Pazopanib

437.518

437.52

7RN5DR86CK

752782

DTXSID8048733

C74547

L01XE11|L - Antineoplastic and immunomodulating agents

29350090

127.41000

3.1

1.4±0.1 g/cm3

285-289°C (dec.)

728.8±70.0 °C at 760 mmHg

394.6±35.7 °C

1.702

In water, 3.3 mg/L at 25 deg C (est)

Store at room temperature between 20 deg C and 25 deg C (68 deg F to 77 deg F); excursions permitted to 15 deg C to 30 deg C (59 deg F to 86 deg F).

3.21X10-14 mm Hg at 25 deg C (est)

Henry's Law constant = 1.10X10-15 atm-cu m/mol at 25 °C (est)

pKa1 = 2.29 (amine); pKa2 = 5.07 (amine); pKa3 = 10.41 (amide) (est)

White to slightly yellow solid. Practically insoluble above pH 4 in aqueous media/Pazopanib hydrochloride/|Hydroxyl radical reaction rate constant = 4.02X10-10 cu cm/molec-sec at 25 °C (est)

43-62/63

36/37/39-28B

Stable if stored as directed; avoid strong oxidizing agents. /Pazopanib hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pazopanib hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pazopanib hydrochloride/

Personal protective equipment as follows: Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles. /Pazopanib hydrochloride/

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes. /Pazopanib hydrochloride/

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves Measures for cleaning/collecting absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, fedreal, state and local regulations/. /Pazopanib hydrochloride/

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients. /Pazopanib hydrochloride/|Information for safe handling: avoid inhalation and contact with skin, eyes and clothing ... . /Pazopanib hydrochloride/

IDENTIFICATION AND USE: Pazopanib is a white to slightly yellow solid formulated into film-coated tablets. Pazopanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. It is used for the treatment of advanced renal cell carcinoma and for patients with advanced soft tissue sarcoma who have received prior chemotherapy. HUMAN EXPOSURE AND TOXICITY: Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases and bilirubin, has been reported in patients receiving pazopanib. If hepatotoxicity occurs, pazopanib dosage should be reduced, or therapy should be interrupted or permanently discontinued. Woman should avoid the use of pazopanib during pregnancy. While there are no adequate and well-controlled studies in pregnant women, pazopanib has been shown to be teratogenic, embryotoxic, fetotoxic, and abortifacient in animal studies. If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, the patient should be apprised of the potential fetal hazard. Prolongation of the QT interval and torsades de pointes and severe and sometimes fatal hemorrhage events have been reported in patients receiving pazopanib. Finally, GI perforation or fistula which can be fatal has also been associated with the use of pazopanib. ANIMAL STUDIES: While carcinogenicity studies with pazopanib have not been conducted, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci occurred in 2 females and a single case of adenoma in another female was observed at a dose of 1000 mg/kg/day. Pazopanib produced fetal teratogenic effects (including cardiovascular malformations and delayed ossification), reduced fetal body weight, and embryo lethality in rats at a dose level as low as 3 mg/kg/day. In rabbits, maternal toxicity (body weight loss, reduced food consumption, and abortion) was observed at doses as low as 30 mg/kg/day, while fetal weight was reduced at doses as low as 3 mg/kg/day. Pazopanib also reduced fertility in female rats at a dose of 300 mg/kg. Increased pre- and post-implantation loss and early resorptions were noted at doses as low as 10 mg/kg/day. Decreased corpora lutea were observed in monkeys and mice and ovarian atrophy was noted in rats. While pazopanib did not affect mating or fertility in male rats, reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentration was observed at doses as low as 100 mg/kg/day for 15 weeks. Following 26 weeks of dosing, male rats given doses of 30 mg/kg/day or greater exhibited decreased testicular and epididymal weights, atrophy and degeneration of the testes with aspermia, hypospermia and cribriform change in the epididymis. In toxicology studies in rats, there were effects in a variety of tissues (bone, teeth, bone marrow, nail beds, reproductive organs, hematological tissues, kidney, adrenal glands, lymph node, pituitary, and pancreas) consistent with vascular endothelial growth factor receptor (VEGFR) inhibition and/or disruption of VEGF signaling pathways with some effects occurring at doses of 3 mg/kg/day. Pazopanib was tested in a standard battery of genotoxicity studies. Pazopanib was found to be nonmutagenic and non-clastogenic when tested in a bacterial cell (Ames) assay, human peripheral lymphocyte chromosome aberration assay and rat micronucleus assay.

