Lapatinib - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Lapatinib is a reversible, selective inhibitor that significantly blocks the tyrosine kinase domains of the human epidermal growth factor receptor-2 (HER-2) and the epidermal growth factor receptor (EGFR). It is approved for use in combination with Capecitabine to treat advanced or metastatic HER-2-positive breast cancer and hormone receptor-positive breast cancer when combined with an aromatase inhibitor.

Patients who have already had Trastuzumab and chemotherapy can also utilize it. Lapatinib, coupled with hormonal therapy, chemotherapy, or Trastuzumab, may improve the prognosis without progression. Lapatinib was authorized by the Food and Drug Administration on March 13, 2007, to treat metastatic (spread) breast cancer that is HER2-positive.

Drug Group

Lapatinib is an antineoplastic used to treat cancer. It belongs to the 4-anilinoquinazoline class of kinase inhibitors and prevents aberrant protein signaling that drives cancer cell proliferation.

Indications

Lapatinib is recommended in combination with capecitabine for women with HER2-positive metastatic or advanced breast cancer whose disease has progressed after prior therapy with Trastuzumab, Anthracyclines, or Taxanes. This combination is generally used after progression on Trastuzumab.

In postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer, Lapatinib may sometimes be combined with an aromatase inhibitor, such as Letrozole. This combination is not a standard first-line therapy and is considered on a case-by-case basis by your oncologist.

Lapatinib with an aromatase inhibitor has not been directly compared with chemotherapy regimens including trastuzumab for metastatic breast cancer.

Contraindications

Patients with a history of extreme hypersensitivity (an exaggerated immune response) to this product or its ingredients, such as anaphylaxis (a severe allergic reaction), should not use Lapatinib.

Dosage Forms and Available Strengths

Lapatinib is available in the form of 250 mg (milligrams) tablets.

For Patients

What Is Breast Cancer?

Breast cancer is a type of cancer that starts in your breast tissue. It occurs when abnormal cells grow and multiply in an uncontrolled way, forming a tumor.

There are different types of breast cancer, depending on where the cancer starts in your breast. Some common types include:

• Ductal carcinoma, which begins in the milk ducts

• Lobular carcinoma, which starts in the milk-producing glands

• Angiosarcoma, a rare cancer that forms in blood or lymph vessels

• Paget’s disease, which affects the skin of the nipple

• Phyllodes tumors, which grow in the connective tissue of the breast

Your risk of breast cancer can be influenced by several factors. These include your age, gender, family history, hormone levels, and lifestyle habits.

You may notice symptoms such as:

• A new lump or mass in your breast or underarm.

• Changes in the size, shape, or appearance of your breast.

• Nipple discharge.

• A rash, redness, or dimpling of the breast skin.

• An inverted nipple.

To diagnose breast cancer, your doctor may use a combination of tests. These can include a physical exam, mammography (a breast X-ray), ultrasound, biopsy, MRI (magnetic resonance imaging) scans, or PET (positron emission tomography) scans to understand the stage of the cancer.

Certain hormonal factors can also increase your risk. These include early onset of menstruation, late menopause, or using hormone replacement therapy.

If you notice any changes in your breasts or have concerns about your risk, it’s important to talk to your doctor. Early detection can make a huge difference in treatment outcomes

How Does Lapatinib Work?

Lapatinib is a dual tyrosine kinase inhibitor that blocks signals that encourage the growth and multiplication of cancer cells. It targets the EGFR and HER2 (ErbB2) pathways, which are hyperactive in HER2-positive breast cancer.

Why is Lapatinib Medication Prescribed?

Lapatinib is a medicine in the kinase inhibitor class. It works by blocking certain proteins in your cancer cells that tell them to grow and divide. By doing this, Lapatinib helps slow down or stop the growth of your cancer.

Your doctor may prescribe Lapatinib along with Capecitabine if you have a specific type of advanced breast cancer and have already received other chemotherapy treatments.

Lapatinib can also be used with Letrozole to treat a certain kind of breast cancer in postmenopausal women (women who have gone through menopause). This is usually for cancer that has spread to other parts of the body.

Your healthcare team will explain whether Lapatinib is the right choice for your treatment plan and how it fits with your other medications.

How Should Lapatinib Medicine be Used?

