Pazopanib

The standard recommended starting dose for Pazopanib in adults with either advanced renal cell carcinoma or advanced soft tissue sarcoma is 800 mg taken orally once daily.

Your healthcare provider may adjust this dose based on how well you tolerate the medication. If you experience significant side effects, your doctor might reduce the dose in 200 mg increments (e.g., decreasing from 800 mg to 600 mg, and then to 400 mg if necessary). If a dose of 400 mg is still not tolerated, the medication is typically discontinued. It is vital to never change your dose without explicit instructions from your oncology team.

Pazopanib is not approved for use in pediatric patients. Clinical studies in juvenile animals have shown that Pazopanib can cause severe issues with organ development and bone growth (epiphyseal growth plate abnormalities). Because of these risks, safety and effectiveness in children have not been established, and the drug is generally avoided in patients under the age of 18.

Renal Impairment

For patients with mild to moderate kidney dysfunction, no initial dose adjustment is typically required, as very little of the drug is excreted through the kidneys. However, there is limited data for patients with severe renal impairment or those on dialysis; in these cases, the drug must be used with extreme caution.

Hepatic Impairment

The liver is responsible for breaking down Pazopanib, so liver function is critical.

• Mild Impairment: No dose adjustment is usually needed.
• Moderate Impairment: The dose is typically reduced to 200 mg once daily.
• Severe Impairment: Pazopanib is not recommended for patients with severe liver dysfunction (Total Bilirubin > 3x Upper Limit of Normal).

Elderly Patients

In clinical trials, no overall differences in safety or effectiveness were observed between patients over 65 and younger patients. However, older adults may be more sensitive to certain side effects, such as high blood pressure or heart issues, and should be monitored closely.

Proper administration is crucial for the safety and efficacy of Pazopanib.

1. 1Empty Stomach: You must take Pazopanib at least 1 hour before a meal or 2 hours after a meal. Taking it with food can double the amount of drug in your system, leading to dangerous toxicity.
2. 2Whole Tablet: Swallow the tablets whole with a glass of water. Do not crush, chew, or break the tablets. Crushing the tablet increases the rate at which the drug is released, which can be harmful.
3. 3Consistency: Try to take your dose at the same time every day to maintain steady levels in your bloodstream.
4. 4Storage: Store the tablets at room temperature (20°C to 25°C or 68°F to 77°F) in their original container, away from moisture and heat.

If you miss a dose of Pazopanib, take it as soon as you remember. However, if your next scheduled dose is less than 12 hours away, skip the missed dose and return to your regular schedule. Do not take two doses at once to make up for a missed one. If you vomit after taking a dose, do not take an extra dose; simply wait until your next scheduled time.

An overdose of Pazopanib can lead to severe hypertension (high blood pressure), extreme fatigue, and liver damage. If you suspect an overdose, seek emergency medical attention or contact a Poison Control Center immediately. Treatment for overdose is supportive, as there is no specific antidote for Pazopanib. Doctors will monitor your blood pressure and liver enzymes closely.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as this could allow your cancer to grow more rapidly.

Most patients taking Pazopanib will experience some side effects. While many are manageable, they require consistent communication with your doctor.

• Diarrhea: This is the most frequently reported side effect. It can range from mild to severe. It is important to stay hydrated and use over-the-counter anti-diarrheal medications only if directed by your doctor.
• Hypertension (High Blood Pressure): Pazopanib commonly causes an increase in blood pressure, often within the first few weeks of treatment. You will likely need to monitor your blood pressure at home daily.
• Hair Color Changes: Many patients notice their hair turning white or losing its pigment (depigmentation) during treatment. This is usually reversible once the drug is stopped.
• Nausea and Vomiting: These gastrointestinal issues are common but can often be managed with anti-nausea medications.
• Fatigue: A profound sense of tiredness or lack of energy is common. It is important to balance rest with light activity.
• Loss of Appetite and Weight Loss: You may find that food tastes different or that you have no desire to eat.

