Vemurafenib is a medication used in the treatment of certain types of skin cancer. It belongs to a class of drugs called kinase inhibitors, specifically targeting a mutated form of the protein known as BRAF. Vemurafenib is primarily used for the treatment of melanoma, particularly melanomas that have specific mutations in the BRAF gene.

When melanoma cells have a certain mutation in the BRAF gene (V600E or V600K), it causes overactive signaling within the cell, leading to uncontrolled cell growth and tumor formation. Vemurafenib works by inhibiting the activity of the mutated BRAF protein, thereby blocking the signaling pathway and slowing down the growth of cancer cells.

Vemurafenib (Zelboraf) stops the cellular proliferation in melanoma cells with mutation by inhibiting tumor growth in melanomas by inhibiting the kinase activity of certain mutated forms of BRAF, including BRAF with V600E mutation. It is a low molecular weight oral BRAF kinase inhibitor.

It is used to treat the following conditions:

• Unresectable or metastatic melanoma in patients having BRAFV600E mutation. It is not used for the treatment of wild-type BRAF melanoma
• Treatment of Erdheim-Chester disease (ECD) in patients having BRAF V600 mutation
• Off Label Usage in Adults include:
  • as off label agent in Melanoma, metastatic (with BRAFV600K mutation)
  • as off label agent in non-small cell lung cancer, refractory (with BRAF V600 mutation)

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Vemurafenib (Zelboraf) Dose in Adult

Vemurafenib Dosage in the treatment of metastatic or unresectable Melanoma, (with BRAF V600E mutation):  

• In the treatment of metastatic or unresectable melanoma with a specific mutation called BRAF V600E, the recommended dose of Vemurafenib is 960 mg taken by mouth every 12 hours.
•  This dosage should be continued until there is evidence of disease progression or if the side effects become too severe to tolerate.

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Vemurafenib Dosage in the treatment of Erdheim-Chester disease (with BRAF V600 mutation):  

• In the treatment of Erdheim-Chester disease with a specific mutation called BRAF V600, the recommended dose of Vemurafenib is 960 mg taken orally every 12 hours.
•  This dosage should be continued until there is evidence of disease progression or if the side effects become too severe to tolerate.

Missed doses:

• If dose is missed, you can take it up to 4 hours before the next scheduled dose.
• However, if it is less than 4 hours until the next scheduled dose, simply take the next dose at the regular time.
• If you experience vomiting after taking a dose, do not take an additional dose.
• Instead, continue with the next scheduled dose as planned.

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Vemurafenib Off label Dosage in the treatment of metastatic or unresectable Melanoma (with BRAF V600K mutation):

• In the treatment of metastatic or unresectable melanoma with a specific mutation called BRAF V600K, the recommended off-label dose of Vemurafenib is 960 mg taken orally every 12 hours.
• This dosage should be continued until there is evidence of disease progression or if the side effects become too severe to tolerate.
• It's important to note that off-label use refers to the use of a medication for a condition or indication that is not specifically approved by regulatory authorities.

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Vemurafenib Off label Dose in the treatment of metastatic or unresectable Melanoma, (with BRAF V600E or V600K mutations) :

• In the off-label combination treatment of metastatic or unresectable melanoma with BRAF V600E or V600K mutations, the recommended dose of Vemurafenib is 960 mg taken orally every 12 hours.
• This dosage is used in combination with another medication called cobimetinib.
• The combination of Vemurafenib and cobimetinib has shown efficacy in clinical studies

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Vemurafenib Off label Dose in the treatment of refractory Non-small cell lung cancer, (with BRAF V600 mutation):  

• In the off-label treatment of refractory non-small cell lung cancer with a specific mutation called BRAF V600, the recommended dose of Vemurafenib is 960 mg taken orally twice daily.
• It is important to note that off-label use refers to the use of a medication for a condition or indication that is not specifically approved by regulatory authorities.
• While there is some evidence supporting the use of Vemurafenib for BRAF V600-mutated non-small cell lung cancer, additional data may be necessary to further define its role in this condition.

