EMEDZ.NET

Dabrafenib mesylate (Tafinlar) - Uses, Dose, Side effects, MOA

Dabrafenib is a targeted therapy drug that is used to treat melanoma and non-small cell lung cancer that have a specific mutation (V600E or V600K) in the BRAF gene. This drug belongs to a class of medications called kinase inhibitors.

Dabrafenib Mesylate (Tafinlar) is a mutant BRAF-kinase inhibitor that is used as monotherapy or in combination with Trametinib (Mekinist) for the treatment of melanoma and other malignancies like anaplastic thyroid carcinoma and metastatic non-small cell lung cancer.

Dabrafenib (Tafinlar) Uses:

Melanoma:
- Used for the adjuvant treatment of melanoma (in combination with trametinib) in patients with a BRAF V600E or BRAF V600K mutation ( detected by an approved test), and lymph node involvement, following complete resection.
- Used for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation (single-agent therapy) or in patients with BRAF V600E or BRAF V600K mutations (in combination with trametinib);
- confirm BRAF V600E or BRAF V600K mutation status with an approved test prior to treatment.
Non-small cell lung cancer, metastatic:
- Used for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation as detected by an approved test (in combination with trametinib).
Thyroid cancer, anaplastic, locally advanced or metastatic:
- Used for the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) (in combination with trametinib) in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.
- Limitations of use: for patients having wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC, Trametinib is not indicated for the treatment of those patients.

Dabrafenib (Tafinlar) Dose in Adults

Note: Before starting the treatment, make sure to check if the patient has the BRAF V600 mutation.

Dabrafenib (Tafinlar) Dose in the treatment of Melanoma, adjuvant treatment (with BRAF V600E or BRAF V600K mutation):

For treating melanoma (with specific BRAF V600E or V600K changes), take Dabrafenib as a pill: 150 mg two times a day (about every 12 hours).
Combine it with trametinib.
Keep taking this for up to 1 year unless the cancer gets worse or there are bad side effects.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic or unresectable melanoma (with BRAF V600E mutation):

For treating advanced melanoma (with a specific BRAF V600E change) that has spread or can't be surgically removed: Take Dabrafenib as a pill, 150 mg two times a day (about every 12 hours).
Take it by itself.
Keep taking it until the cancer gets worse or if there are bad side effects.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic or unresectable melanoma (with BRAF V600E or BRAF V600K mutation):

For treating advanced melanoma (with BRAF V600E or V600K changes) that has spread or can't be removed by surgery: Take Dabrafenib as a pill, 150 mg two times a day (roughly every 12 hours).
Use it with trametinib.
Keep taking both until the cancer gets worse or if there are strong side effects.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic non-small cell lung cancer (with BRAF V600E mutation):

For treating advanced non-small cell lung cancer (with a BRAF V600E change): Take Dabrafenib as a pill, 150 mg two times a day (about every 12 hours).
Combine it with trametinib.
Keep taking both until the cancer worsens or if there are severe side effects.

Dabrafenib (Tafinlar) Dose in the treatment of locally advanced or metastatic anaplastic Thyroid cancer (with BRAF V600E mutation):

For treating advanced thyroid cancer (with a BRAF V600E change) that's spread or grown into nearby areas: Take Dabrafenib as a pill, 150 mg two times a day (roughly every 12 hours).
Use it together with trametinib.
Keep taking both until the cancer gets worse or if bad side effects happen.

If you forget a dose:

If there's more than 6 hours until your next dose, you can take the missed one.
But if it's less than 6 hours until the next dose, skip the missed one and don't try to make up for it.

Use in Children:

Not indicated.

Dabrafenib (Tafinlar) Pregnancy Category: N

Dabrafenib might harm an unborn baby if taken by a pregnant woman, based on how it works and animal studies
Women who can become pregnant should use a strong non-hormone birth control while on this medicine and for 2 weeks after stopping if using only dabrafenib, or 4 months if combined with trametinib
Regular birth control pills might not work properly with this treatment
Also, for men, this drug might affect the production of sperm, as seen in animal tests
It's a good idea for men to discuss family planning and their ability to have children before starting the medicine.

Use of Dabrafenib while breastfeeding

We're not sure if dabrafenib gets into breast milk
But because there's a chance it could seriously harm a breastfeeding baby, the maker of the medicine advises not to breastfeed while taking it and for 2 weeks after stopping if only using dabrafenib, or 4 months if also using trametinib.

Dabrafenib (Tafinlar) Dose in Kidney Disease:

If your kidney function is good (GFR ≥30 mL/minute/1.73 m), you don't need to change the dose.

