Encorafenib is a medication used in the treatment of certain types of cancer, particularly melanoma. It is classified as a BRAF inhibitor and is specifically indicated for use in combination with another medication called binimetinib in the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. These mutations are commonly found in melanoma and can drive the growth of cancer cells.

Encorafenib (Braftovi) is a targeted therapy for the treatment of patients with metastatic or unresectable melanoma. It targets cells with BRAF mutations and inhibits protein kinase B-RAF (BRAF). (see details in the section: Mechanism of action)

Encorafenib Uses:

• Unresectable or metastatic melanoma:
  • It is indicated in patients metastatic or unresectable  melanoma with a BRAF V600E or V600K mutation (in combination with binimetinib)
  • Limitations of use: Not used for wild-type BRAF melanoma.

Encorafenib (Braftovi) Dose in Adults

Note: 

• Before starting treatment, make sure to check if the patient has the specific BRAF V600 mutation.
• This is important because the treatment we are considering works best for people with this particular mutation.
• Checking for this mutation helps ensure that the treatment will be effective for the individual.

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

Standard Dose:

• Take 450 mg of encorafenib orally once a day.
• This is usually done in combination with another medication called binimetinib.
• Keep taking it until the disease either gets worse or you experience severe side effects.

Dosage Adjustment with CYP3A4 Inhibitors:

• If you are also taking medications that strongly or moderately inhibit CYP3A4, it's best to avoid them.
• However, if you can't avoid using them together, your doctor may reduce your encorafenib dose to a third of what you were taking before starting the CYP3A4 inhibitor if it's strong or half if it's moderate.
• After you stop taking the CYP3A4 inhibitor for a certain amount of time (usually 3 to 5 half-lives), you can go back to your regular encorafenib dose.

Missed Doses:

• If you realize you missed a dose and it's less than 12 hours until your next scheduled dose, don't take the missed one.
• If you vomit after taking encorafenib, do not take an extra dose.
• Just continue with your regular dosing schedule and take the next dose as planned.

Dose in Children:

Not indicated.

Encorafenib Pregnancy Category: X

• Encorafenib, due to how it works and findings from animal studies, can potentially harm a developing fetus if taken during pregnancy.
• So, before starting encorafenib treatment, it's crucial to check if a female of reproductive age is pregnant or not.
• If she can become pregnant, she should use a highly effective non-hormonal form of birth control while taking encorafenib and for at least two weeks after the last dose.
• Traditional hormonal contraceptives might not be effective enough for this purpose.
• Additionally, it's important to note that the use of encorafenib might affect fertility in males.

Use Encorafenib while you are breastfeeding

• The presence of encorafenib in breast milk is not well-established.
• However, because there is a potential for serious adverse effects in a breastfed infant, the manufacturer advises against breastfeeding while undergoing treatment with encorafenib and for at least two weeks after the last dose.

Encorafenib (Braftovi) Dose in Kidney disease:

• If your creatinine clearance (CrCl) is equal to or greater than 30 mL/minute, you typically won't need a dosage adjustment. This means that your kidneys are functioning well enough to handle the standard dosage.
• However, if your CrCl is less than 30 mL/minute, there are no specific dosage adjustments recommended in the manufacturer's labeling. This is because the medication hasn't been extensively studied in individuals with severe kidney impairment in clinical trials.
• Encorafenib is not likely to be removed by hemodialysis because it is extensively bound to proteins in the bloodstream. Therefore, hemodialysis is unlikely to significantly affect the levels of encorafenib in the body.

Encorafenib (Braftovi) Dose in Liver disease:

Preexisting Hepatic Impairment:

• If you have mild hepatic impairment (Child-Pugh class A), there is typically no need for a dosage adjustment. Your liver function is still relatively good.
• However, if you have moderate to severe hepatic impairment (Child-Pugh class B or C), there are no specific dosage adjustments recommended in the manufacturer's labeling. This is because the medication hasn't been extensively studied in individuals with significant liver impairment in clinical trials.