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Dosage adjustment for concomitant strong CYP3A4 inducers:

• If you are taking a strong CYP3A4 inducer medication such as carbamazepine, phenytoin, or rifampin, it is generally advised to avoid using them concurrently with Vemurafenib.
• However, if it is necessary to use both medications together, a dosage adjustment for Vemurafenib may be required.
• In such cases, it is recommended to increase the Vemurafenib dose by 240 mg, as tolerated, when used alongside a strong CYP3A4 inducer.
• This adjustment helps to compensate for the potential reduction in Vemurafenib levels caused by the inducer.
• After discontinuing the strong CYP3A4 inducer, it is advised to wait for at least 2 weeks before resuming the Vemurafenib dose that was used prior to initiating the inducer.
• This waiting period allows the effects of the inducer to diminish, and the Vemurafenib dose can be adjusted back to its original level.

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Vemurafenib (Zelboraf) Dose in Childrens

Data not available. Efficacy & safety not established 

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Pregnancy Risk Factor: D

• In studies conducted on animals, no harmful effects were observed in terms of reproduction.
• However, due to how vemurafenib works, it has the potential to harm unborn babies if used during pregnancy or if a patient becomes pregnant while on the medication.
• Therefore, women who are capable of getting pregnant should use reliable birth control methods while receiving treatment with vemurafenib and for at least two weeks after stopping the medication to avoid pregnancy and potential harm to the fetus.
• It is important to discuss contraception options and any plans for pregnancy while taking vemurafenib.

Use Vemurafenib (Zelboraf), during breastfeeding

• The presence of vemurafenib in breast milk is currently unknown.
• However, due to the potential for serious side effects in breastfed infants, the manufacturer does not recommend breastfeeding during treatment with vemurafenib and for two weeks after the last dose.

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Vemurafenib (Zelboraf) dose in renal disease:

Mild to Moderate Impairment (preexisting):

• If patients have mild to moderate impairment, no dosage adjustment is necessary.
• Patients can continue taking the regular dose of the medication.

Severe Impairment (preexisting):

• In cases of severe impairment, the manufacturer's labeling does not provide specific dosage adjustments because there is insufficient data to determine if adjustments are necessary.
• However, caution should be exercised when using vemurafenib in individuals with severe impairment.

Nephrotoxicity/Creatinine Abnormalities during Treatment:

• If patinets experience kidney-related toxicity or abnormal levels of creatinine during treatment, dosage adjustments should be made.
• This can involve reducing the dose, temporarily stopping treatment, or discontinuing it altogether.

Vemurafenib (Zelboraf) Dose in Liver disease:

Mild to Moderate Impairment (preexisting):

• If patients have mild to moderate impairment, no dosage adjustment is necessary.
• Patients can continue taking the regular dose of the medication.

Severe Impairment (preexisting):

• In cases of severe impairment, the manufacturer's labeling does not provide specific dosage adjustments because there is insufficient data to determine if adjustments are necessary.
• However, it is important to use vemurafenib with caution in individuals with severe impairment.

Hepatotoxicity/Lab Abnormalities during Treatment:

• If patients experience liver-related toxicity or abnormal laboratory test results during treatment, dosage adjustments should be made.
• This may involve reducing the dose, temporarily stopping treatment, or discontinuing it altogether.

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Common Side Effects of Vemurafenib (Zelboraf) Include:

• Cardiovascular:
  • Prolonged Q-T Interval On ECG
  • Hypertension
  • Peripheral Edema
• Central Nervous System:
  • Fatigue
  • Peripheral Sensory Neuropathy
  • Headache
• Dermatologic:
  • Maculopapular Rash
  • Alopecia
  • Skin Rash
  • Hyperkeratosis
  • Skin Photosensitivity
  • Xeroderma
  • Palmar-Plantar Erythrodysesthesia
  • Pruritus
  • Nevus
  • Sunburn
  • Papular Rash
  • Erythema
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Vomiting
  • Decreased Appetite
  • Constipation
  • Dysgeusia
• Hematologic & Oncologic:
  • Cutaneous Papilloma
  • Keratoacanthoma
  • Squamous Cell Carcinoma Of Skin
• Hepatic:
  • Increased Gamma-Glutamyl Transferase
• Neuromuscular & Skeletal:
  • Arthralgia
  • Myalgia
  • Limb Pain
  • Back Pain
  • Musculoskeletal Pain
  • Weakness
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Cough
• Miscellaneous:
  • Fibrosis (Dupuytren Contracture)
  • Fever

Less Common Side Effects of Vemurafenib Include:

