Dacomitinib – Uses, Dosage, Side Effects, Interaction

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 were 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 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.

Use in Cancer

Dacomitinib is approved to treat:

• Non-small cell lung cancer (NSCLC) that has metastasized (spread to other parts of the body). It is used as first-line treatment in patients whose tumors have certain EGFR gene mutations.

Dacomitinib is also being studied in the treatment of other types of cancer.

Contraindications

• diarrhea
• pregnancy
• a patient who is producing milk and breastfeeding
• lung tissue problem

Dosage

Strengths: 15 mg; 30 mg; 45 mg

Non-Small Cell Lung Cancer

• 45 mg orally once a day until disease progression or unacceptable toxicity

Tablets:

• 45 mg: blue film-coated, immediate release, round biconvex tablet, debossed with “Pfizer” on one side and “DCB45” on the other side.
• 30 mg: blue film-coated, immediate release, round biconvex tablet, debossed with “Pfizer” on one side and “DCB30” on the other side.

Renal Dose Adjustments

• Mild (60 to less than 90 mL/min) and moderate (30 less than 60 mL/min) renal impairment: No adjustment recommended.
  Severe renal impairment (CrCl less than 30 mL/min): Data not available

Liver Dose Adjustments

• Mild (total bilirubin less than or equal to the upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 x ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 x ULN and any AST) hepatic impairment: No adjustment recommended.
• Severe (total bilirubin greater than 3 to 10 x ULN and any AST) hepatic impairment: Data not available

Dose Adjustments

DOSE REDUCTIONS FOR ADVERSE REACTIONS:

• First dose reduction: 30 mg orally once a day
• Second dose reduction: 15 mg orally once a day

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
INTERSTITIAL LUNG DISEASE (ILD):

• Any Grade: Permanently discontinue therapy.

DIARRHEA:

• Grade 2: Withhold therapy until recovery to Grade 1 or less; resume at the same dose level. For recurrent Grade 2 diarrhea, withhold until recovery to Grade 1 or less; resume at a reduced dose.
• Grade 3 or 4: Withhold therapy until recovery to Grade 1 or less; resume at a reduced dose.

DERMATOLOGIC ADVERSE REACTIONS:

• Grade 2: Withhold therapy until recovery to Grade 1 or less; resume at the same dose level. For recurrent persistent Grade 2 reactions, withhold until recovery to Grade 1 or less; resume at a reduced dose.
• Grade 3 or 4: Withhold therapy until recovery to Grade 1 or less; resume at a reduced dose.

OTHER ADVERSE REACTIONS:

• Grade 3 or 4: Withhold therapy until recovery to Grade 2 or less; resume at a reduced dose.

DOSE MODIFICATIONS FOR ACID-REDUCING AGENTS:

• Avoid concomitant use of proton pump inhibitors (PPIs) with this drug.
• Use locally acting antacids or if using a histamine 2 (H2)-receptor antagonist, administer this drug at least 6 hours before or 10 hours after.

Administration advice:

• This drug may be taken with or without food.
• Take this drug at the same time each day.
• If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose.

Side Effects

The Most Common

• weight loss
• loss of appetite
• mouth sores
• infection of the skin around the fingernails or toenails
• hair loss
• cough
• lack of energy
• constipation
• decreased appetite
• decreased weight
• discharge, excessive tearing
• hair loss or thinning of hair
• increased hair growth on the forehead, back, arms, and legs
• lack or loss of strength
• difficulty falling asleep or staying asleep
• red or swollen eyes (“pink eye”)
• taste changes
• vomiting
• diarrhea
• shortness of breath, cough, and fever
• dry skin, redness, rash, acne, itchy skin, and peeling or blistering of your skin
• chest pain

More common

• Blistering, crusting, irritation, itching, or reddening of the skin
• body aches or pain
• chest pain
• chills
• cough
• cracked lips
• cracked, dry, or scaly skin
• deep cracks, grooves, or lines in the skin
• diarrhea
• difficulty in swallowing
• ear congestion
• fever
• headache
• itching, skin rash
• loosening of the fingernails
• loss of voice
• nasal congestion
• redness or soreness around the fingernails
• redness, swelling, or pain of the skin
• runny nose
• scaling of the skin on the hands and feet
• sneezing
• sore throat sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• swelling
• tightness in the chest
• tingling of the hands and feet
• trouble breathing
• ulceration of the skin
• unusual tiredness or weakness

Rare

• Confusion
• decreased urination
• dizziness
• dry mouth
• fainting
• fever
• increase in heart rate
• lightheadedness
• loss of heat from the body
• rapid breathing
• sunken eyes
• thirst
• diarrhea, loss of appetite;
• weight loss;
• rash, itching, and dry skin;
• eye redness, dryness, or itching;
• hair loss;
• problems with your nails;
• mouth sores, mouth pain; or
• cold symptoms such as stuffy nose, sneezing, and sore throat.
• wrinkled skin

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Advise females of reproductive potential to use effective contraception during therapy and for at least 17 days after the final dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Verify negative pregnancy status in females of reproductive potential prior to initiating therapy.

Animal studies have revealed evidence of embryotoxicity. There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans.

Lactation

There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VIZIMPRO, advise women not to breastfeed during treatment with VIZIMPRO and for at least 17 days after the last dose.

References

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