In large clinical trials, abnormalities in routine liver tests were common in patients treated with pazopanib, with serum aminotransferase elevations occurring in up to half of patients and total serum bilirubin in approximately one-third. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 8% of patients and combinations of ALT and bilirubin elevations in 1% to 2%. In preliminary trials of pazopanib in various solid tumors, there were rare reports of hepatitis with jaundice in

Votrient is not indicated for use in combination with other /cancer therapy/ agents. Clinical trials of Votrient in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.|In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered.|Inhibitors of CYP3A4: Pharmacokinetic interaction (increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of pazopanib) observed during concomitant use of pazopanib ophthalmic solution with ketoconazole (a potent inhibitor of CYP3A4 and an inhibitor of Pgp) or during concomitant use of pazopanib oral tablets with lapatinib (a substrate and weak inhibitor of CYP3A4, Pgp, and BCRP). Concomitant use of pazopanib with a potent CYP3A4 inhibitor (e.g., clarithromycin, ketoconazole, ritonavir) should be avoided; if concomitant use cannot be avoided, pazopanib dosage should be reduced. The manufacturer states that concomitant use with grapefruit or grapefruit juice also should be avoided.|Concomitant use of Votrient and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with Votrient, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for Votrient or consider alternatives to Votrient. Alternatively, consider discontinuing simvastatin. Insufficient data are available to assess the risk of concomitant administration of alternative statins and Votrient.|For more Interactions (Complete) data for Pazopanib (13 total), please visit the HSDB record page.

Pazopanib may cause fetal harm; the drug has been shown to be teratogenic, embryotoxic, fetotoxic, and abortifacient in animals. There are no adequate and well-controlled studies in pregnant women. Pregnancy should be avoided during therapy. If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, the patient should be apprised of the potential fetal hazard.|Hemorrhage, sometimes severe or fatal, has been reported in patients receiving pazopanib. ... Pazopanib has not been evaluated in patients with a history of hemoptysis or patients with cerebral or clinically important GI hemorrhage within the past 6 months; therefore, the manufacturer recommends that pazopanib be avoided in such patients.|Pazopanib should be used with caution in patients who are at increased risk or who have a history of arterial thromboembolic events. Pazopanib has not been evaluated in patients who had experienced an arterial thromboembolic event within the past 6 months; therefore, the manufacturer recommends that pazopanib be avoided in such patients.|In patients with pre-existing moderate hepatic impairment, the starting dose of Votrient should be reduced or alternatives to Votrient should be considered. Treatment with Votrient is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT|Because pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin for elimination), mild elevations in indirect (unconjugated) bilirubin may occur in patients with deficient glucuronidation of bilirubin (i.e., Gilbert's syndrome).

>99% protein bound, independent of concentrations over a range of 10-100 μg/mL.

Treatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated with chemotherapy)|FDA Label|Renal-cell carcinoma (RCC)Votrient is indicated in adults for the first-line treatment of advanced renal-cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease.Soft-tissue sarcoma (STS)Votrient is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo)adjuvant therapy.Efficacy and safety have only been established in certain STS histological tumour subtypes.|Treatment of Ewing sarcoma family of tumours, Treatment of non-rhabdomyosarcoma soft tissue sarcoma, Treatment of rhabdomyosarcoma

Pazopanib is a multi-kinase inhibitor active against vascular endothelial growth factor receptors-1, -2 and -3 that is used in the therapy of advanced renal cell carcinoma and soft tissue sarcomas. Pazopanib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe and even fatal cases of clinically apparent acute liver injury.

Antineoplastic Agents

Votrient is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). /Included in US product label/|Votrient is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. /Included in US product label/|Limitation of Use: The efficacy of Votrient for the treatment of patients with adipocytic soft tissue sarcoma (STS) or gastrointestinal stromal tumors has not been demonstrated.|EXPL THER Pazopanib was evaluated for its ability to inhibit the growth of a variety of human tumor cell lines, HT-29 (colon), MDA-MB-468 (breast), PC3 (prostate), and A375P (melanoma) and normal human fibroblasts (HFF) growing in serum containing media. Pazopanib inhibited proliferation of HFF with an IC50 of 1.01 uM and had no effect on the proliferation of the 4 tumor cell lines at the highest concentration tested (30 uM). To further investigate whether pazopanib can directly modulate the proliferation of tumour cells, the compound was tested in a cell proliferation assay in a panel of 282 human cell lines. Of these, 281 were tumor cell lines derived from various tissue types, and 1 was a non-transformed breast cell line. IC50 values across the cell panel ranged from 0.01 to >10 uM. Only 7 cell lines showed an IC50 <1 uM: GDM1 (AML); ARH-77 (myeloma); NCI-H716 (colon carcinoma); G402 (kidney leiomyoblastoma); CGTH-W-1 (thyroid carcinoma); A204 (rhabdomyosarcoma) and CML-T1 (CML). Hence, pazopanib is a weak or inactive inhibitor of proliferation in the majority of human cell lines tested in vitro. The antitumor activity of pazopanib is, therefore, most likely derived from its anti-proliferative effect on endothelial cells.

