Pazopanib is an oral tyrosine kinase inhibitor (TKI). It primarily targets vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. By inhibiting these receptors, pazopanib hinders the growth and spread of cancer cells. Pazopanib is approved by the U.S. Food and Drug Administration (FDA) and other regulatory agencies for the treatment of certain types of cancers, most notably advanced renal cell carcinoma (kidney cancer).

Pazopanib (Votrient) is a multitargeted Tyrosine kinase inhibitor that inhibits angiogenesis and tumor growth.

Indications of Pazopanib (Votrient):

• Advanced Renal cell carcinoma:
  • It is indicated for the treatment of advanced renal cell carcinoma.
• Advanced Soft tissue sarcoma:
  • It is used for the treatment of advanced soft tissue sarcoma (in patients who have received prior chemotherapy)
  • Limitations of use: The efficacy of pazopanib for the treatment of adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated.
• Off Label Use of Pazopanib in Adults:
  • Advanced differentiated Thyroid cancer

Pazopanib (Votrient) dose in Adults

Pazopanib (Votrient) dose in the treatment of advanced Renal cell carcinoma:

• In the treatment of advanced kidney cancer (renal cell carcinoma), the typical dose of pazopanib is 800 milligrams (mg) taken as a pill once a day.

Pazopanib (Votrient) dose in the treatment of advanced soft tissue sarcoma:

• For treating advanced soft tissue sarcoma (STS), pazopanib is typically given as a pill with a dose of 800 milligrams (mg) once a day.

Pazopanib (Votrient) dose in the treatment of advanced Thyroid cancer, differentiated (off-label):

• For treating advanced differentiated thyroid cancer (a use that isn't officially approved, or "off-label"), the usual dose of pazopanib is 800 milligrams (mg) taken by mouth once a day.
• This treatment continues until the cancer gets worse or the side effects become too much to handle.

Missed doses:

• If you forget to take a dose and there's less than 12 hours until your next scheduled dose, you should skip the missed dose.
• Don't take the missed dose; just continue with the next one as planned.

Concomitant CYP3A4 inhibitors/inducers:

Pazopanib interacts with certain other drugs, especially those affecting an enzyme system called CYP3A4.

CYP3A4 inhibitors:

• These are drugs that reduce the activity of the CYP3A4 enzyme. If you take them with pazopanib, they can increase the amount of pazopanib in your body.
  • Advice: It's best to avoid strong CYP3A4 inhibitors while on pazopanib. If you must take both, your pazopanib dose may need to be reduced to 400 mg once a day. Also, you'll need to be watched closely for side effects, and your dose might be adjusted further if problems come up.

CYP3A4 inducers:

• These are drugs that boost the activity of the CYP3A4 enzyme. If you take them with pazopanib, they can decrease the amount of pazopanib in your body.
  • Advice: Try to avoid strong CYP3A4 inducers while on pazopanib. If you need to be on a strong CYP3A4 inducer for a long time, it might be best not to take pazopanib at all.

Pazopanib (Votrient) use in children:

The efficacy and safety of the drug in children have not been established.

Pregnancy Risk Category: D

• Pazopanib can harm an unborn baby if taken by a pregnant woman.
• Before starting this medicine, women who can become pregnant should check if they're pregnant.
• Such women should avoid getting pregnant and use effective birth control during treatment and for two weeks after the last dose.
• Men, even if they've had a vasectomy, should use condoms if their partner is pregnant or can become pregnant, and continue for two weeks after their last dose of pazopanib.

Use of Pazopanib while breastfeeding

• We're not sure if pazopanib gets into breast milk.
• But because of the possible risks to a nursing baby, it's advised that mothers should stop breastfeeding while taking this medicine and for two weeks after their last dose.

Pazopanib (Votrient) Dose adjustment in renal disease:

• For people with normal or moderately impaired kidney function (CrCl ≥30 mL/minute), there's no need to change the pazopanib dose because kidney problems aren't expected to affect how the body processes the medication.
• For those with severe kidney impairment (CrCl <30 mL/minute), there are no specific dose adjustments recommended in the official guidelines because it hasn't been studied extensively. However, similar to those with better kidney function, renal impairment is not expected to significantly affect how the body handles pazopanib.

Pazopanib (Votrient) Dose adjustment in liver disease:

For people starting pazopanib with already known liver problems:

• Mild liver problems (bilirubin levels slightly raised, up to 1.5 times the normal upper limit, or ALT levels above normal): No change in the usual pazopanib dose.
• Moderate liver problems (bilirubin levels between 1.5 to 3 times the normal limit): Either think about using a different treatment or reduce the pazopanib dose to 200 mg once a day.
• Severe liver problems (bilirubin more than 3 times the normal limit): It's better not to use pazopanib.