• Cardiovascular:
  • Atrial Fibrillation
  • Hypotension
  • Retinal Vein Occlusion
  • Vasculitis
• Central Nervous System:
  • Cranial Nerve Palsy (Facial)
  • Dizziness
  • Peripheral Neuropathy
• Dermatologic:
  • Erythema Nodosum
  • Folliculitis
  • Stevens-Johnson Syndrome
  • Toxic Epidermal Necrolysis
• Endocrine & Metabolic:
  • Weight Loss
• Hematologic & Oncologic:
  • Basal Cell Carcinoma
  • Malignant Melanoma (New Primary)
  • Squamous Cell Carcinoma (Oropharyngeal)
• Hepatic:
  • Increased Serum ALT
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Bilirubin
• Hypersensitivity:
  • Anaphylaxis
  • Hypersensitivity Reaction
• Neuromuscular & Skeletal:
  • Arthritis
  • Panniculitis
• Ophthalmic:
  • Blurred Vision
  • Iritis
  • Photophobia
  • Uveitis

Frequency not defined:

• Hematologic & oncologic:
  • Secondary acute myelocytic leukemia

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Contraindication to Vemurafenib (Zelboraf) Include:

In the United States, the manufacturer's labeling does not list any contraindications for vemurafenib. However, it's important to note that the information provided may vary based on the region and specific labeling guidelines.

In Canada, according to the Canadian labeling, vemurafenib is contraindicated in individuals who have a known hypersensitivity (allergic reaction) to vemurafenib or any component of the formulation. If you have a history of hypersensitivity to vemurafenib or any of its ingredients, it is not recommended to use this medication.

Warnings and precautions

Dermatologic toxicities:

• Dermatologic toxicity is a potential side effect of vemurafenib, and various skin reactions have been reported, including rare cases of severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
• If you experience severe dermatologic toxicity while taking vemurafenib, it is necessary to discontinue the medication permanently.
• This is done to ensure your safety and prevent further harm from the skin reactions.
• It is important for patients to notice any significant skin changes or adverse reactions while using vemurafenib.

Fibroproliferative Disease:

• Fibroproliferative diseases, specifically Dupuytren contracture and plantar fascial fibromatosis, have been reported in some individuals using vemurafenib.
• Studies conducted by Chan in 2015, Perez in 2017, and Vandersleyen in 2016 have documented these cases.
• In June 2017, the manufacturer of vemurafenib issued a letter addressed to healthcare providers, stating that most reported cases were mild to moderate in severity.
• However, some cases of disabling Dupuytren contracture were observed.
• The onset of symptoms typically occurred around 224 days after starting vemurafenib therapy.
• Fortunately, many patients experienced symptom resolution or improvement when vemurafenib treatment was interrupted or discontinued, as noted in the study by Perez.
• According to the manufacturer's recommendations, fibromatoses may require therapy interruption or even discontinuation to manage the condition effectively.

Hepatotoxicity

• Hepatotoxicity, which refers to liver injury, has been reported in individuals using vemurafenib.
• It can lead to functional problems in the liver, such as coagulopathy or other organ dysfunction.
• To monitor for any liver-related issues, it is important to check levels of transaminases, alkaline phosphatase, and bilirubin before starting vemurafenib and monthly during treatment, or as needed based on clinical judgment.
• If liver abnormalities are detected, dosage reduction, temporary interruption of therapy, or discontinuation of vemurafenib may be necessary.
• Regular monitoring can help manage and address any potential hepatotoxicity concerns.

Hypersensitivity

• Hypersensitivity reactions, including anaphylaxis and severe hypersensitivity, can occur during treatment with vemurafenib or when treatment is restarted.
• These reactions can be serious and may involve symptoms such as a widespread rash, redness of the skin, low blood pressure, or a drug rash accompanied by eosinophilia and systemic symptoms (known as DRESS syndrome).
• If a severe hypersensitivity reaction occurs, it is necessary to permanently discontinue the use of vemurafenib.

