Dacomitinib (Vizimpro) - Uses, Dose, Side effects, MOA

Dacomitinib is a medication that falls under the category of tyrosine kinase inhibitors (TKIs). It is primarily used for the treatment of a specific type of cancer called non-small cell lung cancer (NSCLC). More specifically, dacomitinib targets and inhibits the activity of certain proteins known as epidermal growth factor receptor (EGFR) tyrosine kinases.

EGFR is a protein that plays a role in cell growth, division, and survival. Mutations in the EGFR gene can lead to the development and progression of certain cancers, including NSCLC. Dacomitinib works by binding to these EGFR proteins and inhibiting their activity. By blocking the signals that drive cancer cell growth and division, dacomitinib can help slow down or even shrink tumors in individuals with EGFR-mutated NSCLC.

Dacomitinib (Vizimpro) is an irreversible EGFR tyrosine kinase inhibitor that is used in the treatment of metastatic non-small cell lung cancer.

Dacomitinib (Vizimpro) Uses:

  • Metastatic non-small-cell lung cancer:
    • It is used as the first line of treatment in patients with metastatic non-small cell lung cancer who have the following genetic mutations as detected by an approved test:
      • Epidermal growth factor receptor (EGFR) exon 19 deletion or
      • exon 21 L858R substitution mutations.

Dacomitinib (Vizimpro) Dose in Adults

Note:

  • Before starting the treatment, make sure the tumor has specific changes in the EGFR gene, either exon 19 deletions or exon 21 L858R changes.

Dacomitinib (Vizimpro) Dose as the first line of treatment in patients with metastatic non-small cell lung cancer:

For treating a certain type of advanced lung cancer with specific gene changes (EGFR exon 19 deletion or exon 21 L858R mutation), the recommended dose for dacomitinib is:

  • Take by mouth: 45 mg once a day.
  • Keep taking it: Until the cancer gets worse or if the side effects become too much.

If you forget to take a dose or throw up after taking it:

  • Don't take an extra dose to make up for the one you missed.
  • Just take the next dose when you're supposed to.

Use in Children:

Not indicated.

Dacomitinib (Vizimpro) Pregnancy Risk Category: N (not assigned)

  • Using dacomitinib during pregnancy might harm the baby, based on animal tests and how the drug works.
  • Before starting the drug, make sure women who can get pregnant are not already pregnant.
  • These women should also use strong birth control while on the drug and continue for at least 17 days after the last dose.

Use of Dacomitinib while breastfeeding

  • We don't know if dacomitinib gets into breast milk.
  • Because it might harm the baby, the company making the drug says don't breastfeed while taking it and for at least 17 days after the last dose.

Dacomitinib (Vizimpro) Dose in Kidney Disease:

  • If your kidney filters (CrCl) between 30 to 89 mL/minute: You can take the regular dose.
  • If it's less than 30 mL/minute: The company hasn't given any special dosing instructions because they haven't studied it in this situation.

Dacomitinib (Vizimpro) Dose in Liver disease:

  • If you have mild or moderate issues (based on certain blood test numbers): You can take the regular dose.
  • If you have severe issues (again, based on specific blood test numbers): The company hasn't given any special dosing instructions because they haven't looked into it in this situation.

Common Side Effects of Dacomitinib (Vizimpro):

  • Cardiovascular:
    • Chest Pain
  • Central Nervous System:
    • Insomnia
  • Dermatologic:
    • Skin Rash
    • Paronychia
    • Xeroderma
    • Alopecia
    • Pruritus
    • Palmar-Plantar Erythrodysesthesia
    • Dermatitis
  • Endocrine & Metabolic:
    • Hypoalbuminemia
    • Hyperglycemia
    • Hypocalcemia
    • Hypokalemia
    • Hyponatremia
    • Weight Loss
    • Hypomagnesemia
  • Gastrointestinal:
    • Diarrhea
    • Stomatitis
    • Decreased Appetite
    • Nausea
    • Constipation
    • Oral Mucosa Ulcer
  • Hematologic & Oncologic:
    • Anemia
    • Lymphocytopenia
  • Hepatic:
    • Increased Serum Alanine Aminotransferase
    • Increased Serum Aspartate Aminotransferase
    • Increased Serum Alkaline Phosphatase
    • Hyperbilirubinemia
  • Neuromuscular & Skeletal:
    • Limb Pain
    • Asthenia
    • Musculoskeletal Pain
  • Ophthalmic:
    • Conjunctivitis
  • Renal:
    • Increased Creatinine Clearance
  • Respiratory:
    • Cough
    • Nasal Signs And Symptoms
    • Dyspnea
    • Upper Respiratory Tract Infection