• Stomatitis: Painful sores or swelling inside the mouth.
• Dysgeusia: A distortion of the sense of taste, often described as a metallic taste.
• Proteinuria: The presence of excess protein in the urine, which can indicate kidney stress.
• Hypothyroidism: An underactive thyroid gland, which may cause weight gain, cold intolerance, and dry skin.
• Palmar-Plantar Erythrodysesthesia: Also known as Hand-Foot Syndrome, this causes redness, swelling, and pain on the palms of the hands and soles of the feet.

• Pancreatitis: Inflammation of the pancreas, causing severe abdominal pain.
• Pneumothorax: A collapsed lung, which may cause sudden chest pain and shortness of breath.
• Bradycardia: An unusually slow heart rate.

> Warning: Stop taking Pazopanib and call your doctor immediately or seek emergency care if you experience any of the following:

• Liver Toxicity: Yellowing of the skin or eyes (jaundice), dark urine, or severe pain in the upper right side of the stomach. This is a critical risk associated with Pazopanib.
• Heart Failure: Sudden shortness of breath, swelling in your ankles or legs, or rapid weight gain.
• Hemorrhage: Any unusual bleeding, such as coughing up blood, nosebleeds that won't stop, or blood in your stool (which may look black and tarry).
• Gastrointestinal Perforation: Severe stomach pain, fever, nausea, and vomiting. This is a hole that develops in the wall of the stomach or intestine.
• Arterial Thromboembolism: Symptoms of a heart attack or stroke, such as chest pain, numbness on one side of the body, or difficulty speaking.
• QT Prolongation: A heart rhythm disorder that can cause fainting or a racing, pounding heartbeat.

With prolonged use, Pazopanib can lead to chronic conditions that require ongoing management:

• Thyroid Dysfunction: Long-term suppression of thyroid function is common, and many patients eventually require thyroid hormone replacement therapy.
• Cardiac Dysfunction: Over time, the strain on the heart from high blood pressure and direct drug effects can lead to a decreased 'ejection fraction' (the heart's ability to pump blood).
• Kidney Stress: Chronic proteinuria may lead to long-term kidney impairment in some patients.

The FDA has issued a Black Box Warning for Pazopanib regarding Hepatotoxicity (Liver Toxicity). Severe and sometimes fatal liver damage has been observed in clinical trials. Your doctor must perform liver function tests (ALT, AST, and bilirubin) before you start the drug and every 4 weeks for at least the first 4 months of treatment. Periodic monitoring will continue thereafter. If your liver enzymes rise significantly, the drug may need to be paused or permanently discontinued.

Report any unusual symptoms, no matter how minor they seem, to your healthcare provider immediately. Early intervention is key to managing the side effects of Pazopanib.

Pazopanib is a high-alert medication that requires careful supervision by an oncologist. Because it affects the growth of blood vessels and multiple organ systems, the risks are significant. Patients must be proactive in monitoring their health and reporting changes immediately. It is essential to keep all follow-up appointments and laboratory visits while taking this medication.

Hepatotoxicity: Pazopanib can cause severe liver injury that can lead to liver failure or death. In clinical trials, increases in liver enzymes (ALT and AST) and bilirubin were frequently observed. Monitoring is mandatory. Liver function tests must be conducted at baseline, at weeks 3, 5, 7, and 9, then at month 3 and month 4, and periodically thereafter. If you have pre-existing liver disease, you must inform your doctor, as this significantly increases your risk.