Hepatotoxicity during Treatment (Liver Toxicity):

• If you experience certain elevations in liver enzymes (AST or ALT) during your treatment, the actions to take depend on the severity of the elevation:
  • Grade 2 AST or ALT elevations: You can usually continue taking encorafenib. If there's no improvement within four weeks, the medication may be temporarily stopped until the liver enzyme levels return to a lower grade or to their pretreatment/baseline levels. After that, you can resume taking encorafenib at the same dose.
  • Grade 3 AST or ALT elevation: For the first occurrence of grade 3 elevations, encorafenib should be withheld for up to four weeks. If the levels improve to grade 1 or return to pretreatment/baseline levels, you can resume taking encorafenib, but at a reduced dose. If there is no improvement, encorafenib should be permanently discontinued. If grade 3 toxicity recurs, discontinuing encorafenib should be considered.
  • Grade 4 AST or ALT elevation: For the first occurrence of grade 4 elevations, encorafenib should be permanently discontinued or withheld for up to four weeks. If the levels improve to grade 1 or return to pretreatment/baseline levels, you can resume encorafenib, but at a reduced dose. If there is no improvement, encorafenib should be permanently discontinued. If grade 4 toxicity recurs, permanent discontinuation of encorafenib is recommended.

Incidences of adverse effects include those defined during combination therapy with binimetinib.

Common Side Effects of Encorafenib (Braftovi):

• Central Nervous System:
  • Fatigue
  • Headache
  • Dizziness
  • Peripheral Neuropathy
• Dermatologic:
  • Hyperkeratosis
  • Alopecia
  • Palmar-Plantar Erythrodysesthesia
  • Skin Rash
  • Xeroderma
  • Pruritus
  • Dermatological Reaction
  • Erythema
• Endocrine & Metabolic:
  • Increased Gamma-Glutamyl Transferase
  • Hyperglycemia
  • Hyponatremia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Abdominal Pain
  • Constipation
  • Dysgeusia
• Hematologic & Oncologic:
  • Anemia
  • Hemorrhage
  • Leukopenia
  • Lymphocytopenia
  • Neutropenia
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alkaline Phosphatase
• Neuromuscular & Skeletal:
  • Arthralgia
  • Myopathy
  • Back Pain
  • Limb Pain
• Renal:
  • Increased Serum Creatinine
• Miscellaneous:
  • Fever

Less Common Side Effects Of Encorafenib (Braftovi):

• Central Nervous System:
  • Facial Paresis
• Dermatologic:
  • Acneiform Eruption
• Endocrine & Metabolic:
  • Hypermagnesemia
• Gastrointestinal:
  • Pancreatitis
  • Hematochezia
  • Hemorrhoidal Bleeding
• Hypersensitivity:
  • Hypersensitivity
• Hematologic & Oncologic:
  • Squamous Cell Carcinoma Of Skin
  • Malignant Melanoma
  • Rectal Hemorrhage
  • Keratoacanthoma
  • Basal Cell Carcinoma
• Neuromuscular & Skeletal:
  • Panniculitis
• Ophthalmic:
  • Uveitis

Contraindications to Encorafenib (Braftovi):

• According to the manufacturer's labeling, there are no specific contraindications listed for encorafenib.
• This means that there are no absolute medical reasons stated by the manufacturer to completely prohibit the use of encorafenib in a particular patient population.

Warnings and precautions

Dermatologic toxicities:

• Grade 3 or 4 skin problems happened in about 20% of people taking just encorafenib.
• In contrast, only about 2% of people had these severe skin issues when they took both encorafenib and binimetinib together.

Hemorrhage

• When encorafenib is used together with binimetinib, there's a risk of bleeding, including severe bleeding events (grade 3 or worse).
• The most common types of bleeding events involve the gastrointestinal (GI) tract, like rectal bleeding, blood in stools (hematochezia), and hemorrhoids bleeding.
• In some cases, there were reports of fatal bleeding in the brain when there were new or growing cancer masses in the brain.
• Depending on how severe the bleeding is, it might be necessary to pause treatment, reduce the dose of the medication, or even stop using it permanently.

Malignancy

• People treated with BRAF inhibitors, like encorafenib, have experienced new cancers, both on the skin and inside the body.
• When using encorafenib with binimetinib, patients have developed skin cancers such as squamous cell carcinoma (cuSCC) and basal cell carcinoma.
• This typically occurred around 6 months after starting treatment.
• People taking encorafenib alone have also developed skin cancers like squamous cell carcinoma and basal cell carcinoma, as well as new melanoma.
• Doctors should regularly check the skin before treatment, every 2 months during treatment, and for up to 6 months after stopping treatment.
• Suspicious skin lesions may need to be removed and examined by a specialist, but changing the medication dose isn't usually recommended for new skin cancers.
• Because of how encorafenib works, it might also increase the risk of other cancers in places other than the skin.
• Patients should watch for signs of these cancers. If certain types of non-skin cancers are found to have a specific genetic change (RAS mutation), encorafenib should be stopped.