If your kidney function is poor (GFR <30 mL/minute/1.73 m), the medicine's label doesn't give specific dose changes because it hasn't been studied enough in this situation.

Dabrafenib (Tafinlar) Dose in Liver disease:

If you have a mild problem with how your liver works, you can take the usual dose.
But if you have a moderate to serious liver problem, the medicine's label doesn't tell how to adjust the dose because it hasn't been tested enough. But, since the liver mainly handles the drug, those with bigger liver issues might have more of the drug in their system.

Common Side Effects of Dabrafenib (Tafinlar):

Cardiovascular:
- Hypertension
- Peripheral Edema
Central Nervous System:
- Headache
- Chills
Dermatologic:
- Hyperkeratosis
- Skin Rash
- Alopecia
- Palmarplantar Erythrodysesthesia
- Xeroderma
Endocrine & Metabolic:
- Hyperglycemia
- Hypophosphatemia
- Hypoalbuminemia
- Hyponatremia
Gastrointestinal:
- Nausea
- Diarrhea
- Abdominal Pain
- Vomiting
- Constipation
Hematologic & Oncologic:
- Anemia
- Lymphocytopenia
- Papilloma
- Neutropenia
- Hemorrhage
- Malignant Neoplasm Of Skin
Hepatic:
- Increased Serum Alanine Aminotransferase
- Increased Serum Alkaline Phosphatase
- Increased Serum Aspartate Aminotransferase
Neuromuscular & Skeletal:
- Arthralgia
- Myalgia
- Back Pain
Respiratory:
- Cough
Miscellaneous:
- Fever

Less Common Side Effects Of Dabrafenib (Tafinlar):

Cardiovascular:
- Cardiomyopathy
Central Nervous System:
- Dizziness
Gastrointestinal:
- Pancreatitis
- Gastrointestinal Hemorrhage
Hematologic & Oncologic:
- Thrombocytopenia
- Basal Cell Carcinoma
- Malignant Neoplasm
- Malignant Melanoma
Hypersensitivity:
- Hypersensitivity
Ophthalmic:
- Uveitis
Renal:
- Interstitial Nephritis
Respiratory:
- Nasopharyngitis
Miscellaneous:
- Febrile Reaction

Contraindications to Dabrafenib (Tafinlar):

The U.S. label doesn't list any reasons not to take the drug.

But in Canada, you shouldn't take it if you're allergic to dabrafenib or any part of the medicine.

Warnings and precautions

Cardiomyopathy

Heart muscle problems (cardiomyopathy) can happen when using dabrafenib alone or with trametinib.
Before starting the combo treatment, and then every 2 to 3 months during treatment, check the heart's pumping ability.
If there are heart issues, you might need to pause dabrafenib (and check trametinib's guidelines for any changes needed there).
For some, the heart problem went away after adjusting the dose, taking a break, or stopping the drug completely.

Dermatologic toxicities:

Skin problems (like rashes, redness, or even conditions that cause hand and foot discomfort) can happen when using dabrafenib with trametinib.
These issues also occur when using just trametinib.
Some people had to go to the hospital because of severe skin problems or infections.
Watch for skin issues and signs of infection.
Depending on how bad it is, you might need to pause the treatment, take a smaller dose, or stop the medicine.

Febrile reactions

Sometimes, serious fevers and fever-related issues like low blood pressure, shaking, dehydration, and kidney problems can happen with dabrafenib, either alone or with trametinib.
If your fever is 38.5°C (101.3°F) or higher or if you have a serious fever with other problems, stop dabrafenib treatment.
Check for signs of infection and kidney function.
You might need to take less medicine or stop it.
If you get fevers again, corticosteroids can help if your temperature doesn't get back to normal in 3 days, or if the fever causes issues like dehydration or low blood pressure.

Hemorrhage

Bleeding, sometimes in important areas like the brain or stomach, can happen when using dabrafenib alone or with trametinib.
Some serious bleedings have even caused death.
If this happens, you might need to pause the treatment or take a smaller dose.
Stop dabrafenib (and trametinib) for the worst bleeding events or if a serious bleeding doesn't get better after pausing the drug.

Hyperglycemia

High blood sugar can happen when using dabrafenib, whether on its own or with trametinib.
If this occurs, you might need to start or increase diabetes medicines like insulin.
If you already have diabetes or high blood sugar, check your blood sugar levels before starting and during the treatment as needed.

