the 2 treatment arms for progression-free survival (PFS); the secondary endpoints included overall survival (OS), overall response rate (RR), and duration of response.

Of the total of 435 patients enrolled in this trial, 233 patients had no prior systemic therapy (treatment-na´ve subgroup) and 202 patients received one prior IL-2 or INFα-based therapy (cytokine-pretreated subgroup). The baseline demographic and disease characteristics were balanced between the arms receiving VOTRIENT and placebo. The majority of patients were male (71%) with a median age of 59 years. Eighty-six percent of patients were Caucasian, 14% were Asian, and less than 1% were other. Forty-two percent were ECOG performance status 0 and 58% were ECOG performance status 1. All patients had clear cell histology (90%) or predominantly clear cell histology (10%). Approximately 50% of all patients had 3 or more organs involved with metastatic disease. The most common metastatic sites at baseline were lung (74%), lymph nodes (56%), bone (27%), and liver (25%).

A similar proportion of patients in each arm were treatment-na´ve and cytokinepretreated (see Table 5). In the cytokine-pretreated subgroup, the majority (75%) had received interferon-based treatment. Similar proportions of patients in each arm had prior nephrectomy (89% and 88% for VOTRIENT and placebo, respectively).

The analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire trial population. Efficacy results are presented in Table 5 and Figure 1.

Table 5: Efficacy Results in RCC Patients by Independent Assessment

Endpoint/Trial Population VOTRIENT Placebo HR (95% CI)
PFS
Overall ITT N = 290 N = 145  
  Median (months) 9.2 4.2 0.46a (0.34, 0.62)
Treatment-naive subgroup N = 155 (53%) N = 78 (54%)  
  Median (months) 11.1 2.8 0.40 (0.27, 0.60)
Cytokine pre-treated subgroup N = 135 (47%) N = 67 (46%)  
  Median (months) 7.4 4.2 0.54 (0.35, 0.84)
Response Rate (CR + PR) N = 290 N = 145  
  % (95% CI) 30 (25.1, 35.6) 3 (0.5, 6.4) -
Duration of response Median (weeks) (95% CI) 58.7 (52.1, 68.1) -b  
HR = Hazard Ratio; ITT = Intent to Treat; PFS = Progression-free Survival; CR = Complete Response; PR = Partial Response.
aP value < 0.001.
bThere were only 5 objective responses.

Figure 1: Kaplan-Meier Curve for Progression-free Survival in RCC by Independent Assessment for the Overall Population (Treatment-na´ve and Cytokine Pre-treated Populations)

Kaplan-Meier Curve for Progression-free Survival in RCC by Independent Assessment for the Overall Population - Illustration

At the protocol-specified final analysis of OS, the median OS was 22.9 months for patients randomized to VOTRIENT and 20.5 months for the placebo arm [HR = 0.91 (95% CI: 0.71, 1.16)]. The median OS for the placebo arm includes 79 patients (54%) who discontinued placebo treatment because of disease progression and crossed over to treatment with VOTRIENT. In the placebo arm, 95 (66%) patients received at least one systemic anti-cancer treatment after progression compared with 88 (30%) patients randomized to VOTRIENT.

Soft Tissue Sarcoma

The safety and efficacy of VOTRIENT in patients with STS were evaluated in a randomized, double-blind, placebo-controlled, multicenter trial. Patients (N = 369) with metastatic STS who had received prior chemotherapy, including anthracycline treatment, or were unsuited for such therapy, were randomized (2:1) to receive VOTRIENT 800 mg once daily or placebo. Patients with gastrointestinal stromal tumors (GIST) or adipocytic sarcoma were excluded from the trial. Randomization was stratified by the factors of WHO performance status (WHO PS) 0 or 1 at baseline and the number of lines of prior systemic therapy for advanced disease (0 or 1 versus 2+). Progression-free survival (PFS) was assessed by independent radiological review. Other efficacy endpoints included overall survival (OS), overall response rate, and duration of response.

The majority of patients were female (59%) with a median age of 55 years. Seventy-two percent of patients were Caucasian, 22% were Asian, and 6% were other. Forty-three percent of patients had leiomyosarcoma, 10% had synovial sarcoma, and 47% had other soft tissue sarcomas. Fifty-six percent of patients had received 2 or more lines of prior systemic therapy and 44% had received 0 or 1 lines of prior systemic therapy. The median duration of treatment was 4.5 months for patients on the pazopanib arm and 1.9 months for patients on the placebo arm.

Efficacy results are presented in Table 6 and Figure 2.

Table 6: Efficacy Results in STS Patients by Independent Assessment

Endpoint/Trial Population VOTRIENT Placebo HR (95% CI)
PFS Overall ITT N = 246 N = 123 0.35a
  Median (months) 4.6 1.6 (0.26, 0.48)
Leiomyosarcoma subgroup N = 109 N = 49 0.37
  Median (months) 4.6 1.9 (0.23, 0.60)
Synovial sarcoma subgroup N = 25 N = 13 0.43
  Median (months) 4.1 0.9 (0.19, 0.98)
‘Other soft tissue sarcoma’ subgroup N = 112 N = 61 0.39
  Median (months) 4.6 1.0 (0.25, 0.60)
Response Rate (CR + PR)      
 % (95% CI) 4
(2.3, 7.9)b
0
(0.0, 3.0)
-
Duration of response      
  Median (months) (95% CI) 9.0
(3.9, 9.2)
   
HR = Hazard Ratio; ITT = Intent to Treat; PFS = Progression-free Survival; CR = Complete Response; PR = Partial Response.
aP value < 0.001.
bThere were 11 partial responses and 0 complete responses.

Figure 2: Kaplan-Meier Curve for Progression-free Survival in STS by Independent Assessment for the Overall Population

Kaplan-Meier Curve for Progression-free Survival in STS by Independent Assessment for the Overall Population - Illustration

At the protocol-specified final analysis of OS, the median OS was 12.6 months for patients randomized to VOTRIENT and 10.7 months for the placebo arm [HR = 0.87 (95% CI: 0.67, 1.12)].

Read the entire FDA prescribing information for Votrient (Pazopanib Tablets)

Votrient - User Reviews

Votrient User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Votrient sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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