/BOXED WARNING/ WARNING: HEPATOTOXICITY. Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.|Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases (ALT (SGPT), AST (SGOT)) and bilirubin, has been reported in patients receiving pazopanib. Most (92.5%) cases of aminotransferase elevations (of any grade) occurred during the first 18 weeks of therapy. In the randomized, placebo-controlled study (VEG105192) in patients with renal cell carcinoma, increases in ALT concentrations exceeding 3 or 10 times the upper limit of normal (ULN) were reported in approximately 18 or 4%, respectively, of patients receiving pazopanib. Concurrent increases in concentrations of ALT (exceeding 3 times the ULN) and bilirubin (exceeding twice the ULN) in the absence of substantial (exceeding 3 times the ULN) increases in alkaline phosphatase concentrations were reported in approximately 2% of patients receiving pazopanib. In an analysis of data from 11 studies involving 977 patients who received pazopanib as a single agent for a variety of tumor types (including 586 patients with renal cell carcinoma), death (resulting from disease progression and hepatic failure) occurred in approximately 0.2% of patients receiving pazopanib. Because pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin for elimination), mild elevations in indirect (unconjugated) bilirubin may occur in patients with deficient glucuronidation of bilirubin (i.e., Gilbert's syndrome). Liver function tests should be performed prior to initiation of pazopanib, at least once every 4 weeks for at least the first 4 months of therapy or as clinically indicated, and periodically thereafter. If hepatotoxicity occurs, pazopanib dosage should be reduced, or therapy should be interrupted or permanently discontinued.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|Prolongation of the QT interval and torsades de pointes have been reported in patients receiving pazopanib. In the VEG105192 study, prolongation of the QT interval (500-549 msec) was reported in approximately 1 or 0% of patients receiving pazopanib or placebo, respectively. In an analysis of pooled data from 3 studies involving 55815 patients with renal cell carcinoma, prolongation of the QT interval (500 msec or greater) or torsades de pointes was reported in approximately 2% or less than 1%, respectively, of patients receiving pazopanib. Pazopanib should be used with caution in patients with a history of prolongation of the QT interval, in patients receiving antiarrhythmic agents or other drugs that cause prolongation of the QT interval, and in patients with relevant preexisting cardiac disease. ECG should be monitored prior to initiation of pazopanib and periodically during treatment; serum electrolytes (e.g., calcium, magnesium, potassium) should be maintained within the normal range.|For more Drug Warnings (Complete) data for Pazopanib (23 total), please visit the HSDB record page.

Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.

Absorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;|Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.|Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4)|CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism.|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.|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 ug hr/mL and 58.1 ug/mL (equivalent to 132 uM), respectively. There was no consistent increase in AUC or Cmax at pazopanib doses above 800 mg.|Elimination is primarily via feces with renal elimination accounting for <4% of the administered dose.|Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 ug/mL.|For more Absorption, Distribution and Excretion (Complete) data for Pazopanib (8 total), please visit the HSDB record page.

Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma radioactivity.|In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.|Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. In this two-part study, ... the metabolism, disposition of (14)C-pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer /was investigated. In part A, three men each received a single oral dose of (14)C-pazopanib in suspension (400 mg, 70 uCi). Two metabolites derived from hydroxylation and one from N-demethylation were ,,, circulating, but were minor, each accounting for <5% of plasma radioactivity. ...|The routes of metabolism observed in human liver microsomes and hepatocytes were monooxygenation, di-oxygenation, and possibly oxidation to a carboxylic acid. Glucuronidation of a monooxygenated metabolite was also detected in human hepatocytes. There were no unique human phase I metabolites observed in either liver microsomal or hepatocyte incubations. However, a phase II metabolite, i.e., a glucuronide potentially derived from a carboxylic acid metabolite, was observed only in human hepatocytes. Its presumed precursor was identified in vivo as a significant component (<19%) in bile from bile duct cannulated monkeys. In conclusion, the combined in vitro and in vivo metabolic data indicated no major species differences in metabolism.|The extent of metabolism of pazopanib was low in human liver microsomal and hepatocyte incubations as well as in most of the preclinical species. Pazopanib was more extensively metabolized by rabbit and dog hepatocytes than by those from the other species studied. Following PO administration, unchanged pazopanib was the predominant component in feces from all species including humans.|Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. In this two-part study, ... the metabolism, disposition of (14)C-pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer /was investigated. In part A, three men each received a single oral dose of (14)C-pazopanib in suspension (400 mg, 70 uCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. ...