Malignancy

Certain skin cancers and new melanomas were seen more often in people using just dabrafenib compared to those on other treatments in studies.
Some patients got these more than once.
Using dabrafenib with trametinib reduced the chance of these skin cancers.
Some lung cancer patients also got these skin cancers.
Even though it's rare, basal cell skin cancer happened too, sometimes more than once for a patient.
Before starting the drug, get a skin check, then every 2 months while on the drug, and for 6 months after stopping.
There have been a few cases of cancers in other parts of the body with the combined treatment.
Look out for signs of these.
If you get a certain type of non-skin cancer with a RAS mutation, stop dabrafenib for good, but you don't need to change the trametinib dose.

Ocular toxicities:

Some eye problems can happen when using dabrafenib with trametinib, like parts of the retina detaching
This might affect your central vision
If you notice vision problems, see an eye doctor within a day
You don't need to change the dabrafenib dose for this, but trametinib might need adjustment
Get regular eye checks during the combo treatment
Uveitis, which affects the middle part of the eye, can also happen with these drugs
If you experience symptoms like eye pain, light sensitivity, or vision changes, use eye drops and see a doctor
This could require a break from dabrafenib or stopping it, but trametinib doesn't have to change.

Extension of QT

Using dabrafenib, alone or with trametinib, can sometimes cause the heart's QT interval to lengthen, which might lead to heart rhythm problems
This is rare but be careful if you're already at risk for irregular heartbeats.

Venous thromboembolism

When using dabrafenib with trametinib, there's a chance of blood clots forming in veins, which can be deadly
These clots and lung problems from clots happen more often with the combo treatment
If you feel short of breath, have chest pain, or swelling in an arm or leg, get medical help fast
For simple blood clots, you can keep using dabrafenib
But if there's a very serious clot in the lungs, stop using trametinib for good.