• Hypertension (High Blood Pressure): This is one of the most common complications. Blood pressure should be well-controlled before starting Pazopanib. Most patients will require the start of, or an increase in, blood pressure medications. If blood pressure cannot be controlled, Pazopanib must be stopped.
• QT Prolongation and Torsades de Pointes: Pazopanib can affect the electrical activity of the heart, potentially leading to a dangerous heart rhythm called Torsades de Pointes. This risk is higher if you have low potassium or magnesium levels or if you take other medications that affect the heart rhythm.
• Cardiac Dysfunction: There is a risk of heart failure and decreased pumping strength of the heart. Patients with a history of heart disease require baseline and periodic 'ECHO' or 'MUGA' scans to check heart function.
• Hemorrhagic Events: Because Pazopanib inhibits VEGF, it can interfere with the body's ability to maintain blood vessel integrity, leading to internal bleeding. Fatal bleeding events have occurred.
• Arterial and Venous Thromboembolism: There is an increased risk of blood clots in the arteries (leading to heart attack or stroke) and veins (leading to deep vein thrombosis or pulmonary embolism).
• Wound Healing: Pazopanib interferes with the growth of new blood vessels, which is essential for wound healing. If you are scheduled for surgery, you must stop taking Pazopanib at least 7 days before the procedure. It should not be restarted for at least 2 weeks after surgery and only once the wound is fully healed.

While taking Pazopanib, you will need frequent testing:

• Liver Function Tests (LFTs): ALT, AST, and Bilirubin (Every 4 weeks for the first 4 months).
• Blood Pressure: Daily monitoring at home is highly recommended.
• Thyroid Function Tests (TFTs): To check for hypothyroidism.
• Urinalysis: To check for protein in the urine (proteinuria).
• Electrolytes: Specifically potassium, magnesium, and calcium.
• EKGs: To monitor the QT interval of the heart.

Pazopanib can cause significant fatigue and occasional dizziness. You should see how the medication affects you before driving or operating heavy machinery. If you feel excessively tired or faint, avoid these activities.

There is no direct contraindication for alcohol, but since both Pazopanib and alcohol are processed by the liver, heavy drinking can increase the risk of hepatotoxicity. It is best to limit alcohol consumption significantly while on this treatment.

Do not stop taking Pazopanib suddenly unless directed by your doctor. If you stop the drug, your tumor may begin to grow again. There is no known withdrawal syndrome, but the underlying cancer may progress rapidly upon cessation.

> Important: Discuss all your medical conditions, especially liver, heart, or bleeding disorders, with your healthcare provider before starting Pazopanib.

Certain medications should never be used with Pazopanib because the interaction is too dangerous to manage.

• Strong CYP3A4 Inhibitors: Drugs like Ketoconazole, Itraconazole, Ritonavir, and Clarithromycin can dramatically increase the concentration of Pazopanib in your blood, leading to life-threatening toxicity.
• Strong CYP3A4 Inducers: Drugs like Rifampin, Phenytoin, and Carbamazepine can lower the levels of Pazopanib so much that the drug becomes ineffective against the cancer.
• Simvastatin: Co-administration with Pazopanib increases the risk of ALT (liver enzyme) elevations. If a statin is needed, your doctor will likely choose an alternative to simvastatin.

• QT-Prolonging Drugs: Medications such as Amiodarone, Haloperidol, and certain antibiotics (like Levofloxacin) increase the risk of dangerous heart rhythms when taken with Pazopanib.
• Anticoagulants and Antiplatelets: Drugs like Warfarin, Aspirin, or Clopidogrel increase the risk of bleeding. Since Pazopanib already carries a risk of hemorrhage, combining these requires extreme caution.
• Gastric Acid-Reducing Agents: Pazopanib requires an acidic environment in the stomach to be absorbed. Proton Pump Inhibitors (PPIs) like Omeprazole should be avoided. If you must use an antacid, it should be taken at least several hours apart from your Pazopanib dose.

• CYP2D6 and CYP2C8 Substrates: Pazopanib may increase the levels of other drugs processed by these enzymes (such as certain antidepressants or heart medications), potentially increasing their side effects.
• P-gp and BCRP Inhibitors: These can alter the transport of Pazopanib in and out of cells, affecting its efficacy and safety.

• High-Fat Meals: Taking Pazopanib with a high-fat meal can increase the drug's absorption by 200%. This is why the drug must be taken on an empty stomach (1 hour before or 2 hours after food).
• Grapefruit and Grapefruit Juice: Grapefruit is a potent inhibitor of the CYP3A4 enzyme. Consuming grapefruit while on Pazopanib can lead to dangerously high levels of the medication. Avoid all grapefruit products.

