VIZIMPRO 15 MG TABLETS

Indications

• Non-small cell lung cancer (NSCLC) with EGFR-activating mutations
• Advanced or metastatic NSCLC after prior therapy
• Patients with resistance mutations such as T790M

Dosage

Children: Dacomitinib is not typically indicated for use in paediatric patients. Refer to the

Adults: The usual adult dose is 45 mg once daily, taken orally, with adjustments based on tolerability and specific clinical circumstances as indicated in product literature.

Mechanism of action

Dacomitinib irreversibly inhibits the activity of EGFR family tyrosine kinases (EGFR/HER1, HER2, HER4) by covalently bonding to cysteine residues in their catalytic domains. The drug's affinity for these targets is notable, with an IC50 of 6 nmol/L. This inhibition blocks downstream signaling pathways involved in tumor growth and resistance, such as Ras-Raf-MAPK and PI3K/AKT, which are activated through tyrosine phosphorylation.

Pharmacodynamics

Preclinical studies indicate that dacomitinib enhances the inhibition of EGFR kinase activity and effectively reduces cell viability in cancer cell lines with resistant mutations, such as T790M. Patients with advanced NSCLC showed a 5% objective response rate and a median progression-free survival of 2.8 months. Phase III trials revealed significant improvements in progression-free survival compared to gefitinib in patients with EGFR-activating mutations.

Pharmacokinetics

Dacomitinib exhibits absorption and distribution characteristics suitable for therapeutic efficacy. The metabolism primarily occurs in the liver, with its elimination half-life allowing for once-daily dosing. It undergoes hepatic metabolism and can be affected by various drug interactions, particularly with medications that alter CYP450 enzyme activity.

Contra-indications

• Hypersensitivity to dacomitinib or any of its components
• Patients with a history of interstitial lung disease

Adverse effects

• Diarrhoea
• Rash
• Decreased appetite
• Fatigue
• Nausea
• Vomiting
• Stomatitis
• Dry skin
• Pruritus
• Alopecia
• Palmar-plantar erythrodysesthesia
• Interstitial lung disease
• QT interval prolongation

Interactions

• Severe interactions with beta-blockers (increases exposure)
• Severe interactions with tricyclic antidepressants (increases exposure)
• Moderate interaction with atomoxetine (increases exposure)

Precautions

• Monitor for interstitial lung disease, especially in patients with pre-existing lung conditions
• Caution in elderly patients due to potential increased sensitivity
• Assess cardiac function before initiating therapy
• Regular monitoring of liver function tests is recommended

Pregnancy

Dacomitinib is contraindicated in pregnancy due to potential harm to the fetus. Women of childbearing potential should use effective contraception during treatment and for at least 17 days after the last dose.

Breast-feeding

It is unknown if dacomitinib is excreted in human milk. Caution should be exercised when administered to a nursing mother.

Storage

Store at room temperature (15°C to 25°C). Keep in a dry place away from light. Keep out of reach of children.

Formulations

• Dacomitinib 30 mg tablets
• Dacomitinib 45 mg tablets
• Dacomitinib 60 mg tablets

Mechanism of action

Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus. Around 40% of cases show amplification of EGFR gene and 50% of the cases present the _EGFRvIII_ mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor.

Pharmacodynamics

Preclinical data suggested that dacomitinib increases the inhibition of the epidermal growth factor receptor kinase domain as well as the activity in cell lines harboring resistance mutations such as T790M. This activity further produced a significant reduction of EGFR phosphorylation and cell viability. In these studies, non-small cell lymphoma cancer cell lines with L858R/T790M mutations where used and an IC50 of about 280 nmol/L was observed. In clinical trials with patients with advanced non-small cell lung carcinoma who progressed after chemotherapy, there was an objective response rate of 5% with a progression-free survival of 2.8 months and an overall survival of 9.5 months. As well, phase I/II studies showed positive dacomitinib activity despite prior failure with tyrosine kinase inhibitors. Phase III clinical trials (ARCHER 1050), done in patients suffering from advanced or metastatic non-small cell lung carcinoma with EGFR-activating mutations, reported a significant improvement in progression-free survival when compared with gefitinib.