Dabrafenib: 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).
Antidiabetic Agents	Hyperglycemia-Associated Agents can reduce the therapeutic effects of Antidiabetic Agents.
Clofazimine	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
CloZAPine	CloZAPine serum concentrations may be decreased by CYP3A4 Inducers Moderate
Codeine	CYP3A4 Inducers Moderate may reduce serum levels of active metabolites of Codeine.
CYP2B6 Substrates (High Risk with Inducers).	Dabrafenib could lower the serum concentration of CYP2B6 Substrates (High Risk with Inducers).
Moderate CYP2C8 inhibitors	Might decrease metabolism of CYP2C8 substrates (High Risk with Inhibitors).
Strong CYP3A4 Inducers	It may decrease serum levels of Dabrafenib.
Moderate CYP3A4 inhibitors	Might decrease metabolism of CYP3A4 substrates (High Risk with Inhibitors).
Deferasirox	High risk of Inhibitors causing an increase in serum CYP2C8 Substrates concentrations
Estriol (Systemic).	Moderate CYP3A4 Inducers may reduce the serum Estriol (Systemic) concentration.
Estriol (Topical).	Moderate CYP3A4 Inducers may reduce serum Estriol (Topical) concentrations
FentaNYL	FentaNYL serum concentration may be decreased by CYP3A4 Inducers Moderate
Pibrentasvir and Glecaprevir	Moderate CYP3A4 Inducers may reduce serum levels of Glecaprevir or Pibrentasvir.
Ifosfamide	CYP3A4 Moderate Inducers may reduce serum levels of Ifosfamide's active metabolite(s). CYP3A4 Moderate may increase serum levels of Ifosfamide's active metabolite(s).
Lumacaftor	May increase serum concentrations of CYP2C8 substrates (High risk with inhibitors or inducers). Lumacaftor could decrease serum concentrations of CYP2C8 substrates (High-Risk with Inhibitors and Inducers).
Agents that prolong QT (Highest risk)	QT-prolonging agents (Indeterminate risk - Caution), may increase the QTc prolonging effect of QT Prolonging Agents. When using these agents together, be sure to monitor for QTc interval prolongation or ventricular arrhythmias. Patients at higher risk for QTc prolongation might have additional risk factors.
Risk Factor D (Consider therapy modifications)
Brigatinib	Moderate CYP3A4 Inducers may reduce the serum Brigatinib concentration. Management: If possible, avoid concurrent use of brigatinib and moderate CYP3A4 inducers. Combination: Increase the daily dose of Brigatinib by 30 mg increments for 7 days following treatment with current dose. Maximum of twice the dose.
CYP2C19 Substrates: High risk with Inducers	Dabrafenib can decrease serum concentrations of CYP2C19 substrates (High Risk with Inducers). Management: If possible, seek alternatives to the CYP2C19 substrat. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
CYP2C8 Substrates, High risk with Inducers	Dabrafenib can decrease serum concentrations of CYP2C8 substrates (High Risk with Inducers). Management: If possible, seek alternatives to the CYP2C8 substrat. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
CYP2C9 Substrates - High risk with Inducers	Dabrafenib can decrease serum concentrations of CYP2C9 substrates (High Risk with Inducers). Management: If possible, seek alternatives to the CYP2C9 substrat. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
CYP3A4 Substrates - High risk with Inducers	Dabrafenib can decrease serum concentrations of CYP3A4 substrates (High Risk with Inducers). Management: If possible, seek alternatives to the CYP3A4 substrate. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
Daclatasvir	Moderate CYP3A4 Inducers may reduce the serum level of Daclatasvir. Management: If you are using a moderate CYP3A4 inducer, increase the daclatasvir dosage to 90 mg daily.
Erdafitinib	Moderate CYP3A4 Inducers may reduce the serum level of Erdafitinib. Management: Modifications to the dose of Erdafitinib might be necessary. For more information, please refer to the full monograph.
Contraceptive: Estrogen Derivatives	The serum concentrations of Estrogen Derivatives may be decreased by dabrafenib (Contraceptive). Management: After discontinuing dabrafenib treatment, females with reproductive potential should consider an alternative, highly effective, nonhormonal method of contraception.
GuanFACINE	Moderate CYP3A4 inducers may cause a decrease in serum GuanFACINE. Management: Concomitant therapy using moderate CYP3A4 inducers may increase the guanfacine dosage by as much as twice. If moderate CYP3A4 inducer therapy is just starting, gradually increase the guanfacine dosage over 1-2 weeks.
Lorlatinib	CYP3A4 Moderate Inducers may increase the hepatotoxic effects of Lorlatinib. CYP3A4 Moderate Inducers may lower the serum Lorlatinib concentration. Use lorlatinib only with moderate CYP3A4 inducers. Monitor AST, ALT and bilirubin as soon as possible after starting the combination, and at least three times during the first week.
Lurasidone	Moderate CYP3A4 inducers may cause a decrease in serum Lurasidone. Management: Watch for decreased lurasidone effects when combined with moderate CYP3A4 inducers. If coadministered for seven or more days, consider increasing the lurasidone dosage.
Palbociclib	Moderate CYP3A4 Inducers may reduce the serum level of Palbociclib. Management: Although the US label doesn't give specific guidelines for moderate CYP3A4 inducers, the Canadian label suggests avoiding moderate CYP3A4 stimulators.
Perampanel	Perampanel serum concentration may be decreased by moderate CYP3A4 inducers (Moderate). Management: Perampanel can be used in conjunction with strong and moderate CYP3A4 inducers to increase the starting dose of perampanel to 4 mg/day.
Contraceptive Progestins	The serum concentration of Progestins may be decreased by dabrafenib (Contraceptive). Management: After discontinuing dabrafenib treatment, females with reproductive potential should consider an alternative, highly effective, nonhormonal method of contraception.
St John's Wort	The serum concentration of Dabrafenib may be decreased. Management: If possible, consider other options to St. John's Wort. Concomitant therapy should be avoided if possible. If this happens, watch out for decreased therapeutic effects of dabrafenib.
Stiripentol	High risk of Inhibitors causing an increase in serum concentrations of CYP3A4 substrates. Management: Avoid stiripentol use with CYP3A4 Substrates that have a narrow therapeutic Index. This is to avoid adverse effects and toxicities. Monitoring of any CYP3A4 substrate that is used with stiripentol should be closely done.
Risk Factor X (Avoid Combination)
Abemaciclib	Moderate CYP3A4 Inducers may reduce serum Abemaciclib concentrations.
Asunaprevir	Moderate CYP3A4 Inducers may reduce serum Asunaprevir concentrations.
Axitinib	Moderate CYP3A4 Inducers may reduce the serum concentrations of Axitinib.
Bedaquiline	Moderate CYP3A4 Inducers may reduce the serum concentrations of Bedaquiline.
Bosutinib	Moderate CYP3A4 Inducers may reduce the serum Bosutinib concentration.
Cobimetinib	Moderate CYP3A4 Inducers may reduce serum Cobimetinib concentrations.
Conivaptan	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Strong CYP2C8 inhibitors	May increase serum Dabrafenib concentrations
Strong CYP3A4 inhibitors	May increase serum Dabrafenib concentrations
Dasabuvir	Moderate CYP3A4 Inducers may reduce serum levels of Dasabuvir.
Deflazacort	Moderate CYP3A4 Inducers may reduce serum concentrations for the active metabolite(s), Deflazacort.
Elbasvir	CYP3A4 Inducers Moderate may reduce the serum Elbasvir concentration.
Encorafenib	CYP3A4 Inducers Moderate may reduce the serum Encorafenib concentration.
Flibanserin	Flibanserin serum concentration may be decreased by CYP3A4 Inducers Moderate
Fusidic Acid (Systemic).	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Grazoprevir	CYP3A4 Inducers Moderate may reduce the serum concentrations of Grazoprevir.
Idelalisib	High risk of Inhibitors causing an increase in serum CYP3A4 Substrates concentrations
Neratinib	CYP3A4 Inducers Moderate may reduce the serum concentrations of Neratinib.
Nisoldipine	CYP3A4 Inducers Moderate may reduce the serum Nisoldipine concentration.
Olaparib	Moderate CYP3A4 Inducers may reduce the serum level of Olaparib.
Ranolazine	Ranolazine serum concentration may be decreased by CYP3A4 Inducers Moderate
Simeprevir	Moderate CYP3A4 Inducers may reduce the serum Simeprevir concentration.
Sonidegib	Moderate CYP3A4 Inducers may reduce Sonidegib serum concentrations.
Trametinib	May increase the toxic/adverse effects of Dabrafenib.
Velpatasvir	Moderate CYP3A4 Inducers may reduce the serum Velpatasvir concentration.
Venetoclax	Moderate CYP3A4 Inducers may reduce the serum concentrations of Venetoclax.