• St. John’s Wort: This herbal supplement is a strong inducer of CYP3A4 and will significantly reduce the effectiveness of Pazopanib. It should be avoided entirely.
• Supplements that increase bleeding risk: Garlic, Ginkgo Biloba, and high-dose Vitamin E should be used with caution as they may compound the bleeding risks of Pazopanib.

Pazopanib does not typically interfere with the chemical results of lab tests, but it causes physiological changes that will be reflected in your labs, such as:

• Elevated ALT/AST/Bilirubin (Liver damage)
• Increased TSH (Hypothyroidism)
• Increased Glucose (Hyperglycemia)
• Decreased White Blood Cell count (Neutropenia)

For each major interaction, the primary mechanism is usually the inhibition or induction of the CYP3A4 enzyme or the alteration of gastric pH. The clinical consequence is either increased toxicity (which can be fatal) or reduced efficacy (allowing the cancer to grow). The management strategy is typically to avoid the interacting drug or to adjust the dose of Pazopanib under strict supervision.

> Important: Tell your doctor about ALL medications, over-the-counter drugs, supplements, and herbal products you are taking. Even 'natural' products can have deadly interactions with chemotherapy.

There are certain situations where Pazopanib must never be used because the risks far outweigh any potential benefits.

• Severe Hepatic Impairment: Patients with severe liver disease (Total Bilirubin > 3x the upper limit of normal) should not take Pazopanib. Because the liver is the primary organ that clears the drug, severe impairment leads to toxic accumulation and potential liver failure.
• Hypersensitivity: If you have had a severe allergic reaction (anaphylaxis) to Pazopanib or any of its inactive ingredients, you cannot take this medication.
• Pregnancy: Pazopanib is known to cause fetal harm and is contraindicated in pregnant women. The mechanism involves the inhibition of VEGF, which is essential for fetal blood vessel development and placental health.

These are conditions that require a careful risk-benefit analysis by your oncologist before starting treatment:

• History of Hemoptysis (Coughing up blood): Patients who have recently coughed up blood are at a much higher risk for fatal pulmonary hemorrhage while on Pazopanib.
• Recent Major Surgery: Because Pazopanib severely impairs wound healing, it should not be started in patients who have had major surgery within the last 2 to 4 weeks, or until the surgical site is completely healed.
• Pre-existing Hypertension: If high blood pressure is not controlled with medication, starting Pazopanib can lead to hypertensive crisis or stroke.
• Cardiac History: Patients with a recent heart attack (within 6 months), unstable angina, or significant congestive heart failure are at high risk for cardiac complications.
• Gastrointestinal Disorders: Those with a history of fistulas or gastrointestinal perforation should be treated with extreme caution, as Pazopanib increases the risk of these events recurring.

While there is no documented cross-sensitivity with other tyrosine kinase inhibitors (like Sunitinib or Sorafenib), patients who have had severe, idiosyncratic reactions to other drugs in this class should be monitored with extra vigilance, as they may share similar metabolic pathways or target-organ sensitivities.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of blood clots, bleeding, or heart disease, before prescribing Pazopanib.

Pazopanib is classified as a significant reproductive hazard. Based on its mechanism of action (inhibiting angiogenesis), it is expected to cause fetal harm when administered to a pregnant woman. Animal studies have shown that even at doses lower than the human equivalent, Pazopanib causes embryo-fetal lethality and severe structural abnormalities.

• Contraception: Females of reproductive potential must use effective contraception during treatment and for at least 2 weeks after the last dose.
• Male Fertility: Men with female partners of reproductive potential should use condoms during treatment and for at least 2 weeks after the last dose to prevent potential fetal exposure.

It is not known if Pazopanib is excreted in human milk. However, because many drugs are excreted in milk and because of the potential for serious adverse reactions in a nursing infant (including effects on growth and organ development), breastfeeding is not recommended during treatment with Pazopanib and for at least 2 weeks after the final dose.