You take Lapatinib as a pill by mouth. Usually, it is taken once a day, at least one hour before or one hour after eating.

If you are using Lapatinib for advanced or metastatic breast cancer, your doctor may ask you to take it once daily from days 1 to 21 of a 21-day cycle, along with Capecitabine on days 1 to 14. Your doctor will tell you if the cycle needs to be repeated.

If you are taking Lapatinib with Letrozole for postmenopausal breast cancer, it is usually taken once daily. Take all your Lapatinib pills at the same time, do not split, chew, or crush the tablets. Swallow them whole, and try to take the medicine at the same time every day.

Pay close attention to the instructions on your prescription label. If anything is unclear, ask your doctor or pharmacist. Take Lapatinib exactly as prescribed. Do not take more or less, and don’t change the timing without consulting your doctor.

Your doctor may modify your dose during treatment depending on how well the medicine is working and whether you experience side effects. Even if you feel better, continue taking Lapatinib. Never stop it on your own.

You can also check with your doctor or pharmacist for a patient information leaflet from the manufacturer, which gives more details about your treatment.

What Are the Benefits of Lapatinib?

• Targeted Therapy: Because HER2-positive breast cancer cells overexpress the HER2 protein, Lapatinib selectively targets them. By blocking this pathway, it helps delay the spread of cancer.

• Combination Therapy: It is frequently used along with other drugs (such as Capecitabine) to increase treatment efficacy.

• Oral Administration: Patients can easily take Lapatinib because it is administered orally as a tablet.

• Metastatic Breast Cancer: When breast cancer has progressed and spread outside of the breast, it can be effectively treated.

How Is Lapatinib Administered?

You take Lapatinib as a tablet by mouth, usually before or after a meal.

For breast cancer that has spread or progressed, your doctor may ask you to take it daily from days 1 to 21 of a 21-day cycle, often together with Capecitabine. If needed, your doctor may repeat this cycle.

If you are taking Lapatinib with Letrozole for breast cancer that has returned after menopause, take it once daily as directed.

Take all your tablets at the same time each day to get the correct dose. Follow the instructions on your prescription label carefully. If anything is unclear, you can ask your doctor or pharmacist.

Do not crush, split, or chew the tablets; swallow them whole.

Your doctor may adjust your dose depending on how your treatment is going and any side effects you experience. Even if you feel better, keep taking Lapatinib and do not stop it without talking to your doctor.

What Side Effects Can Lapatinib Cause?

There may be side effects from Lapatinib. If any of these symptoms of Lapatinib are severe or persistent, let the physician know:

• Feeling sick and throwing up.

• Heartburn.

• Ulcers in the throat, lips, or mouth.

• Decrease in appetite.

• Hands and feet that are tingling, aching, numb, or red.

• Dry skin.

• Discomfort in the back, arms, or legs.

• Inability to fall or stay asleep.

Certain adverse effects of Lapatinib may be dangerous. Call the doctor right away if you encounter any of the following symptoms:

• Breathlessness.

• Dry cough.

• Coughing up bloody or pink mucus.

• Rapid, erratic, or pounding heartbeat.

• Weakness.

• Swelling in the ankle, feet, hands, or lower legs.

• Rash.

• Blistering or peeling skin.

• Fever.

Lapatinib may cause changes in the heart's rhythm and blood flow throughout the body. The physician will closely check whether Lapatinib has impacted cardiac health.

What Lapatinib Precautions Should I Follow?

Before you start Lapatinib, it’s important to tell your doctor if you have any allergies to this medicine.

Let your doctor and pharmacist know about all the medications, vitamins, or dietary supplements you are taking, including over-the-counter products. This helps avoid interactions with Lapatinib.

Diarrhea is a common side effect of Lapatinib. If you experience severe diarrhea, you should contact your doctor right away.

Also, inform your doctor if you have ever had:

• Long QT syndrome (a heart rhythm condition)

• Heart problems

• Liver disease (Lapatinib can sometimes cause serious liver problems)

• Electrolyte imbalances

If you are pregnant, planning to conceive, or breastfeeding, talk to your doctor before starting Lapatinib.

• A negative pregnancy test may be required before treatment.

• Both men and women should use effective birth control while taking Lapatinib to prevent pregnancy.

• Birth control should continue for at least one week after the last dose.

• If pregnancy occurs while you or your partner is taking Lapatinib, contact your doctor immediately.

• While taking Lapatinib and for at least a week after your last dose, do not breastfeed.

Following these precautions helps keep you safe while getting the most benefit from your treatment.

Dietary Considerations

Grapefruit and grapefruit juice should not be consumed while taking Lapatinib.

Missed Dose

Avoid taking a double dose of Lapatinib to make up for missing a Lapatinib dose; instead, skip it and stick to the regular dosing schedule.

Overdose

Clinical trials have limited oral dosages of Lapatinib to 1,800 mg per day, and there is no known antidote for Lapatinib overdose. Missed doses should not be made up, as repeated doses could increase toxicity.

Reports of overdose cases with daily doses between 2,500 and 9,000 mg and durations between one and 17 days have been made.

Mucosal inflammation, sinus tachycardia (fast heartbeat), sore scalp, and Lapatinib-associated events are among the symptoms.

Lapatinib binds to plasma proteins so strongly that hemodialysis (artificial kidney) is ineffective. Comprehensive supportive measures should be part of the Lapatinib overdose treatment.

Where Should I Keep Lapatinib?

Lapatinib should be kept at room temperature, ranging from 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), in its original container, securely closed, and out of children's reach.

All medication should be kept out of children's sight and reach because many containers, including those for eye drops, creams, patches, and inhalers, as well as weekly pill minders, are not kid-resistant and are easy for small children to open.

Disposal

Dispose of unneeded Lapatinib tablets in a way that keeps them out of the reach of kids, pets, and other people.

Use the FDA's medicine take-back program to eliminate those Lapatinib medications.

For Doctors

Description:

Lapatinib is a tiny molecule that belongs to the kinase inhibitor class known as 4-anilinoquinazoline. It is found as the tosylate salt monohydrate. It has a molecular weight of 943.5 g/mol. There are 405 milligrams of Lapatinib ditosylate monohydrate in every 250 mg tablet of lapatinib, 398 mg of Lapatinib ditosylate, or 250 mg of Lapatinib free base. Some inactive components include microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate, and an orange film coat.

What Are the Pharmacological Actions of Lapatinib?

Pharmacodynamics

An analysis of the impact of Lapatinib on QT intervals in patients with advanced solid tumors was conducted. Over four days, Lapatinib 2,000 mg was given in three doses, and a placebo was used in this trial.

A peak QTcF (corrected QT interval by Fredericia) (90 percent confidence interval or CI) of 8.75 ms (milliseconds) was recorded 10 hours following the third 2000 mg Lapatinib dosage. The upper bound 90 percent CIs and the ΔΔQTcF (change from baseline corrected QT interval by Fredericia) surpassed the 5 ms threshold and the 10 ms threshold at various points. The QTcF effects increased in a concentration-dependent manner.

Mechanism of Action

Human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor receptors (HER1/EGFR/ERBB1) had their intracellular tyrosine kinase domains inhibited by Lapatinib. In vitro and animal models, it suppresses the growth of ERBB-driven tumor cells. Lapatinib and 5-Fluorouracil were discovered to have additive effects in an in vitro study. Lapatinib continued to exhibit strong anti-breast cancer cell line activity in a Trastuzumab-conditioned cell line study, indicating no cross-resistance between the two medications.

Pharmacokinetics

• Absorption: Lapatinib's absorption is variable and incomplete. Serum concentrations peak around four hours after oral administration.

• Distribution: Lapatinib is highly bound to albumin, with a binding affinity of over 99 percent, and alpha-1 acid glycoprotein.

• Metabolism: The cytochrome P450 enzymes CYP3A4 (Cytochrome P450 3A4) and CYP3A5 (Cytochrome P450 3A5), as well as, to a lesser extent, CYP2C19 (cytochrome P450) and CYP2C8 (cytochrome P450), are principally responsible for Lapatinib's hepatic metabolism. These enzymes transform Lapatinib into oxidized metabolites.

• Excretion: Less than 2% of Lapatinib is excreted in the urine, with the majority, 27%, eliminated in the feces. Its half-life in effect is roughly 24 hours following repeated doses.

Toxicity

A study reported that patients receiving 3,000 mg of Lapatinib for ten days had grade 3 diarrhea and vomiting. Lapatinib-associated toxicity includes diarrhea, rash, cardiac toxicity, and liver toxicity.

What Are the Drug Interactions of Lapatinib?

• It has been demonstrated that Lapatinib increases exposure to drugs that are CYP2C8, CYP3A4, or P-glycoprotein (ABCB1) substrates.

• When co-administered with potent CYP3A4 inhibitors, Lapatinib should be avoided; if necessary, patients may consider a dose reduction.

• When co-administered with potent CYP3A4 inducers, Lapatinib should be avoided. If necessary, patients may consider a gradual dose increase.

Clinical Studies

HER2-Positive Metastatic Breast Cancer: The Phase III clinical trial that supported Lapatinib's authorization showed that patients treated with Lapatinib and Capecitabine had a longer time to progression (TTP) and a higher response rate than those treated with Capecitabine alone.

The trial was done on study participants with advanced HER2-positive breast cancer who had been treated with anthracyclines, taxanes, and Trastuzumab. Although no significant difference in overall survival was observed between the groups, combination therapy with Lapatinib and Capecitabine showed promising results in disease management. Lapatinib frequently causes fatigue, nausea, rash, and diarrhea as adverse effects.

Warnings and Precautions

• Left ventricular ejection fraction (LVEF) reductions have been associated with Lapatinib side effects; roughly 57 percent of these reductions have been observed during the first 12 weeks of treatment. Long-term exposure data, however, are limited. To ensure a baseline LVEF within the institution's standard norms, patients with conditions that may impair left ventricular function should exercise caution and be tested both before and during treatment.

• Clinical trials and post-marketing experience have shown evidence of hepatotoxicity, which is defined by high ALT (alanine transaminase) and AST (aspartate aminotransferase) values and has the potential to cause serious side effects, including death. Testing liver function should be done before and after treatment, and any significant alterations should prompt stopping treatment.

• Patients with significant hepatic impairment should take less Lapatinib; patients with severe hepatotoxicity should stop taking it altogether; and patients with severe hepatotoxicity should not get further treatment.

• Patients with severe hepatic impairment should think about Lapatinib; if significant hepatotoxicity develops, stop the medication. During therapy, diarrhea can happen; it is important to treat it quickly because it is frequently severe and deadly. Patients should seek out antidiarrheal medications and report any changes in bowel movements.

• Pneumonitis and interstitial lung disease have been related to Lapatinib; therefore, patients experiencing Grade 3 or worse pulmonary symptoms should stop using this medication.

• Patients with hypokalemia, hypomagnesemia, congenital long QT syndrome, antiarrhythmic drugs, and cumulative high-dose anthracycline therapy should be closely monitored, as Lapatinib may induce concentration-dependent QT prolongation. Before taking Lapatinib, treat hypokalemia or hypomagnesemia.

• Treatment should be stopped if life-threatening symptoms like toxic epidermal necrolysis, erythema multiforme, or Stevens-Johnson syndrome are detected, since Lapatinib has been associated with severe cutaneous responses.

• Anti-estrogen drugs such as Lapatinib can harm a developing fetus if given to a pregnant woman. Research on animals reveals that at unsafe dosages for mothers, rabbits experience miscarriages, and rats experience fetal mortality. Females who are capable of reproducing should be made aware of the risks involved in pregnancy.

Use in Specific Populations

• Pregnancy: The use of Lapatinib during pregnancy should be avoided due to the risks of harm or birth abnormalities. It is advised to use effective birth control. If patients taking Lapatinib get pregnant, notify the doctor immediately.

• Breastfeeding: If nursing is being considered, it is advisable to speak with a doctor, as the possible effects of Lapatinib on breastfeeding are unknown.

• Pediatric Use: The safety and efficacy of Lapatinib in pediatric patients are unknown.

• Renal Impairment: Renal impairment is unlikely to alter Lapatinib's pharmacokinetics because the kidneys remove less than two percent of the dose; however, the pharmacokinetics of Lapatinib in patients undergoing hemodialysis have not been examined.

• Hepatic Impairment: Lapatinib's pharmacokinetics were investigated in healthy control subjects and patients with mild to severe hepatic impairment. If a patient experiences significant hepatotoxicity, the treatment should be stopped and the dose reduced.