Dacomitinib

Usage

• Dacomitinib is prescribed for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring specific epidermal growth factor receptor (EGFR) mutations, namely exon 19 deletion or exon 21 L858R substitution. These mutations must be confirmed by an FDA-approved test before starting treatment.
• Pharmacological classification: Kinase inhibitor, specifically a tyrosine kinase inhibitor (TKI).
• Mechanism of action: Dacomitinib irreversibly inhibits multiple tyrosine kinases, including EGFR, HER2, and HER4, thereby blocking downstream signaling pathways involved in cell growth and proliferation in cancer cells with these specific EGFR mutations.

Alternate Names

• International Nonproprietary Name (INN): Dacomitinib
• Brand Name: Vizimpro®

How It Works

• Pharmacodynamics: Dacomitinib exerts its anti-cancer effect by irreversibly inhibiting EGFR, HER2, and HER4 tyrosine kinases. This inhibition disrupts downstream signaling cascades that promote tumor cell growth, survival, and angiogenesis.
• Pharmacokinetics:
  • Absorption: Dacomitinib is administered orally and reaches peak plasma concentrations within 6 hours. Food intake does not significantly affect absorption.
  • Metabolism: Primarily metabolized in the liver via CYP2D6 and CYP3A4. The major metabolite is O-desmethyl dacomitinib, which exhibits similar potency to the parent drug.
  • Elimination: Excreted mainly through feces, with minor renal excretion. The elimination half-life is approximately 48 hours, allowing for once-daily dosing.
• Mode of action: Dacomitinib binds irreversibly to the ATP-binding site of the target kinases, preventing ATP from binding and thereby inhibiting kinase activity.
• Receptor binding/Enzyme inhibition: Irreversible binding to EGFR, HER2, and HER4 tyrosine kinases.
• Elimination pathways: Primarily hepatic metabolism followed by fecal excretion, with minimal renal elimination.

Dosage

Standard Dosage

Adults:

• 45 mg orally once daily, taken at approximately the same time each day, with or without food. Treatment is continued until disease progression or unacceptable toxicity.

Children:

• The safety and efficacy of dacomitinib in pediatric patients have not been established.

Special Cases:

• Elderly Patients (≥65 years): No initial dose adjustment is necessary. However, closer monitoring for adverse events is recommended due to a higher incidence of serious adverse events in this population.
• Patients with Renal Impairment: No initial dose adjustment is needed for mild or moderate renal impairment (CrCl ≥30 mL/min). The recommended dose for severe renal impairment (CrCl <30 mL/min) has not been established.
• Patients with Hepatic Dysfunction: No initial dose adjustment is required for mild or moderate hepatic impairment (Child-Pugh A or B). For severe hepatic impairment (Child-Pugh C), an initial dose of 30 mg once daily is recommended, which may be increased to 45 mg once daily after at least 4 weeks based on individual tolerability and safety.
• Patients with Comorbid Conditions: Use with caution in patients with pre-existing cardiac conditions.

Clinical Use Cases

Dacomitinib is specifically indicated for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitutions. Its use in other clinical settings (intubation, surgical procedures, mechanical ventilation, ICU, emergency situations) is not established.

Dosage Adjustments

Dose reductions (to 30 mg then to 15 mg once daily) or treatment interruption may be necessary depending on the severity and recurrence of adverse reactions. Specific dosage adjustments are recommended for diarrhea, dermatologic reactions, and other Grade 3 or 4 toxicities. Consult the Vizimpro prescribing information for detailed guidelines. Avoid concomitant use with proton pump inhibitors (PPIs). If H2-receptor antagonists are needed, administer dacomitinib at least 6 hours before or 10 hours after the H2-receptor antagonist.

Side Effects

Common Side Effects:

Diarrhea, rash, paronychia, stomatitis, dry skin, decreased appetite, weight loss, fatigue, nail disorders, conjunctivitis, and alopecia.

Rare but Serious Side Effects:

Interstitial lung disease (ILD)/pneumonitis, severe diarrhea (can be fatal), severe skin reactions, and cardiac toxicity.

Long-Term Effects:

Potential long-term effects are not fully characterized but may include pulmonary fibrosis if ILD develops.

Adverse Drug Reactions (ADR):

ILD/pneumonitis, severe diarrhea, severe skin reactions requiring hospitalization, and cardiac events.

Contraindications

Hypersensitivity to dacomitinib or any of its components.

Drug Interactions

• CYP450 Interactions: Dacomitinib is metabolized by CYP2D6 and CYP3A4. Strong inhibitors or inducers of these enzymes may alter dacomitinib levels.
• Proton Pump Inhibitors (PPIs): Avoid concomitant use, as PPIs decrease dacomitinib concentrations and reduce efficacy. Use antacids or H2-receptor antagonists as alternatives.
• H2-receptor antagonists: Administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist.
• Other Interactions: Dacomitinib can inhibit CYP2D6 and may increase the concentrations of drugs metabolized by this enzyme (e.g., dextromethorphan).
• Food and lifestyle factors: No clinically significant interactions reported. However, for optimal drug level stability, it’s recommended to take the dose always fasted or always after the same meal.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Dacomitinib can cause fetal harm and is contraindicated during pregnancy. Effective contraception must be used during treatment and for at least 2 months after the last dose.
• Breastfeeding: Dacomitinib may be excreted in breast milk. Breastfeeding is contraindicated during treatment and for 2 months after the last dose.

Drug Profile Summary

• Mechanism of Action: Irreversible inhibitor of EGFR, HER2, and HER4 tyrosine kinases.
• Side Effects: Diarrhea, rash, paronychia, stomatitis, dry skin, ILD, severe diarrhea.
• Contraindications: Hypersensitivity to dacomitinib, pregnancy.
• Drug Interactions: PPIs, CYP2D6 inhibitors/inducers, H2 antagonists, CYP2D6 substrates.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 45 mg orally once daily; adjustments for adverse reactions and hepatic impairment.
• Monitoring Parameters: Monitor for respiratory symptoms (ILD), diarrhea, skin reactions, and liver function tests.

Popular Combinations

Dacomitinib is typically used as monotherapy. Combinations with other anticancer agents have not been established in the first-line setting for metastatic NSCLC with the specified EGFR mutations.

Precautions

• General Precautions: Evaluate patients for EGFR mutations, monitor for ILD/pneumonitis, diarrhea, skin reactions, and liver function.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Contraindicated.
  • Children & Elderly: Not established for children. Elderly patients require closer monitoring.
• Lifestyle Considerations: No specific restrictions related to alcohol, smoking, or diet are needed.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dacomitinib?

A: The recommended starting dose for adults is 45 mg orally once daily, taken at approximately the same time each day. Dose reductions (to 30mg then to 15mg once daily) may be necessary based on individual safety and tolerability.

Q2: How should Dacomitinib be administered?

A: Orally, once daily, with or without food. However, to minimize drug fluctuations, it’s recommended to take the medication under consistent conditions.

Q3: What are the most common side effects of Dacomitinib?

A: Diarrhea, rash, paronychia, stomatitis, dry skin, decreased appetite, and nail changes.

Q4: What should be done if a patient misses a dose of Dacomitinib?

A: Do not take an additional dose. Resume the normal schedule with the next dose.

Q5: What are the serious side effects of Dacomitinib that require immediate attention?

A: Interstitial lung disease (ILD)/pneumonitis, severe diarrhea, severe skin reactions, and cardiac events.

Q6: Can Dacomitinib be used during pregnancy or breastfeeding?

A: No. Dacomitinib is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus/infant.

Q7: Are there any specific drug interactions I should be aware of with Dacomitinib?

A: Avoid concomitant use with proton pump inhibitors (PPIs). H2 receptor antagonists may be used as an alternative, but timing of administration needs to be adjusted. Dacomitinib can affect the metabolism of other medications.

Q8: How is Dacomitinib metabolized?

A: Primarily via CYP2D6 and CYP3A4 hepatic enzymes.

Q9: How should diarrhea caused by Dacomitinib be managed?

A: Anti-diarrheal medications (e.g., loperamide) should be initiated at the first onset of diarrhea. Adequate hydration is crucial. Dose reduction or interruption of Dacomitinib may be necessary for persistent or severe diarrhea.

Q10: What are the key monitoring parameters for patients taking Dacomitinib?

A: Monitor respiratory status for signs and symptoms of ILD/pneumonitis (cough, dyspnea, fever). Regularly evaluate for diarrhea and skin reactions. Conduct periodic liver function tests. Monitor general condition and nutritional status of the patient due to potential for weight loss and decreased appetite.