35 hours. Oral absorption is not the rate limiting step of elimination from the plasma.|The pharmacokinetics of pazopanib and/or its dihydrochloride salt has been studied in several animal species. The terminal elimination half-life was comparable among the animal species (half life = 2-6 hr) but significantly lower than observed in humans (half life = 21-51 hr).|Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg.

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 tumour blood vessel for tumour survival and growth.|Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. /SRP: triple negative = breast cancers lacking all three common targets of chemotherapy: the estrogen receptor, the progesterone receptor and Her2/neu, the epidermal growth factor receptor 2/ Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor beta (at tyrosine 751; p751-PDGFRbeta) was identified around perivascular brain micrometastases. p751-PDGFRbeta(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, /it was/ reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. /In this study/ the effect of pazopanib on the brain neuroinflammatory microenvironment /was evaluated/. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRbeta(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Treatment of overdose with Votrient should consist of general supportive measures. There is no specific antidote for overdosage of Votrient. Hemodialysis is not expected to enhance the elimination of Votrient because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.|For more Antidote and Emergency Treatment (Complete) data for Pazopanib (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases (ALT (SGPT), AST (SGOT)) and bilirubin, has been reported in patients receiving pazopanib.|/SIGNS AND SYMPTOMS/ Hemorrhage, sometimes severe or fatal, has been reported in patients receiving pazopanib.|/SIGNS AND SYMPTOMS/ Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.|/SIGNS AND SYMPTOMS/ GI perforation or fistula, sometimes fatal, has been reported in patients receiving pazopanib.|For more Human Toxicity Excerpts (Complete) data for Pazopanib (16 total), please visit the HSDB record page.

GW 780604

Oral: Tablets, film-coated: 200 mg (of pazopanib), Votrient (GlaxoSmithKline). /Pazopanib hydrochloride/

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC/MS-MS) method has been developed and validated for the quantitative determination of pazopanib in mouse plasma and brain tissue homogenate. Single liquid-liquid extraction step with ethyl acetate was employed for analysis of pazopanib and the internal standard (IS); vandetanib. HPLC separation was performed on an XTerra MS C18 column 50 mm x 4.6 mm, 5.0 um. The mobile phase consisted of 70% acetonitrile and 30% water with 0.1% formic acid, pumped at a flow rate of 0.25 mL/min. Analysis time was 3.5 min per run and both the analyte and IS eluted within 1.8-2.0 min. Multiple reactions monitoring (MRM) mode was utilized to detect the compounds of interest. The mass spectrometer was operated in the positive ion mode for detection. The precursor to product ions (Q1 to Q3) selected for pazopanib and internal standard during quantitative optimization were (m/z) 438.1 to 357.2 and 475.0 to 112.2 respectively. The calibration curves were linear over the range of 3.9-1000 ng/mL in both biological matrices. Lower limit of quantification (LLOQ) for mouse plasma and brain tissue was 3.9 ng/mL. The values for inter and intra day precision and accuracy were well within the ranges acceptable for analytical assessment (<15%). This method was applied to determine brain to plasma concentration ratio and relevant pharmacokinetic parameters of pazopanib after a single intravenous dose of 5 mg/kg in FVB wild type mice.|A quantitative bioanalytical liquid chromatography-tandem mass spectrometric assay for the tyrosine kinase inhibitor pazopanib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing pazopanib-d(4) as internal standard. The extract was injected into the chromatographic system after dilution with water (1:9, v/v). The system consisted of a sub-2 um particle, trifunctional bonded octadecyl silica column with isocratic elution using 0.005% (v/v) of formic acid in a mixture of water (76%, v/v) and acetonitrile (24%, v/v). The analyte was quantified using the selected reaction monitoring mode of a triple quadrupole mass spectrometer with a heated electrospray interface. The assay was validated in a 0.1-100 ug/mL calibration range. Within day precisions were 3.6-5.2%, between day precisions 4.0-8.3% and accuracies between 106% and 113% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients treated with pazopanib.

Human drugs -> Votrient -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans