Drug information of Pazopanib

Mechanism of effect

Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumor blood vessel for tumor survival and growth.

Pharmacodynamic

A reduction in tumor blood flow, increased tumor apoptosis, inhibition of tumor growth, reduction in tumor interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.

Pharmacokinetics

Peak Plasma Time: 2-4 hr

Peak Plasma Concentration: 58.1 mcg/mL

AUC: 1,037 hr•mcg/mL

Cmax and AUC increased 2-fold with food; also increased if table crushed

Protein Bound: >99%

Pgp substrate

Metabolism: Metabolized by CYP3A4 (major), CYP1A2 and CYP2C8 (minor)

Half-Life: 30.9 hr

Excretion: Feces (Primarily); urine (<4%)

Drug indications

Soft Tissue Sarcoma , Renal Cell Carcinoma

Dosage

Adult

Advanced Renal Cell Carcinoma

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

Soft Tissue Sarcomas

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

 

Pediatric

Safety and efficacy not established; not indicated for use in pediatric patients

Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development, particularly in children younger than 2 years

 

Drug contraindications

Hypersensitivity

Side effects

Diarrhea , Headache , Proteinuria , weight decrease , nausea , chest pain , vomiting , asthenia , hypothyroidism , anorexia , rectal hemorrhage , hemorrhage , Hyperbilirubinemia , ECG prolonged QT , tiredness , swelling of the face , Abdominal pain , Leukopenia , Rash , Hair depigmentation , Myocardial dysfunction , Skin depigmentation , Hemorrhagic death

Interactions

Zafirlukast , teriflunomide , nelfinavir , Dolasetron , vandetanib , sparfloxacin , Mefloquine , Dofetilide , Magnesium hydroxide , Halofantrine , Grepafloxacin , Darifenacin , cobicistat , Delavirdine , Aluminium Mg , aluminum hydroxide/magnesium carbonate , Aprepitant , Erythromycin , Esomeprazole , Ondansetron , Pantoprazole , Posaconazole , quinupristin and dalfopristin , vemurafenib , Fluticasone and Vilanterol , st. john's wort , revefenacin , elagolix , ivosidenib , Darolutamide , Entrectinib , glasdegib , conivaptan , Panobinostat , Inotuzumab‎ , Aluminium hydroxide , Idelalisib , Erdafitinib , Dexlansoprazole , Fosamprenavir , ibuprofen + famotidine , Eluxadoline , Nizatidine , Palifermin , Indinavir , Toremifene , Grapefruit , Nefazodone , dronedarone , ritonavir , saquinavir , Voriconazole , Carbamazepine , Ketoconazole , Clarithromycin , Rifabutin , Darunavir , Fluvoxamine , Fluconazole , Lansoprazole , Lapatinib , Nilotinib , Verapamil , Deferiprone , Rabeprazole , Ranitidine , Rifampin , Cimetidine , Famotidin , ELBASVIR/GRAZOPREVIR , oleandomycin , Bepridil , bedaquiline , Gemtuzumab , Meningococcal conjugate vaccine , tucatinib

Alerts

• Severe hepatotoxicity, including fatalities, has been reported
• Increases in serum transaminase levels and bilirubin observed; severe and fatal hepatotoxicity has occurred; measure liver chemistries before initiation of treatment and regularly during treatment
• Patients >65 years are at greater risk for hepatotoxicity
• Hypertension, including hypertensive crisis have occurred; blood pressure should be well controlled prior to initiating therapy; monitor blood pressure within one week after starting therapy and frequently thereafter
• Rare occurrences of QT prolongation and torsades de pointes reported during clinical trials; consider monitoring electrocardiograms and electrolytes
• Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) observed; permanently discontinue therapy if TMA occurs
• Hematologic parameter alterations (ie, leukopenia, neutropenia, thrombocytopenia, lymphocytopenia) reported in 31-37%
• Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase pazopanib serum levels
• CYP3A4 inducers (eg, rifampin, carbamazepine) decrease pazopanib serum levels
• Gastrointestinal perforation or fistula reported; fatal perforation events have occurred; use with caution in patients at risk for gastrointestinal perforation or fistula
• Events of cardiac dysfunction (decreased LVEF and congestive heart failure) have been observed; baseline and periodic evaluation of LVEF recommended in patients at risk of cardiac dysfunction
• Avoid concomitant use with drugs that raise gastric pH; consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists; separate antacid and pazopanib dosing by several hr
• Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed and can be fatal; permanently discontinue therapy in patients developing RPLS
• Interruption of therapy recommended in patients undergoing surgical procedures
• Hypothyroidism may occur; monitoring of thyroid function tests recommended
• Monitor urine protein. interrupt treatment for 24-hr urine protein ≥3 g and discontinue for repeat episodes despite dose reductions
• Serious infections (with or without neutropenia), some with fatal outcome, reported; monitor for signs and symptoms and treat active infection promptly; interrupt or discontinue therapy
• Interstitial lung disease/pneumonitis reported; monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue therapy in patients developing ILD or pneumonitis
• Fatal hemorrhagic events reported; therapy has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients
• Arterial thromboembolic events that can be fatal reported; use with caution in patients who are at increased risk for these events
• Venous thromboembolic events (VTE) reported, including fatal pulmonary emboli (PE); monitor for signs and symptoms of VTE and PE.
• Animal studies have shown therapy can severely affect organ growth and maturation during early post-natal development; safety and effectiveness in pediatric patients not established
• Can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential of the potential hazard to fetus and to use effective contraception during treatment and for at least 2 weeks after last dose

 

Black Box Warnings

Severe hepatotoxicity including fatalities reported in postmarketing survaillance

 

Points of recommendation

• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• Call your doctor right away if you have any signs of infection like fever, chills, flu-like signs, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or a wound that will not heal.
• A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with pazopanib. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
• Very bad and sometimes deadly blood problems like thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) have happened with pazopanib in some people. Call your doctor right away if you feel very tired or weak or have any bruising or bleeding; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; change in eyesight; change in strength on 1 side is greater than the other, trouble speaking or thinking, or change in balance; or fever.
• Very bad and sometimes deadly lung problems have happened with pazopanib. Call your doctor right away if you have lung or breathing problems that are new or worse like cough or shortness of breath.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during treatment and for 2 weeks after your last dose.
• If you are a man and your sex partner gets pregnant while you take pazopanib or within 2 weeks after your last dose, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking pazopanib and for at least 2 weeks after stopping the drug.
• If you get pregnant while taking pazopanib or within 2 weeks after your last dose, call your doctor right away.

• Take on an empty stomach. Take 1 hour before or 2 hours after meals.
• Swallow whole. Do not chew, break, or crush.
• Do not take antacids at the same time as pazopanib. Talk with your doctor.
• Avoid grapefruit and grapefruit juice.
• To gain the most benefit, do not miss doses.
• Keep taking pazopanib as you have been told by your doctor or other health care provider, even if you feel well.
• High blood pressure has happened with pazopanib. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your urine checked as you have been told by your doctor.
• If you have upset stomach, throwing up, diarrhea, or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• This medicine may affect how wounds heal. If you have surgery, you may need to stop pazopanib before surgery. Start taking it again after surgery as you are told by your doctor.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.

• Take a missed dose as soon as you think about it.
• If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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