Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Dacomitinib is an antineoplastic agent belonging to the pharmacological class of Tyrosine Kinase Inhibitors, specifically Epidermal growth factor receptor (EGFR) inhibitors.
The FDA approved Dacomitinib for treating metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitutions.
When taken orally, dacomitinib illustrates an 80% mean absolute bioavailability unaffected by food. It primarily distributes widely to α1-acid glycoprotein and albumin. The CYP2D6 isoenzyme mainly regulates liver metabolism, and it is eliminated chiefly as faeces (79%), with 20% remaining unchanged.
Dacomitinib's most common side effects include diarrhoea, rash, stomatitis, nail inflammation, decreased appetite, dry skin, decreased weight, alopecia (hair loss), cough, and pruritus.
Dacomitinib is available in oral tablets.
The molecule is available in India, the United States, the United Kingdom, Australia, Germany, France, Canada, Japan, Brazil, China and Spain.
Dacomitinib is an antineoplastic agent belonging to the pharmacological class of Tyrosine Kinase Inhibitors, specifically Epidermal growth factor receptor (EGFR) inhibitors.
Dacomitinib is an irreversible inhibitor of the EGFR/HER1, HER2, and HER4 human kinase activity and some EGFR activating mutations (exon 19 deletion or exon 21 L858R substitution mutation). At clinically meaningful concentrations, dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 in vitro.
Maximum plasma concentration for dacomitinib is achieved at 108 ng/mL.
The maximum plasma concentration is reached after a single 45-mg dose is 6 hours.
A steady state was achieved in 14 days for dacomitinib with an AUC of 2213 ng·hr/mL.
Dacomitinib is available as an oral tablet.
Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.
As the physician recommends, take the medication orally once daily. It can be taken with or without food as directed.
Orally: Patients orally consume Dacomitinib daily by swallowing tablets with water. To maintain efficacy in treating non-small cell lung cancer, patients follow the recommended schedule and dosage, taking the whole tablet with or without food. Patients should not chew, crush, or break the tablets unless instructed by medical professionals. In the event of vomiting or a missed dose, patients avoid taking an extra dose or making up for the missed dose and continue instead with the next scheduled dose.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Dacomitinib is available as an oral tablet.
Dose Adjustment in Adult Patients:
Non-small Cell Lung Cancer
45 mg PO qDay
Continue until disease progression or unacceptable toxicity occurs
Modifications in Dosage
30 mg per day is the first dosage reduction.
15 mg qDay is the second dosage reduction.
While taking Dacomitinib, maintain regular meals without following any particular dietary guidelines. Whole grains, high-protein foods, healthy fats, and nutrient-dense foods should all be included in an individual's diet in case of chronic illness, including cancer. Select plant-based proteins, which are high in vitamins and minerals and can be found in legumes, beans, and seeds. This is especially beneficial for individuals who are undergoing chemotherapy. Add leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, cabbage, and beans and herbs. Avoid alcohol and tobacco. Avoid fast food, fried foods, processed meats, refined carbohydrates, and added sugars for ideal health.
The dietary restriction should be individualized as per patient requirements.
- Lactation.
- Hypersensitivity to Dacomitinib or any of the excipients.
- Interstitial Lung Disease (ILD): Immediately confirm the diagnosis of ILD. If ILD is found to be present, stop taking Dacomitinib permanently to reduce the chance of developing this potentially fatal illness.
- Diarrhoea: Monitor for diarrhoea and modify Dacomitinib dosage following severity. Temporary withholding and dose reduction may be required to control and lessen side effects related to diarrhoea.
- Dermatologic Adverse Reactions: Proceed with caution when dealing with adverse reactions in dermatology. Should such reactions arise, stop taking Dacomitinib and, depending on how severe the reaction is, think about lowering the dosage. Minimizing adverse events related to dermatology requires close observation and the implementation of the necessary measures.
- Embryo-Fetal Toxicity: Dacomitinib carries the risk of embryo-fetal toxicity. To minimize any potential harm to the developing fetus, advise females who are capable of reproducing to use effective contraception during treatment and for a specified time afterwards.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Dacomitinib can be categorized as:
- Common Adverse Effects(All grades): Diarrhea, rash, paronychia, stomatitis, anaemia, hypoalbuminemia, lymphopenia, increased liver enzymes (ALT and AST), hypocalcemia, hypokalemia, and hyponatremia, as well as decreased appetite, dry skin, and weight loss.
- Less Common Adverse Effects: Hyperglycemia, Cough and dyspnea, Interstitial lung disease, decreased appetite, dehydration and gastrointestinal symptoms such as nausea and constipation.
- Rare Adverse Effects(Grade 3 or 4): Alopecia (hair loss), pruritus (itching), palmar-plantar erythrodysesthesia syndrome (skin rash on palms and soles), musculoskeletal pain, insomnia, anaemia, increased alkaline phosphatase levels, hypomagnesemia, hyperbilirubinemia, and increased AST (aspartate aminotransferase) levels.
The clinically relevant drug interactions of Dacomitinib are briefly summarized here.
- CYP2D6 Substrates: The concentration of medications that are CYP2D6 substrates rises when dacomitinib is used concurrently, potentially raising the risk of these medications becoming toxic. Avoid using Dacomitinib and CYP2D6 substrates concurrently, as even small increases in substrate concentration have the potential to cause highly harmful or fatal side effects.