Monitoring parameters:

General Checks:

Mutation Status: Confirm BRAFV600K or V600E before treatment.
Blood Sugar: Keep an eye on sugar levels, especially if you have diabetes or high sugar.
Electrolytes and Kidney: Check salt levels and kidney function.
Skin Checks: Examine the skin before starting, every 2 months during treatment, and 6 months after stopping to look for new skin cancers.
Fever and Infections: Look out for high temperatures and signs of infections.
Eye Issues: Watch for eye pain, sensitivity to light, and vision changes.
Other Symptoms: Check for signs of anemia, skin problems (and related infections), and cancers outside the skin.

For Combination with Trametinib:

Liver Check: Monitor liver function.
Blood Check: Look at the complete blood count regularly.
Heart Check: Test heart function (LVEF) at the start, after 1 month, and then every 2-3 months.
Bleeding & Clots: Look out for signs of heavy bleeding and blood clots.
Lung Issues: Watch for symptoms of lung problems.
Eye Problems: Check for RPED or issues with retinal veins.

Always: Make sure patients are taking their medicine as directed.

How to administer Dabrafenib (Tafinlar)?

Take the pill by mouth.
Make sure to take it 1 hour before eating or 2 hours after eating.
Doses should be spaced out by about 12 hours.
Don't open, crush, or break the capsules.
If you're taking it with trametinib, take trametinib's once-a-day dose at the same time every day. This can be with either the morning or evening dose of dabrafenib.

Mechanism of action of Dabrafenib (Tafinlar):

Dabrafenib targets mutated forms of a protein called B-raf (BRAF).
Certain mutations in the BRAF gene (like V600) cause it to stay active all the time, leading to abnormal cell growth.
Dabrafenib blocks this abnormal growth by stopping the overactive BRAF.
Dabrafenib on its own slows down cancer cell growth by hitting this target.

Combination with Trametinib:

Dabrafenib is even more effective when combined with trametinib.
Together, they strongly block a pathway called MAPK, which is critical for cancer cell growth.
This combo works especially well in melanoma with BRAF V600 mutations, causing the cells to die.
In lung cancer with the same mutation, this combo also stops cell growth significantly.

In short, dabrafenib hampers mutated BRAF, while combining it with trametinib boosts its effects against cancer cells.

Absorption:

It's best not to take with a high-fat meal (like one with ~1,000 calories and 58 to 75 grams of fat) because the body takes in less of the drug.

Distribution:

It spreads out in the body, occupying about 70.3 L of space.

Binding:

It tightly sticks to plasma proteins at a rate of 99.7%.

Metabolism:

The liver changes it into its active form called hydroxy-dabrafenib through enzymes CYP2C8 and CYP3A4. This active form is further changed to another active form, desmethyl-dabrafenib, by the CYP3A4 enzyme.

Bioavailability:

About 95% of the drug gets into the body's circulation after it's taken orally.

Half-life:

The original drug lasts about 8 hours in the body. The first active form (hydroxy-dabrafenib) stays around for 10 hours. The second active form (desmethyl-dabrafenib) remains for 21 to 22 hours.

Peak Time: