Dabrafenib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Dabrafenib is an orally bioavailable inhibitor of B-RAF (BRAF) protein with antineoplastic activity. Dabrafenib selectively binds to and inhibits the activity of B-RAF, which may inhibit the proliferation of tumor cells that contain a mutated BRAF gene. B-RAF belongs to the RAF/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/Extracellular Signal-regulated Kinases signaling pathway, which may be constitutively activated due to BRAF gene mutations.

Dabrafenib causes inhibition of phosphorylated extracellular signal-regulated kinase (ERK). This indicates a decrease in cell proliferation. Furthermore, within 24 hours of administration, downstream mediators of the MAPK pathway were inhibited. The melanoma approval for use with Mekinist is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection. Patients received doses of Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Thus, Tafinlar in combination with Mekinist treats melanoma. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Indications

  • Tafinlar is a kinase inhibitor that was initially indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Tafinlar in combination with [DB08911] is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of a durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for Tafinlar in combination with trametinib. In May 2018, Tafinlar (dabrafenib) and Mekinist ([DB08911]) have been approved in combination to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene.
  • Melanoma – Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
  • Adjuvant treatment of melanoma – Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
  • Non-small cell lung cancer (NSCLC) – Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
  • Non-small cell lung cancer (NSCLC) – Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation
  • Treatment of melanoma, Treatment of solid malignant tumors (excluding melanoma)
  • Dabrafenib was initially indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.[rx] Later, it was used in combination with trametinib for the treatment of unresectable or metastatic melanoma with V600E or V600K mutations, either as primary treatment or adjuvant treatment.[rx]
  • Metastatic Anaplastic Thyroid Cancer
  • Metastatic Melanoma
  • Metastatic Non-Small Cell Lung Cancer
  • Unresectable Melanoma
  • Unresectable or Metastatic Solid Tumors
  • Locally advanced Thyroid Cancer, Anaplastic

Use in Cancer

Dabrafenib mesylate is approved to be used alone or with trametinib to treat patients whose cancer has a certain mutation in the BRAF gene, including:

  • Anaplastic thyroid cancer is locally advanced or has spread to other parts of the body and cannot be treated with local therapy. It is used with trametinib.
  • Melanoma. It is used:
    • Trametinib in patients who have had surgery to remove cancer that has spread to the lymph nodes.
    • Alone or with trametinib in patients whose cancer cannot be removed by surgery or has spread to other parts of the body.
  • Non-small cell lung cancer that has metastasized. It is used with trametinib.
  • Solid tumors. It is used with trametinib in adults and children aged 6 years and older whose tumors cannot be removed by surgery or have spread to other parts of the body and have gotten worse after other treatments and cannot be treated with other therapies.¹

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that dabrafenib mesylate provides a clinical benefit in these patients.

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

Contraindications

  • Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC
  • squamous cell carcinoma
  • diabetes
  • inflammation of the iris – the colored part of the eyeball
  • inflammation of the uvea of the eye
  • chronic heart failure
  • abnormal EKG with QT changes from birth
  • bleeding
  • a body temperature higher than 101 degrees Fahrenheit
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • basal cell carcinoma of the skin
  • anemia from pyruvate kinase and G6PD deficiencies
  • a type of slow growing skin cancer called a keratoacanthoma
  • progression of cancer with the RAS mutation
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 75 mg; 50 mg

Non-Small Cell Lung Cancer

  • 150 mg orally 2 times a day, either as monotherapy or in combination with trametinib
  • Duration of Therapy: Until disease progression or unacceptable toxicity occurs
  • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to treatment initiation with FDA-approved test.
  • Take doses approximately 12 hours apart.
  • Take this drug at least 1 hour before or 2 hours after a meal.
  • Do not take a missed dose within 6 hours of the next dose.
  • Do not open, crush, or break capsules.
  • As a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an approved test
  • In combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an approved test, and involvement of lymph node(s), following complete resection
  • In combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