- Effect of Other Drugs on Dacomitinib: Dacomitinib concentrations are lowered when used concurrently with a PPI, potentially decreasing Dacomitinib efficacy. Avert using PPIs and dacomitinib at the same time. Use an H2-receptor antagonist or locally acting antacids as an alternative to PPIs. Give Dacomitinib at least six hours before or ten hours following the administration of an H2-receptor antagonist.
- Pregnancy
Pregnant women who receive certain medications may experience fetal harm due to the medication's mechanism of action and results from animal studies.
Pregnancy-related data on use are not currently available.
Before starting treatment, determine if any females are potentially pregnant.
Advise women who are fertile to use birth control during their treatment and for at least 17 days following the last dosage.
Animal data
Oral dacomitinib administration during the organogenesis period to pregnant rats during animal reproduction studies resulted in reduced fetal body weight and increased incidence of postimplantation loss at doses that matched the 45 mg human dose.
In animals, the absence of EGFR signalling caused both embryonic lethality and postnatal death.
Inform expectant mothers about the potential risk to the fetus.
- Nursing Mothers
Their effects on nursing infants or milk production regarding dacomitinib or its metabolites in human milk are unknown.
It is advised that women avoid breastfeeding during treatment and for at least 17 days following the last dose due to the possibility of severe adverse reactions in breastfed infants.
- Pediatric Use
As per the FDA, Dacomitinib's use in pediatric patients has not been established.
Dose Adjustment in Kidney Impairment Patients:
Mild or moderate (estimated by the Cockcroft-Gault equation at CrCl 30-89 mL/min): No dosage modification is needed.
Severe ( 30 mL/min for CrCl): Not established is the recommended dosage.
Dose Adjustment in Hepatic Impairment Patients:
There is no recommended dosage modification if a patient has mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C).
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Dacomitinib.
Signs and Symptoms
Overconsumption of Dacomitinib may lead to gastrointestinal, dermatological, and constitutional reactions (e.g. malaise, fatigue, weight loss).
Management
For dacomitinib, there isn't a known antidote. Both symptoms-based therapy and general supportive measures should be implemented for the treatment of dacomitinib overdose.
Pharmacodynamics
Dacomitinib has been shown in preclinical studies to enhance the inhibition of the kinase domain of the epidermal growth factor receptor and its activity in cell lines that carry resistance mutations, like T790M. Additionally, EGFR phosphorylation and cell viability were significantly reduced due to this activity. An IC50 of roughly 280 nmol/L was seen in these investigations using non-small cell lymphoma cancer cell lines with L858R/T790M mutations.
There was an objective response rate of 5%, progression-free survival of 2.8 months, and overall survival of 9.5 months in clinical trials involving patients with advanced non-small cell lung carcinoma who progressed after chemotherapy. Moreover, phase I/II trials demonstrating positive dacomitinib activity were conducted despite prior tyrosine kinase inhibitor failure.
When compared to gefitinib, phase III clinical trials (ARCHER 1050) showing patients with EGFR-activating mutations in advanced or metastatic non-small cell lung carcinoma showed a significant rise in progression-free survival.
Pharmacokinetics:
- Absorption: When administered orally, the mean absolute bioavailability of dacomitinib is 80%, and the presence of food does not impact its pharmacokinetics.
- Distribution: Dacomitinib's distribution characteristics show a significant volume of distribution, measuring 1,889 L. Roughly 98% of it attaches itself to plasma proteins, mainly albumin and α1-acid glycoprotein.
- Metabolism: Dacomitinib is metabolized in the liver by glutathione conjugation and oxidation, mainly assisted by the CYP2D6 isoenzyme. O-desmethyl dacomitinib, which has been identified as the active major metabolite, is produced by this metabolic process. At the same time, the isoenzyme CYP3A4 aids in the synthesis of small oxidative metabolites.
- Excretion: Most dacomitinib excretion occurs in faeces, accounting for 79% of the drug's removal, with 20% remaining unchanged. Less than 1% of the drug remains unchanged, while the remaining 3% is eliminated through urine. Dacomitinib has an elimination half-life of roughly 70 hours.
- Lavacchi D, Mazzoni F, Giaccone G. Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives. Drug Des Devel Ther. 2019 Sep 6;13:3187-3198. doi: 10.2147/DDDT.S194231. PMID: 31564835; PMCID: PMC6735534.
- Nagano T, Tachihara M, Nishimura Y. Dacomitinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to treat non-small cell lung cancer. Drugs Today (Barc). 2019 Apr;55(4):231-236. doi: 10.1358/dot.2019.55.4.2965337. PMID: 31050691.
- Li HS, Zhang JY, Yan X, Xu HY, Hao XZ, Xing PY, Wang Y. A real-world study of dacomitinib in later-line settings for advanced non-small cell lung cancer patients harboring EGFR mutations. Cancer Med. 2022 Feb;11(4):1026-1036. doi: 10.1002/cam4.4495. Epub 2022 Jan 12. PMID: 35023313; PMCID: PMC8855913.
- Zhang B, Shi C, Gao Z, Zhong H, Xiong L, Gu A, Wang W, Chu T, Zhang W, Wang H, Zhang X, Zhong R, Han B. Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study). BMC Cancer. 2022 Mar 19;22(1):294. doi: 10.1186/s12885-022-09409-3. PMID: 35305596; PMCID: PMC8933987.
- https://www.ncbi.nlm.nih.gov/books/NBK547996/
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf
- https://pdf.hres.ca/dpd_pm/00049805.PDF
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
