Pazopanib

Each tablet contains Pazopanib HCl 217 mg and 433 mg equivalent to Pazopanib free base 200 mg and 400 mg, respectively.

Pazopanib also contains the following excipients: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone (K30) and sodium starch glycollate. Tablet Film-Coat: Hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide (E171) and red iron oxide (E172) (200-mg tablet only).

Pazopanib® is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Pazopanib is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Limitation Of Use

The efficacy of Pazopanib for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

Pazopanib is an anticancer medicine that is used to treat adults with kidney cancer (advanced renal cell carcinoma). It is also used to treat advanced soft tissue sarcoma (STS) in patients who have received cancer treatments.

Pazopanib interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by Pazopanib, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with Pazopanib, you and your doctor should talk about the benefits Pazopanib will do as well as the risks of using it.

Pazopanib is available only with your doctor's prescription.

Recommended Dose: 800 mg orally once daily.

Dose Modifications: Initial dose reduction should be from 800 mg to 400 mg daily. Subsequent dose modification, either an increase or decrease in dose, should be in 200-mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The dose of Pazopanib should not exceed 800 mg.

CYP3A4 Inhibitor: The concomitant use of strong CYP3A4 inhibitors may increase Pazopanib concentrations and should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If co-administration of a strong CYP3A4 inhibitor is warranted, a dose reduction to Pazopanib 400 mg is recommended based on pharmacokinetic studies. This dose is predicted to adjust the Pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors.

Elderly: No alteration of dosage, dosing frequency or route of administration is required in patients >65 years.

Renal Impairment: There is no experience of Pazopanib in patients with severe renal impairment or in patients undergoing peritoneal dialysis or haemodialysis; therefore, use of Pazopanib is not recommended in these patients. In a population, pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of Pazopanib. Renal impairment is not expected to have a clinically relevant effect on Pazopanib pharmacokinetics given the low renal excretion of Pazopanib and metabolites, and dose adjustment is not necessary.

Hepatic Impairment: The safety and pharmacokinetics of Pazopanib in patients with preexisting hepatic impairment have not been fully established.

Pharmacokinetic data from patients with normal hepatic function (n=12) and moderate (n=7) hepatic impairment indicate that Pazopanib clearance was decreased by approximately 50% in those with moderate hepatic impairment [total bilirubin >1.5-3 times the upper limit of normal (ULN)]. The dose of Pazopanib should be reduced to 200 mg/day in patients with moderate hepatic impairment. There are no data in patients with severe hepatic impairment [total bilirubin >3 x ULN regardless of any level of alanine aminotransferase (ALT)]; therefore, use of Pazopanib is not recommended in these patients. There are no data to support dosing recommendation in patients with mild hepatic impairment.

Missed Dose: If a dose is missed, Pazopanib should not be taken if it is <12 hrs until the next dose.

Administration: Pazopanib should be taken without food (at least 1 hr before or 2 hrs after a meal). It should be taken whole with water and must not be broken or crushed.

See also:
What is the most important information I should know about Pazopanib?

Do not use Pazopanib if you are pregnant. It could harm the unborn baby.

Before you take Pazopanib, tell your doctor if you have liver disease, heart disease, high blood pressure, underactive thyroid, an ulcer or other stomach disorder, or a history of Long QT syndrome, blood clot, or bleeding (stomach, intestinal, or brain).

There are many other drugs that can interact with Pazopanib. Tell your doctor about all medications you use.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Visit your doctor regularly.

If you need surgery, tell the surgeon ahead of time that you are using Pazopanib. You may need to stop using the medicine for a short time.

Stop using Pazopanib and call your doctor at once if you have a serious side effect such as bloody or tarry stools, coughing up blood, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes), sudden numbness or weakness, problems with speech or balance, chest pain, or vision and hearing problems.

Use Pazopanib as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Pazopanib comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Pazopanib refilled.
• Take Pazopanib by mouth on an empty stomach at least 1 hour before or 2 hours after eating.
• Swallow Pazopanib whole. Do not break, crush, or chew before swallowing.
• Do not eat grapefruit or drink grapefruit juice while you use Pazopanib.
• If you take an antacid while taking Pazopanib, ask your doctor or pharmacist how to take it with Pazopanib.
• Take Pazopanib on a regular schedule to get the most benefit from it.
• Continue to take Pazopanib even if you feel well. Do not miss any doses.
• If you miss a dose of Pazopanib, take it as soon as possible. If there are less than 12 hours before your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Pazopanib.

Pazopanib is used to treat kidney cancer. It may also be used to treat certain other types of cancer (soft tissue sarcoma). Pazopanib belongs to a class of drugs known as tyrosine kinase inhibitors. It works by decreasing the blood supply to the cancer tumor to slow tumor growth.

This medication should not be used in children, especially younger than 2 years of age, because of the risk of serious side effects.

How to use Pazopanib

Read the Medication Guide provided by your pharmacist before you start taking Pazopanib and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth without food as directed by your doctor, usually once daily. It is very important to take this medication on an empty stomach, at least 1 hour before or 2 hours after food.

Swallow this medication whole. Do not crush, chew, or break the tablets. Doing so can release all of the drug at once, increasing the risk of side effects.

Avoid eating grapefruit or drinking grapefruit juice while taking this medication. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Medications that reduce/block stomach acid (such as antacids, H2 blockers such as famotidine/ranitidine, proton pump inhibitors-PPIs such as omeprazole/lansoprazole) may reduce the absorption of Pazopanib, making it work less well. Do not take H2 blockers or PPIs while using this medication. If you are taking antacids, ask your pharmacist about how to best take them, such as taking antacids at least several hours apart from when you take Pazopanib. Ask your doctor or pharmacist if you are taking any of these medications.

Dosage is based on your medical condition, laboratory tests, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Your doctor will order lab tests to find the best dose for you. Keep all medical and lab appointments.

Do not increase your dose or take this drug more often than prescribed. Your condition will not improve any faster, and your risk of serious side effects will increase. Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Follow your doctor's instructions carefully.

Since this medication can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

Tell your doctor if your condition worsens.

See also:
What other drugs will affect Pazopanib?

Drugs That Inhibit Or Induce Cytochrome P450 3A4 Enzymes

In vitro studies suggested that the oxidative metabolism of Pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of Pazopanib.

CYP3A4 Inhibitors

Coadministration of Pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases Pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of Pazopanib to 400 mg. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of Pazopanib.

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease plasma Pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib should not be used if chronic use of strong CYP3A4 inducers cannot be avoided.

Drugs That Inhibit Transporters

In vitro studies suggested that Pazopanib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of Pazopanib may be influenced by products that affect P-gp and BCRP.

Concomitant treatment with strong inhibitors of P-gp or 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 P-gp or BCRP should be considered.

Effects Of Pazopanib On CYP Substrates

Results from drug-drug interaction trials conducted in cancer patients suggest that Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19.

Concomitant use of Pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Effect Of Concomitant Use Of Pazopanib And Simvastatin

Concomitant use of Pazopanib and simvastatin increases the incidence of ALT elevations. Across monotherapy trials with Pazopanib, 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 Pazopanib or consider alternatives to Pazopanib. Alternatively, consider discontinuing simvastatin. Insufficient data are available to assess the risk of concomitant administration of alternative statins and Pazopanib.

Drugs That Raise Gastric pH

In a drug interaction trial in patients with solid tumors, concomitant administration of Pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of Pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of Pazopanib with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2-receptor antagonists. Separate antacid and Pazopanib dosing by several hours to avoid a reduction in Pazopanib exposure.

See also:
What are the possible side effects of Pazopanib?

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Potentially serious adverse reactions with Pazopanib included:

• Hepatotoxicity
• QT prolongation and torsades de pointes
• Cardiac dysfunction
• Hemorrhagic events
• Arterial and venous thromboembolic events
• Thrombotic microangiopathy
• Gastrointestinal perforation and fistula
• Interstitial Lung Disease (ILD)/Pneumonitis
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
• Hypertension
• Infection
• Increased toxicity with other cancer therapies

Renal Cell Carcinoma

The safety of Pazopanib has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range: 0.1 to 27.6), the most commonly observed adverse reactions ( ≥ 20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.

The data described below reflect the safety profile of Pazopanib in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial. The median duration of treatment was 7.4 months (range: 0 to 23) for patients who received Pazopanib and 3.8 months (range: 0 to 22) for the placebo arm. Forty-two percent of patients on Pazopanib required a dose interruption. Thirty-six percent of patients on Pazopanib were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥ 10% of patients who received Pazopanib.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients with RCC Who Received Pazopanib

Diarrhea

Diarrhea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations

In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of Pazopanib, clinical pancreatitis was observed in < 1% (4/586) of patients.

Pneumothorax

Two of 290 patients treated with Pazopanib and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of Pazopanib for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with Pazopanib and in no patients on the placebo arm.

Bradycardia

In the randomized trial of Pazopanib for the treatment of RCC, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (52/280) of patients treated with Pazopanib and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with Pazopanib compared with < 1% (1/145) of patients treated with placebo. In the randomized trial of Pazopanib for the treatment of STS, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (45/238) of patients treated with Pazopanib and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with Pazopanib compared with < 1% (1/123) of patients treated with placebo.

Adverse Reactions In East Asian Patients

In an analysis of pooled clinical trials (N=1938) with Pazopanib, 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%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pazopanib. 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.