For people who develop liver problems while on pazopanib:

• If ALT levels are raised 3 to 8 times the normal level: Keep taking the same dose, but check liver function every week until ALT goes back to near normal.
• If ALT levels are more than 8 times the normal level: Stop taking pazopanib until ALT returns to near normal. If the benefits of taking pazopanib are more significant than the liver risks, you can start taking it again but at a reduced dose of 400 mg daily, while checking the liver function every week for 8 weeks. If ALT rises again, stop pazopanib permanently.
• If ALT rises more than 3 times the normal limit and bilirubin more than 2 times the normal limit at the same time: Stop taking pazopanib forever and monitor the liver.
• For people with Gilbert syndrome (a mild liver condition) showing a slight increase in indirect bilirubin and ALT more than 3 times the normal: Follow the guidelines for raised ALT as above.

Common Side Effects of Pazopanib (Votrient):

• Cardiovascular:
  • Hypertension
  • Bradycardia
  • Peripheral Edema
  • Cardiac Insufficiency
• Central Nervous System:
  • Fatigue
  • Tumor Pain
  • Headache
  • Dizziness
• Dermatologic:
  • Hair Discoloration
  • Exfoliative Dermatitis
  • Alopecia
  • Dermatological Disease
  • Hypopigmentation
  • Palmar-Plantar Erythrodysesthesia
• Endocrine & Metabolic:
  • Weight Loss
  • Increased Serum Glucose
  • Increased Thyroid-Stimulating Hormone
  • Decreased Serum Albumin
  • Decreased Serum Phosphate
  • Decreased Serum Sodium
  • Decreased Serum Magnesium
  • Decreased Serum Glucose
  • Increased Serum Potassium
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Decreased Appetite
  • Anorexia
  • Vomiting
  • Dysgeusia
  • Increased Serum Lipase
  • Gastrointestinal Pain
  • Abdominal Pain
  • Mucositis
  • Stomatitis
• Hematologic & Oncologic:
  • Leukopenia
  • Lymphocytopenia
  • Thrombocytopenia
  • Neutropenia
  • Hemorrhage
• Hepatic:
  • Increased Serum AST
  • Increased Serum ALT
  • Increased Serum Bilirubin
  • Increased Serum Alkaline Phosphatase
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Myalgia
  • Weakness
• Respiratory:
  • Dyspnea
  • Cough
• Miscellaneous:
  • Tumor Pain

Uncommon Side Effects Of Pazopanib (Votrient):

• Cardiovascular:
  • Chest Pain
  • Left Ventricular Systolic Dysfunction
  • Venous Thrombosis
  • Ischemia
  • Myocardial Infarction
  • Prolonged Q-T Interval On ECG
  • Facial Edema
  • Transient Ischemic Attacks
• Central Nervous System:
  • Insomnia
  • Voice Disorder
  • Chills
• Dermatologic:
  • Skin Rash
  • Skin Depigmentation
  • Xeroderma
  • Nail Disease
• Endocrine & Metabolic:
  • Hypothyroidism
• Gastrointestinal:
  • Dyspepsia
  • Anal Hemorrhage
  • Gastrointestinal Fistula
  • Gastrointestinal Perforation
• Genitourinary:
  • Proteinuria
  • Hematuria
• Hematologic & Oncologic:
  • Oral Hemorrhage
  • Rectal Hemorrhage
• Ophthalmic:
  • Blurred Vision
• Respiratory:
  • Epistaxis
  • Pneumothorax
  • Hemoptysis

Rare side effects of Pazopanib (Votrient):

• Cardiovascular:
  • Decreased Left Ventricular Ejection Fraction
  • Hypertensive Crisis
• Central Nervous System:
  • Reversible Posterior Leukoencephalopathy Syndrome
• Hematologic & Oncologic:
  • Hemolytic-Uremic Syndrome
  • Neutropenic Infection
  • Thrombotic Thrombocytopenic Purpura
• Hepatic:
  • Hepatotoxicity
  • Severe Hepatotoxicity
• Infection:
  • Serious Infection
• Neuromuscular & Skeletal:
  • Arthralgia
• Muscle Spasm

Contraindication to Pazopanib (Votrient):

In the U.S., the manufacturer hasn't listed any specific reasons you absolutely shouldn't take pazopanib.

However, in Canada, there are two reasons they advise against its use:

• If you're allergic to pazopanib or any ingredient in the medication.
• For children under 2 years old, because of the way the drug affects blood vessel formation.

Warnings and precautions

Perforation/fistula of the gastrointestinal tract

• Pazopanib can sometimes cause serious stomach or intestine issues, like holes (perforations) or abnormal connections (fistulas).
• Some of these situations have even been deadly.