Pazopanib is not recommended for use in children. Safety has not been established in patients under 18 years of age. In juvenile animal studies, Pazopanib caused severe toxicity, particularly in the lungs, liver, and bones. Most notably, it caused abnormalities in the epiphyseal growth plates (the areas at the ends of long bones where growth occurs), which could lead to permanent growth failure or skeletal deformities.

Approximately 30% to 40% of patients in clinical trials for RCC and STS were 65 years of age or older. While no overall differences in the drug's effectiveness were noted between older and younger patients, elderly patients may be at a higher risk for certain side effects, such as:

• Severe hypertension
• Decreased appetite and weight loss
• Fatigue
• Hydration issues related to diarrhea

Careful monitoring of blood pressure and kidney function is particularly important in this population.

Since only about 4% of Pazopanib is excreted in the urine, kidney dysfunction does not significantly change the levels of the drug in the body. No dose adjustment is required for patients with a Creatinine Clearance (CrCl) > 30 mL/min. However, there is no data for patients with a CrCl < 30 mL/min or those on dialysis; these patients should be treated with extreme caution.

Liver function is the most critical factor in Pazopanib dosing.

• Mild Impairment: No adjustment needed.
• Moderate Impairment: The starting dose should be reduced to 200 mg once daily. This is because the liver cannot clear the drug effectively, leading to higher blood levels.
• Severe Impairment: Use is not recommended. The risk of liver failure is too high in this population.

> Important: Special populations require individualized medical assessment and often more frequent laboratory monitoring.

Pazopanib is a multi-target tyrosine kinase inhibitor (TKI). It works by competing with adenosine triphosphate (ATP) for the binding site on the intracellular domain of various receptors. By binding to these sites, it prevents the phosphorylation and subsequent activation of downstream signaling pathways.

The primary targets of Pazopanib are:

• VEGFR-1, -2, and -3: Inhibiting these receptors stops the growth of new blood vessels (angiogenesis) that tumors need to survive.
• PDGFR-α and -β: These receptors are involved in cell growth and the recruitment of supporting cells for blood vessels.
• c-KIT: This receptor is often mutated or overexpressed in certain cancers and is involved in cell survival and proliferation.

By inhibiting these pathways simultaneously, Pazopanib exerts a 'multi-pronged' attack on the cancer, making it difficult for the tumor to develop resistance through a single pathway.

The pharmacodynamic effect of Pazopanib is most clearly seen in its effect on blood pressure. Hypertension is considered an 'on-target' effect, meaning it is a sign that the drug is successfully inhibiting the VEGF pathway. Studies have shown a correlation between the development of hypertension and improved clinical outcomes (progression-free survival) in kidney cancer patients. However, this must be balanced against the risks of high blood pressure.

| Parameter | Value |

|---|---|

| Bioavailability | ~14-21% (highly variable, increased by food) |

| Protein Binding | >99% (primarily to albumin and alpha-1 acid glycoprotein) |

| Half-life | ~31 hours |

| Tmax | 2 to 4 hours |

| Metabolism | Primarily Hepatic (CYP3A4; minor CYP1A2, 2C8) |

| Excretion | Fecal (82%), Renal (4%) |

• Molecular Formula: C21H23N7O2S·HCl
• Molecular Weight: 473.98 g/mol (as hydrochloride salt)
• Solubility: Very slightly soluble in water; solubility is pH-dependent (more soluble at lower pH).
• Structure: Pazopanib is a pyrimidine derivative. It consists of a benzenesulfonamide group attached to a complex nitrogen-containing ring system that allows it to mimic the structure of ATP.

Pazopanib is classified as a Kinase Inhibitor [EPC]. It belongs to the broader category of targeted therapies and antineoplastic agents. Related medications in the same class include Sunitinib (Sutent), Sorafenib (Nexavar), and Axitinib (Inlyta). Unlike traditional chemotherapy, which kills all rapidly dividing cells, Pazopanib is designed to be more selective for the pathways used by cancer cells.