Less Common Side Effects Of Dacomitinib (Vizimpro):

  • Central Nervous System:
    • Fatigue
  • Dermatologic:
    • Skin Fissure
    • Exfoliation Of Skin
    • Hypertrichosis
  • Endocrine & Metabolic:
    • Dehydration
  • Gastrointestinal:
    • Vomiting
    • Dysgeusia
  • Ophthalmic:
    • Keratitis
  • Respiratory:
    • Interstitial Pulmonary Disease

Contraindications to Dacomitinib (Vizimpro):

  • In the US: There are no listed reasons to avoid the drug.
  • In Canada: Don't take it if you're allergic to dacomitinib or anything else in the pill.

Warnings and precautions

Dermatologic toxicities:

  • Rash and skin problems can happen with dacomitinib.
  • Rash is common, affecting many patients.
  • Sunlight can make these skin problems worse, so use sunscreen and avoid too much sun.
  • Start using moisturizers when you start taking dacomitinib.
  • If you have bad rash (grade 2 or worse), stop taking dacomitinib until it gets better (grade 1 or less). You might restart at the same dose or lower dose.
  • For mild rash (grade 1), use creams. For worse rash (grade 2 or more), use oral antibiotics.
  • Dry skin and nail issues are also common with this drug.

Gastrointestinal toxicities:

  • Severe and even deadly diarrhea can happen with dacomitinib.
  • Most patients experience diarrhea, with some having very bad cases.
  • If you have moderate to severe diarrhea (grade 2 or worse), stop taking dacomitinib. Restart at the same or lower dose when the diarrhea improves to mild or none (grade 1 or less).
  • If you get diarrhea, start taking diarrhea medicine right away, like loperamide.
  • Mouth sores (mucositis/stomatitis) can also occur with this drug.

Toxicity in the lungs:

  • A lung problem called Interstitial Lung Disease (ILD), which can be severe or even deadly, has been seen with dacomitinib.
  • Watch out for symptoms like trouble breathing, cough, and fever.
  • If someone has worsening breathing symptoms, stop taking dacomitinib and quickly check if it's ILD.
  • If it's confirmed to be ILD, don't take dacomitinib again.

Dacomitinib: Drug Interaction

Note: Drug Interaction Categories:

  • Risk Factor C: Monitor When Using Combination
  • Risk Factor D: Consider Treatment Modification
  • Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).

Amphetamines

Strong CYP2D6 inhibitors may increase serum levels of Amphetamines

Benzhydrocodone

CYP2D6 inhibitors (Strong), may reduce serum levels of active metabolites of Benzhydrocodone.

CloZAPine

CloZAPine serum concentrations may be increased by strong CYP2D6 inhibitors (Strong).

DULoxetine

CYP2D6 inhibitors (Strong) can increase serum levels of DULoxetine.

Fesoterodine

CYP2D6 inhibitors may increase serum levels of active metabolites of Fesoterodine.

Galantamine

Galantamine may be increased by strong CYP2D6 inhibitors.

HYDROcodone

CYP2D6 inhibitors (Strong), may reduce serum levels of active metabolites of HYDROcodone. Hydromorphone concentrations may decrease.

Lofexidine

Lofexidine may be increased by CYP2D6 inhibitors (Strong).

Nebivolol

CYP2D6 inhibitors (Strong), may increase serum levels of Nebivolol.

Nicergoline

CYP2D6 inhibitors (Strong), may increase serum levels of active metabolites of Nicergoline. Concentrations of the MMDL metabolite could be increased. CYP2D6 inhibitors (Strong), may reduce serum levels of active metabolites of Nicergoline. Concentrations of the MDL metabolite could be decreased.