Reaction to skin on the hand-foot:

• Hand-foot skin reaction (HFSR) is a skin problem seen with drugs like pazopanib, which is different from a similar reaction with other cancer drugs.
• With HFSR, people feel burning or tingling in their hands and feet, often within the first few weeks of treatment.
• This can lead to rough, dry, or cracked skin, and even blisters in areas that experience pressure, like the palms or soles.
• Pazopanib has a lower chance of causing this compared to similar drugs.
• Before starting treatment, it's good to check the skin and remove any thickened areas.
• Using a moisturizer twice a day can help, and if the skin gets worse, you might need a special moisturizer, cream, or even a break from the medicine.
• It's also good to avoid tight shoes and too much rubbing on the affected areas.

Heart Failure:

• Pazopanib can sometimes start or make heart failure worse.
• Especially if someone has had certain cancer treatments before, like anthracyclines, or has high blood pressure, they're at a higher risk.
• It's recommended to regularly check heart function for these patients.
• It's essential to watch out for any signs of heart trouble while on this medicine.

Hemorrhage

• Pazopanib can sometimes cause bleeding problems, and some of these have been serious or even fatal.
• In studies, kidney cancer patients mainly experienced blood in urine, nosebleeds, coughing up blood, or rectal bleeding.
• People with soft tissue sarcoma had nosebleeds, mouth bleeding, and anal bleeding.
• If someone has had serious bleeding issues, like coughing up blood, brain bleeding, or significant stomach bleeding in the past 6 months, they shouldn't take pazopanib, as these people weren't included in the trials.

Hepatotoxicity: [US Boxed Warning]

• Pazopanib has a serious warning about liver damage, which can be severe or even deadly.
• This warning is highlighted in a special "boxed warning" in the U.S.
• It's important to regularly check liver function when taking this medicine.
• You should get liver tests at the start, then several times in the first few months, and afterwards as needed.
• Most liver issues happen early in treatment.
• If someone already has serious liver problems, they shouldn't take pazopanib.
• For moderate liver problems, the dose should be reduced.
• People with a mild condition called Gilbert syndrome might only see a slight increase in a liver substance called bilirubin.
• If they also have high ALT (a liver enzyme), follow the guidelines for high ALT.
• Older adults, especially those over 65, have a higher risk of liver problems with this drug.

Hypertension

• Pazopanib can cause or make high blood pressure worse, and in some cases, it can lead to a dangerous rise in blood pressure called hypertensive crisis.
• Before starting the drug, it's important to have blood pressure under control.
• While on pazopanib, keep a close eye on blood pressure, and if it goes up, blood pressure medicine might be needed.
• This high blood pressure issue usually shows up early after starting treatment.
• If blood pressure stays high even with medicine, the pazopanib dose might need to be lowered.
• If someone has a hypertensive crisis or if their high blood pressure can't be controlled with a lower dose and medicine, then pazopanib should be stopped.

Infections

• Pazopanib can sometimes lead to severe or even deadly infections.
• If you're taking this medicine, watch out for any signs of an infection.
• If a serious infection occurs, you might need to stop taking pazopanib either for a short time or permanently, depending on the situation.

Ocular toxicities:

• There have been reports of eye problems, specifically the retina detaching or tearing, in people taking pazopanib.

Proteinuria

• Pazopanib can sometimes cause increased protein levels in the urine.
• Before starting the medicine, and periodically while on it, it's a good idea to test the urine to check protein levels.
• If the levels are high (more than 3 grams in 24 hours), the dose of pazopanib might need to be lowered.
• If high protein levels keep coming back, the medicine might need to be stopped.

Toxicity in the lungs:

• Pazopanib can sometimes cause lung problems like interstitial lung disease (ILD) or pneumonitis.
• These can be serious and even deadly.
• If you're taking this drug and notice breathing issues or other lung symptoms, it's essential to see a doctor right away.
• If these lung conditions develop, you'll likely need to stop taking pazopanib.

Extension of QTc:

• Pazopanib can sometimes cause a change in the heart's rhythm, making the QTc interval on an ECG longer.
• This can lead to a dangerous heartbeat called torsade de pointes.
• If someone has had heart rhythm issues, is on medicines that can affect heart rhythm, or has heart disease, they should be careful when taking pazopanib.
• It's good to get a heart test (ECG) before starting the medicine and at times while on it.
• Also, make sure levels of important minerals like potassium, calcium, and magnesium are normal before and during treatment.

Reversible posterior Leukoencephalopathy Syndrome (RPLS).

• Pazopanib can, although rarely, lead to a condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
• This can be life-threatening.
• Watch out for signs like sudden blindness, confusion, headaches, tiredness, seizures, or other changes in vision or thinking.
• High blood pressure might also happen alongside these symptoms.
• If someone develops RPLS while on pazopanib, they should stop the medication permanently.

Events that are thromboembolic:

• Pazopanib can sometimes increase the risk of blood clots in veins or arteries.
• Conditions like deep vein thrombosis (DVT), lung clots (pulmonary embolism), chest pain (angina), brief stroke-like symptoms (transient ischemic attack), heart attack (MI), and stroke were seen more in people taking pazopanib compared to a placebo in studies.
• Some of these events were fatal.
• If on this drug, watch out for signs of blood clots or lung clots.
• If someone has had blood clots or is at a high risk for them, they should be extra careful.
• It's not recommended to take pazopanib if they've had an arterial clotting event in the past 6 months since it hasn't been studied in such cases.

Thrombotic microangiopathy

• Pazopanib can lead to a condition called thrombotic microangiopathy (TMA), which includes serious issues like thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).
• These problems have been seen when taking pazopanib alone or combined with other drugs, like bevacizumab or topotecan (which is not the standard use).
• TMA usually appears within the first 90 days of starting the treatment.
• If on this drug, it's essential to watch out for signs of TMA.
• If someone develops TMA while on pazopanib, they should stop the medication permanently.

Thyroid disorders

• Pazopanib can sometimes cause low thyroid function, known as hypothyroidism.
• If you're taking this drug, it's a good idea to regularly check your thyroid levels to ensure they're okay.

Wound healing complications

• Pazopanib, which is a type of drug that blocks VEGF receptors, can interfere with the body's ability to heal wounds.
• If you're planning to have surgery, it's recommended to stop taking the drug at least 7 days before the operation.
• After the surgery, your doctor will decide when it's safe to start the medication again.
• If a wound reopens after it's started to heal, you should stop taking pazopanib.

Renal impairment:

• Patients with mild or moderate kidney issues were part of the studies on pazopanib.
• However, there's no detailed data on how the drug works in people with severe kidney problems who are on dialysis (both peritoneal and hemodialysis).
• But, based on what's known, severe kidney problems aren't expected to majorly change how the body processes or reacts to pazopanib.

Pazopanib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Liver Function:
  • Check ALT, AST, bilirubin levels initially.
  • Then at weeks 3, 5, 7, 9.
  • Then at months 3, 4.
  • After month 4, check occasionally (or more often if needed).
• Electrolytes:
  • Keep an eye on calcium, magnesium, and potassium levels.
• Urine Tests:
  • Check for protein in urine initially and occasionally.
  • Do a 24-hour urine protein test if needed.
• Thyroid Function:
  • Check TSH and T initially.
  • Monitor TSH every 6 to 8 weeks during treatment.
• Pregnancy:
  • Make sure women who can become pregnant aren't pregnant before starting the drug.
• Blood Pressure:
  • Keep a regular check.
• Heart Health:
  • ECG: Get an initial reading and then occasional checks.
  • LVEF: Check initially and occasionally if there's a risk of heart issues.
• Look out for signs/symptoms of:
  • Stomach or intestine issues (GI perforation or fistula).
  • Blood clots in veins or arteries.
  • Lung clots (pulmonary embolism).
  • Lung issues (interstitial lung disease/pneumonitis).
  • Infections.
  • Heart failure.
  • Changes in brain function or symptoms.
• Medication Adherence:
  • Ensure the patient is taking the medication as prescribed.

How to administer Pazopanib (Votrient)?

• When to Take:
  • Take it on an empty stomach.
  • Either 1 hour before eating or 2 hours after a meal.
• How to Take:
  • Swallow the tablet whole.
  • Do not crush the tablet, as it can change how quickly your body absorbs the medicine and its overall effect.

Mechanism of action of Pazopanib (Votrient):

• Pazopanib is a type of drug called a tyrosine kinase inhibitor.
• It helps slow down tumor growth by blocking certain pathways that tumors use to grow and spread.
• It mainly targets specific receptors on cell surfaces, like VEGFR and PDGFR, which are involved in blood vessel formation for tumors.
• It also affects other receptors that play roles in tumor growth and the body's immune response.
• In short, pazopanib blocks multiple pathways that cancer cells use to thrive.

Protein Binding:

• It binds strongly to proteins in the blood (over 99% of the drug).

Metabolism:

• It's mainly processed in the liver. The primary enzyme responsible is CYP3A4, but CYP1A2 and CYP2C8 also play minor roles.

Bioavailability:

• The body absorbs it better when taken with food. Crushing the tablets can also increase its absorption, but you shouldn't crush them.

Half-life:

• It takes about 31 hours for the body to get rid of half the drug.

Peak Time:

• The highest amount of the drug in the blood is reached between 2 to 4 hours after taking it.

Excretion:

• It's mostly gotten rid of in feces, with a very small amount (less than 4%) leaving through urine.

Pazopanib Brand Names (International):

• Votrient
• Votrieny
• Vottrient

Pazopanib Brand Names in Pakistan:

Update soon.