Ocular toxicities:

• When using encorafenib together with binimetinib, some patients have experienced eye inflammation, which includes conditions like uveitis, iritis, and iridocyclitis.
• It's essential to keep an eye on any eye-related issues during treatment. Healthcare providers should regularly check the eyes, and patients should report any new or worsening vision problems.
• Depending on how severe the eye issues are, treatment might need to be paused, the medication dose reduced, or the medication stopped permanently.

Extension of QT

• Encorafenib can affect the time it takes for the heart to recharge between beats, called the QTc interval, and this effect can increase with higher doses.
• In rare cases, in clinical trials where encorafenib was used with binimetinib, some patients had a significant QTc interval prolongation, where the heart's rhythm was slower than normal (QTcF >500 msec).
• It's important to keep an eye on patients who are at risk of developing QTc prolongation. This includes those with known long QT syndromes, severe or uncontrolled heart failure, certain heart rhythm problems (bradyarrhythmias), or those taking other medications that can prolong the QT interval.
• Before starting treatment, any low levels of potassium (hypokalemia) or magnesium (hypomagnesemia) should be corrected.
• If there are significant QT prolongation issues, it might be necessary to pause treatment, reduce the medication dose, or even stop the medication, depending on the severity of the heart rhythm problem.

Encorafenib: 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

Monitoring parameters:

• BRAFV600K or V600E Mutation Status: Check if the patient has a BRAFV600K or V600E mutation before starting treatment.
• Electrolytes: Make sure the patient's electrolyte levels are balanced.
• Verify Pregnancy Status: For females who could become pregnant, confirm if they are pregnant before beginning treatment.

During and After Treatment:

• Dermatologic Evaluations: Check the patient's skin before treatment, every 2 months while on treatment, and for up to 6 months after stopping to look for new skin cancers.
• Monitor for Uveitis: Keep an eye out for signs like eye pain, sensitivity to light (photophobia), and changes in vision that could indicate uveitis.
• Watch for Hemorrhage: Pay attention to any signs of bleeding.
• Dermatologic Toxicity: Be on the lookout for skin problems.
• Noncutaneous Malignancies: Monitor for signs and symptoms of cancers in places other than the skin.
• Monitor Adherence: Make sure the patient is taking the medication as prescribed.

How to administer Encorafenib (Braftovi)?

• You should take this medication by mouth once a day.
• You can take it with or without food, whichever you prefer.

Mechanism of action of Encorafenib (Braftovi):

• Encorafenib is a medication that works by inhibiting a protein called B-raf (BRAF), which is a part of a signaling pathway known as the MAPK pathway.
• This pathway is involved in cell growth and can become overactive due to mutations in BRAF, such as V600E, V600D, and V600K mutations.
• These mutations can stimulate tumor growth.
• Encorafenib specifically targets these mutated forms of BRAF, and it has a unique feature—it stays bound to its target for a longer time compared to other BRAF inhibitors.
• This sustained inhibition is beneficial because it effectively stops the overactive pathway for a more extended period.
• When BRAF V600 mutations are present, they constantly activate the BRAF pathway, promoting the growth of cancer cells.
• By inhibiting BRAF, encorafenib puts a halt to this uncontrolled cell growth.
• Additionally, when combined with another drug called binimetinib, encorafenib demonstrates even more significant antitumor activity, especially in cells with BRAF V600 mutations.
• In animal studies, this combination therapy also delayed the development of resistance in cells with BRAF V600E mutations, which is a promising outcome in cancer treatment.

Absorption:

• When you take encorafenib, at least 86% of the dose is absorbed by your body.

Distribution:

• It's distributed throughout the body, with a volume of distribution of 164 liters.
• This means it spreads quite widely in your body.

Protein Binding:

• Encorafenib binds to proteins in your blood plasma.
• Specifically, about 86% of the drug attaches to these proteins.

Metabolism:

• The primary way your body breaks down encorafenib is through a process called N-dealkylation.
• The main enzyme responsible for this is CYP3A4, although CYP2C19 and CYP2D6 also play smaller roles in clearing the drug from your body.

Half-life Elimination:

• Encorafenib has a relatively short half-life of about 3.5 hours.
• This means that it takes roughly 3.5 hours for half of the drug to be eliminated from your body.

Time to Peak:

• It reaches its highest concentration in your bloodstream around 2 hours after you take it.

Excretion:

• Your body eliminates encorafenib through both feces (47%, with 5% as unchanged drug) and urine (47%, with 2% as unchanged drug).

International Brand Names of Encorafenib:

• Braftovi

Encorafenib Brand Names in Pakistan:

Not available.