Melanoma – Metastatic

  • 150 mg orally 2 times a day, either as monotherapy or in combination with trametinib
    Duration of Therapy: Until disease progression or unacceptable toxicity occurs
  • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to treatment initiation with FDA-approved test.
  • Take doses approximately 12 hours apart.
  • Take this drug at least 1 hour before or 2 hours after a meal.
  • Do not take a missed dose within 6 hours of the next dose.
  • Do not open, crush, or break capsules.
  • As a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an approved test
  • In combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an approved test, and involvement of lymph node(s), following complete resection
  • In combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

Thyroid Cancer

  • 150 mg orally 2 times a day, either as monotherapy or in combination with trametinib
    Duration of Therapy: Until disease progression or unacceptable toxicity occurs
  • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to treatment initiation with FDA-approved test.
  • Take doses approximately 12 hours apart.
  • Take this drug at least 1 hour before or 2 hours after a meal.
  • Do not take a missed dose within 6 hours of the next dose.
  • Do not open, crush, or break capsules.
  • As a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an approved test
  • In combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an approved test, and involvement of lymph node(s), following complete resection
  • In combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an approved test
  • In combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

For Oral

For oral dosage form (capsules):

For melanoma (skin cancer), non-small cell lung cancer, anaplastic thyroid cancer, and solid tumors:

  • Adults—150 milligrams (mg) 2 times a day, taken 12 hours apart. Your doctor may adjust your dose as needed and tolerated.
  • Children 6 years of age and older—The dose is based on body weight and must be determined by your doctor.
  • Weighing 51 kilograms (kg) or more—150 milligrams (mg) 2 times a day, taken 12 hours apart. Your doctor may adjust your dose as needed and tolerated.
  • Weighing 38 to 50 kg—100 mg 2 times a day, taken 12 hours apart. Your doctor may adjust your dose as needed and tolerated.
  • Weighing 26 to 37 kg—75 mg 2 times a day, taken 12 hours apart. Your doctor may adjust your dose as needed and tolerated.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.

Dose Adjustments

DOSE REDUCTIONS FOR ADVERSE REACTIONS:

  • First Dose Reduction: 100 mg twice a day
  • Second Dose Reduction: 75 mg twice a day
  • Third Dose Reduction: 50 mg twice a day
  • Subsequent Modification: Permanently discontinue treatment if unable to tolerate 50 mg twice a day.

For New Primary Cutaneous Malignancies that develop: No dose modifications are recommended.
For New Primary Non-Cutaneous Malignancies: Permanently discontinue in patients who develop RAS mutation-positive non-cutaneous malignancies.

Fever 101.3F to 104F:

  • Withhold dabrafenib until the adverse reaction resolves, then resume at the same dose or at a reduced level.
  • NEW PRIMARY CUTANEOUS MALIGNANCIES: No adjustment is recommended.
  • NEW PRIMARY NON-CUTANEOUS MALIGNANCIES: Permanently discontinue treatment in patients who develop RAS mutation-positive non-cutaneous malignancies.

CARDIAC:

  • Symptomatic Congestive Heart Failure; Absolute Decrease in Left Ventricular Ejection Fraction [LVEF] of Greater Than 20% from Baseline that is Below Lower Level of Normal [LLN]): Withhold treatment, then resume at the same dose upon recovery of cardiac function.

PYREXIA:

  • Fever of 101.3 to 104 Degrees Fahrenheit: Withhold treatment until fever resolves, then resume at the same or lower dose level.
  • Fever Higher Than 104 Degrees Fahrenheit; Fever Complicated by Rigors, Hypotension, Dehydration, or Renal Failure: Withhold treatment until fever resolves, then resume at a lower dose level OR permanently discontinue treatment.

SKIN TOXICITY (Intolerable Grade 2, Grade 3, or Grade 4): Withhold treatment for up to 3 weeks

  • If Improved: Resume at a lower dose.
  • If Not Improved: Permanently discontinue treatment.

UVEITIS (Severe OR Mild/Moderate that Does Not Respond to Ocular Therapy): Withhold treatment for up to 6 weeks.

  • If Improved to Grade 0 to 1: Resume at same or lower dose level.
  • If Not Improved: Permanently discontinue treatment.

OTHER ADVERSE REACTIONS:
INTOLERABLE GRADE 2; ANY GRADE 3: Withhold treatment.

  • If Improved to Grade 0 to 1: Resume at a lower dose level.
  • If Not Improved: Permanently discontinue treatment.

FIRST OCCURRENCE OF ANY GRADE 4: Withhold treatment until improvement to Grade 0 to 1, then resume at a lower dose level OR permanently discontinue treatment.
RECURRENT GRADE 4: Permanently discontinue treatment.
Comments:

  • Dose adjustments are NOT recommended for this drug when it is administered in combination with trametinib for the following adverse reactions: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease (ILD)/pneumonitis, and uncomplicated venous thromboembolism.
  • Consult the manufacturer’s product information for trametinib dosing recommendations.

Administration Advice:

  • Direct patients to take this drug at least 1 hour before or 2 hours after a meal, and at similar times every day with an interval of approximately 12 hours between doses.
  • Instruct patients to swallow drug capsules whole with water, and not to open, crush, chew, or break capsules.
  • Warn patients not to mix capsule contents with food or liquids due to the chemical instability of this drug.
  • Advise patients not to take a missed dose within 6 hours of the next scheduled dose.
  • In the event of a vomited dose, counsel patients not to retake that dose and to resume dosing with the next scheduled dose.
  • Consult the manufacturer product information for trametinib dosing recommendations prior to initiation of combination treatment with this drug.

Side Effects

The Most Common

  • headache
  • joint, muscle, or back pain
  • nausea
  • diarrhea
  • constipation
  • loss of appetite
  • cough, runny nose, or sore throat
  • hair loss
  • tiredness
  • changes in skin (new wart, skin sore, or red bump that bleeds or does not heal)
  • change in size or color of a mole
  • rash, red skin, or pimples
  • fever
  • fainting
  • dizziness, lightheadedness, or weakness
  • chills
  • decreased urination
  • swelling of hands, feet, ankles, or lower legs
  • frequent urination
  • increased thirst
  • eye pain
  • red or swollen eyelids
  • sensitivity to light
  • blurred vision or vision changes, including seeing halos (blurred outline around objects) or colored dots
  • swelling, pain, redness, or peeling of skin on the palms and soles of the feet
  • ongoing pain that begins in the stomach area but may spread to the back
  • unusual bleeding or bruising
  • bloody or black, tarry stools
  • coughing up or vomiting blood or material that looks like coffee grounds
  • chest pain
  • shortness of breath
  • swelling of the hands, feet, ankles or lower legs
  • fast, irregular, or pounding heartbeat
  • yellowing of the skin and eyes

More common

  • Bleeding gums
  • bloody, black, or tarry stools
  • bloody or cloudy urine
  • blurred vision
  • coughing up blood
  • difficulty in breathing or swallowing
  • dizziness
  • dry mouth
  • fever
  • flushed, dry skin
  • fruit-like breath odor
  • greatly decreased frequency of urination or amount of urine
  • headache
  • heartburn
  • increased hunger
  • increased thirst
  • increased urination
  • indigestion
  • lump or growth on the skin
  • nausea
  • nosebleed
  • prolonged bleeding from cuts
  • red or black, tarry stools
  • red or dark brown urine
  • redness, swelling, or pain of the skin
  • scaling of the skin on the hands and feet
  • skin blisters
  • skin rash
  • stomach pain or cramps
  • sweating
  • swelling of the feet or lower legs
  • tingling of the hands and feet
  • ulceration of the skin
  • unable to move
  • unexplained weight loss
  • unusual tiredness or weakness
  • vomiting
  • vomiting of material that looks like coffee grounds, severe and continuing

Rare

  • Blurred vision or other change in vision
  • change in color vision
  • difficulty seeing at night
  • eye pain
  • increased sensitivity of the eyes to sunlight
  • redness of the eye
  • tearing
  • Blistering, peeling, loosening of the skin
  • chills
  • cough
  • diarrhea
  • itching
  • joint or muscle pain
  • red skin lesions, often with a purple center
  • sore throat
  • sores, ulcers, or white spots in the mouth or on lips
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • yellow eyes or skin

Drug Interaction

You Might Also Read  Tapentadol Contraindications, Pregnancy Category
You Might Also Read  Tretinoin Acne Tropical Creams - Uses, Indications
You Might Also Read  Zanubrutinib - Uses, Dosage, Side Effects, Interaction

Drug-Food Interactions

  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of dabrafenib.
  • Avoid St. John’s Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dabrafenib.
  • Do not take with or immediately after a high-fat meal. Dabrafenib’s bioavailability is reduced when taken with a high-fat meal.
  • Take on an empty stomach. Take dabrafenib at least one hour before or two hours after a meal.

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on animal studies, this drug may cause fetal harm and impair fertility. This drug may decrease the efficacy of hormonal contraceptives; counsel female patients of reproductive potential to use an effective non-hormonal method of contraception during therapy and for 2 to 4 weeks after the last dose of this drug and 4 months after the last dose of trametinib when given in combination with this drug. Advise male patients of the potential risk for impaired spermatogenesis, which may be irreversible. Adequate methods of contraception should be encouraged. 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.

Lactation

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

How should this medicine be used?

Dabrafenib comes as a capsule to take by mouth. It is usually taken twice a day on an empty stomach, 1 hour before or 2 hours after a meal. Take dabrafenib about 12 hours apart at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take dabrafenib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Do not stop taking dabrafenib without talking to your doctor.

Swallow the capsules whole; do not open, break, or crush them.

Your doctor may adjust your dose or temporarily or permanently stop your treatment depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with dabrafenib and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before taking dabrafenib,

  • tell your doctor and pharmacist if you are allergic to dabrafenib, any other medications, or any of the ingredients in dabrafenib capsules. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: clarithromycin (Biaxin, in PrevPac); dexamethasone; gemfibrozil (Lopid); ketoconazole; midazolam; nefazodone; rifampin (Rifadin, in Rifamate, in Rifater, Rimactane); and warfarin (Coumadin, Jantoven). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with dabrafenib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have or have ever had diabetes; glucose-6-phosphate dehydrogenase (G6PD) deficiency (a genetic condition); bleeding problems; eye problems; heart failure or other heart problems; liver or kidney disease; or any other medical condition.
  • tell your doctor if you are pregnant or plan to become pregnant, or if you plan to father a child. If you are female, you will need to have a pregnancy test before you start treatment, and you should use effective birth control to prevent pregnancy during your treatment and for 2 weeks after your final dose. If you are a male and your partner can become pregnant, you should use a condom while taking this medication, and for 2 weeks after your treatment, even if you have had a vasectomy (surgery to prevent sperm from leaving your body and causing pregnancy). You should know that this medication may decrease fertility in men and women; however, you should not assume that you cannot get pregnant or that you cannot get someone else pregnant. If you or your partner becomes pregnant while taking dabrafenib, call your doctor. Dabrafenib may harm the fetus.
  • you should know that dabrafenib may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, implants, and injections). You should use another method of birth control to prevent pregnancy in yourself or your partner during your treatment with dabrafenib and for 2 weeks after your final dose. Talk to your doctor about birth control methods that will work for you.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while taking dabrafenib and for 2 weeks after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking dabrafenib.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/202806s022lbl.pdf
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib-mesylate
  4. https://en.wikipedia.org/wiki/Dabrafenib
  5. https://medlineplus.gov/druginfo/meds/a613038.html
  6. https://go.drugbank.com/drugs/DB08912
  7. https://www.drugs.com/mtm/dabrafenib.htm
  8. https://www.webmd.com/drugs/2/drug-164393/dabrafenib-oral/details/list-contraindications
  9. https://www.mayoclinic.org/drugs-supplements/dabrafenib-oral-route/proper-use/drg-20061178
  10. ChemIDplus Chemical Information Classification
  11. CompTox Chemicals Dashboard Chemical Lists
  12. N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
    N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
  13. NCI Thesaurus Tree
  14. Guide to Pharmacology Target Classification
  15. LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    NORMAN Suspect List Exchange Classification
  16. PubChem
  17. Protein Kinase Inhibitors
  18. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  19. NCBI