Pitolisant

CYP2D6 inhibitors (Strong) can increase serum Pitolisant concentrations

Tamsulosin

CYP2D6 inhibitors (Strong), may increase serum Tamsulosin concentrations.

TraMADol

CYP2D6 inhibitors (Strong), may decrease the therapeutic effects of TraMADol. CYP2D6 inhibitors (Strong), may lower serum levels of TraMADol's active metabolite(s). CYP2D6 inhibitors (Strong), may increase TraMADol serum concentration.

Valbenazine

CYP2D6 inhibitors (Strong), may raise serum levels of active metabolites of Valbenazine.

Risk Factor D (Still a possibility of therapy modification)

ARIPiprazole

Strong CYP2D6 inhibitors may raise serum levels of ARIPiprazole. Management: Refer to the full interaction monograph.

ARIPiprazole

Strong CYP2D6 inhibitors may raise serum levels of active metabolites of ARIPiprazole. Management: Refer to the full interaction monograph for more information about the recommended dose adjustments.

AtoMOXetine

Strong CYP2D6 inhibitors may cause an increase in serum AtoMOXetine. Management: Start atomoxetine treatment at a lower dose in patients who are receiving strong CYP2D6 inhibitors. Patients up to 70kg should take 0.5 mg/kg/day. Patients 70 kg and over should take 40 mg/day.

Brexpiprazole

CYP2D6 inhibitors (Strong) can increase the serum level of Brexpiprazole. Management: Lower the dose of brexpiprazole to half of its usual dose if you are using a strong CYP2D6 inhibitor. If combined with a strong CYP3A4 inhibitor, your dosage will be reduced to 25%. These recommendations do not apply to major depressive disorders.

Codeine

CYP2D6 inhibitors (Strong) can reduce the therapeutic effects of Codeine. These CYP2D6 Inhibitors (Strong) may block the metabolic conversion of Codeine to its active metabolite morphine.

CYP2D6 Substrates High Risk with Inhibitors

Dacomitinib can increase serum concentrations of CYP2D6 substrates (High Risk with Inhibitors). Management: Do not use dacomitinib concurrently with CYP2D6 Substrates that have a narrow therapeutic Index.

Deutetrabenazine

CYP2D6 inhibitors (Strong) can increase serum levels of Deutetrabenazine. Management: A daily maximum dose of 36 mg of Deutetrabenazine is recommended. The maximum single dose of Deutetrabenazine should be no more than 18 mg if there are concurrent strong CYP2D6 inhibitors.

DOXOrubicin Conventional

CYP2D6 inhibitors (Strong) can increase serum levels of DOXOrubicin. (Conventional). Treatment: If possible, seek alternatives to strong CYP2D6 inhibitors for patients who have been treated with doxorubicin. These combinations should be avoided according to one U.S. manufacturer, Pfizer Inc.

Eliglustat

Strong CYP2D6 inhibitors (Strong). This may increase the serum Eliglustat concentration. Management: Lower the daily eliglustat dose by 84 mg. Use eliglustat only in combination with a strong CYP2D6 inhibitor and a strong, moderate or strong CYP3A4 inhibitor.

Antagonists of the Histamine H2 Receptors

The serum concentration of Dacomitinib may be decreased. Administration: Take dacomitinib at the least 6 hours before or 10 after a histamine H2receptor antagonist.

Iloperidone

CYP2D6 inhibitors (Strong), may raise serum levels of active metabolites of Iloperidone. Concentrations of P88, the active metabolite, may increase. CYP2D6 inhibitors (Strong), may reduce serum levels of active metabolites of Iloperidone. Concentrations of P95, the active metabolite, may decrease. Strong CYP2D6 inhibitors may increase serum Iloperidone. Treatment: Use a strong CYP2D6 inhibitor to reduce the iloperidone dosage by half.

Metoclopramide

Strong CYP2D6 inhibitors may raise the serum Metoclopramide concentration. Management: Limit metoclopramide to 5 mg four times per day (30 minutes before meals and at bedtime), and reduce the daily maximum dose to 20 mg if you take strong CYP2D6 inhibitors.

Perhexiline

Perhexiline serum concentration may be increased by CYP2D6 inhibitors. Management: If possible, consider other options. Monitor for elevated perhexiline serum levels and toxicities (eg hypoglycemia or neuropathy, liver dysfunction) if the combination is used. Perhexiline doses should be reduced.

Primaquine

CYP2D6 Inhibitors (Strong), may reduce the therapeutic effects of Primaquine. Monitoring: Patients who are taking strong CYP2D6 inhibitors should be aware of signs and symptoms that could indicate a possible treatment failure with primaquine. You may need to adjust therapies if primaquine's efficacy is impaired.

Tetrabenazine

CYP2D6 inhibitors (Strong), may increase serum Tetrabenazine concentrations. Concentrations of active alpha-, beta-dihydrotetrabenazine metabolismites could be increased. Management: When starting a strong CYP2D6 inhibitor, the adult dose of tetrabenazine should be decreased by 50%. When used in combination with a strong CYP2D6 inhibitor, the maximum adult dose of tetrabenazine is 50 mg/day

Vortioxetine

Strong CYP2D6 inhibitors may raise serum Vortioxetine levels. When combined with a strong CYP2D6 inhibitor, the vortioxetine dosage should be decreased by 50%. The vortioxetine dosage should be reduced by 50% after discontinuing use of the strong CYP2D6 inhibitor.

Risk Factor X (Avoid Combination)

Mequitazine

CYP2D6 inhibitors (Strong), may increase serum levels of Mequitazine.

Pimozide

CYP2D6 inhibitors (Strong) can increase the serum level of Pimozide.

Inhibitors of the proton pump

The serum concentration of Dacomitinib may be decreased. Management: Do not use dacomitinib concurrently with proton pump inhibitors. Antabics can be used. Histamine H2-receptor antagonists may be used (HR2A), provided that dacomitinib has been given at least 6 or 10 hours before the H2RA.

Tamoxifen

Strong CYP2D6 inhibitors may reduce serum levels of active metabolites of Tamoxifen. Particularly, strong CYP2D6 inhibitors can decrease the metabolism of potent active metabolites.

Thioridazine

CYP2D6 inhibitors may increase Thioridazine serum concentrations.

Monitoring parameters:

Before Starting Treatment:

  • Check for specific gene changes: exon 19 deletion or exon 21 L858R changes.
  • For women who can get pregnant, do a pregnancy test.

While on Treatment:

  • Watch out for lung issues like trouble breathing, cough, and fever.
  • Keep an eye on diarrhea and skin problems.
  • Make sure the patient is taking the medication as prescribed.

How to administer Dacomitinib (Vizimpro)?

  • Take it at the same time every day, with or without food.
  • Don't take dacomitinib with medicines called proton pump inhibitors.
  • If using an H2 blocker or antacid, take dacomitinib 6 hours before or 10 hours after that medicine.

Mechanism of action of Dacomitinib (Vizimpro):

  • Dacomitinib is a drug that permanently blocks certain cell receptors (EGFR/HER1, HER2, HER4) and specific changes in them (like exon 19 deletion or exon 21 L858R change).
  • This mainly helps stop some cancer cells from growing.
  • It also affects a few other targets in the lab, like DDR1, EPHA6, and some others.

Distribution:

  • Volume of distribution: 1,889 liters (a measure of how the drug spreads in the body)

Protein Binding:

  • Binds to proteins in the blood: About 98% of the drug attaches to proteins.

Metabolism:

  • Processed by the liver: Primarily broken down in the liver through chemical changes like oxidation and joining with glutathione.
  • Specific enzymes involved: CYP2D6 helps create O-desmethyl dacomitinib (which is active), and CYP3A4 helps form minor products through oxidation.

Bioavailability:

  • Amount that gets into bloodstream: Around 80% of the drug taken gets into the bloodstream.

Half-life:

  • Time it takes to reduce by half: The drug takes about 70 hours to decrease in the body by half.

Time to Peak:

  • When it's highest in the blood: It usually takes around 6 hours after taking the drug to reach its highest level in the blood. This can vary between 2 to 24 hours.

Excretion:

  • Leaving the body: Most of the drug leaves through the feces (79%), with only a small amount (3%) in the urine. Only a fraction of this is the original drug; the rest is transformed.

International Brand Names of Dacomitinib:

  • Vizimpro

Dacomitinib Brand Names in Pakistan:

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