Malignancies

• Malignancies, such as cutaneous squamous cell carcinomas (cuSCC), keratoacanthomas, and melanoma, have been reported in patients receiving vemurafenib at a higher rate compared to control groups.
• cuSCC typically occurs early in the treatment, with a median onset of 7 to 8 weeks in melanoma patients and approximately 12 weeks in Erdheim Chester disease (ECD) patients.
• These malignancies are managed by surgically removing the affected area while continuing vemurafenib treatment.
• About one-third of melanoma patients may experience more than one occurrence of cuSCC, with a median time between occurrences of 6 weeks.
• Age over 65 years, a history of skin cancer, or chronic sun exposure are potential risk factors for cuSCC.
• It is important to monitor for skin lesions with regular dermatology evaluations at the start of treatment and every 2 months during treatment.
• Consider continued monitoring for 6 months after completing treatment.
• In rare cases, new primary malignant melanomas have been reported in patients receiving vemurafenib for melanoma.
• Noncutaneous squamous cell carcinomas (non-cuSCC) of the head and neck have also been observed, so close monitoring for signs and symptoms is essential.
• Vemurafenib may potentially contribute to the development of other malignancies associated with RAS activation, so it's important to watch for signs and symptoms of other malignancies as well.
• Additionally, myeloid malignancies have been reported in patients with ECD receiving vemurafenib, so monitoring of complete blood counts (CBC) is advised in patients with ECD and concurrent myeloid malignancies.

Nephrotoxicity

• Nephrotoxicity, which refers to kidney damage, can occur with the use of vemurafenib.
• This can manifest as acute kidney injury, interstitial nephritis, acute tubular necrosis, or elevated levels of serum creatinine (graded from 1 to 4).
• It is important to monitor the levels of serum creatinine, a marker of kidney function, during treatment with vemurafenib.
• Regular monitoring allows for early detection of any kidney-related abnormalities or changes, which can help in managing and addressing them promptly.

Ocular toxicities:

• Ocular toxicity is a potential side effect of vemurafenib.
• It may include uveitis (including iritis), blurred vision, and sensitivity to light (photophobia).
• It is important to monitor for any signs and symptoms of ocular toxicity during treatment.
• If uveitis occurs, it can be managed with the use of corticosteroid and mydriatic eye drops.
• It is crucial to promptly report any ocular-related symptoms to your healthcare provider for appropriate evaluation and management.
• Additionally, retinal vein occlusion has been reported in clinical trials, indicating the need for monitoring and awareness of this potential complication.
• Regular ophthalmic examinations and close communication can help patients to identify and address ocular toxicity associated with vemurafenib.

Pancreatitis

• Pancreatitis, although rare, has been reported in some cases with the use of vemurafenib.
• It typically occurs within 2 weeks after starting treatment, and there have been instances where the condition worsened when vemurafenib was reintroduced at a lower dose.
• If you experience unexplained abdominal pain, it is advisable to consider evaluating for pancreatitis.
• This may involve tests such as measuring serum lipase and amylase levels and performing an abdominal CT scan, as determined by your healthcare provider based on clinical indications.

Photosensitivity

• Photosensitivity reactions, ranging from mild to severe, have been reported in individuals using vemurafenib.
• To minimize the risk of photosensitivity, it is important to advise patients to avoid direct sun exposure and take precautions when outdoors.
• This includes wearing protective clothing (such as hats and long sleeves) and using effective sunscreen that protects against UVA and UVB rays.
• The sunscreen should have a sun protection factor (SPF) of at least 30.
• If photosensitivity reactions become intolerable, with erythema (redness) affecting 10% to 30% of the body surface area, dosage modifications may be necessary.
• It is crucial to follow these recommendations and take appropriate measures to protect your skin from the harmful effects of sunlight while using vemurafenib.

Extension of QT

• Vemurafenib has the potential to cause QT prolongation, a condition where the electrical activity of the heart is disrupted, leading to an increased risk of ventricular arrhythmia, including a specific type called torsade de pointes.
• To monitor and manage this risk, it is important to assess the levels of electrolytes (calcium, magnesium, and potassium) before starting treatment and during dosage adjustments.
• Electrocardiogram (ECG) readings should be obtained at the beginning of treatment, 15 days after initiation, and then monthly for the first three months.
• Subsequently, ECGs should be performed every three months unless there is a need for more frequent monitoring based on the individual's clinical condition.
• If the baseline QT interval (QTc) is greater than 500 milliseconds, treatment with vemurafenib should not be initiated.
• During treatment, if the QTc exceeds 500 milliseconds, treatment should be temporarily interrupted while correcting electrolyte imbalances and addressing other factors that can contribute to QT prolongation.
• Once the QTc falls below 500 milliseconds, treatment can be reinitiated with a reduced dose.
• However, if the corrected QTc continues to increase above 500 milliseconds despite risk factor correction, or if there is an increase of more than 60 milliseconds from baseline, vemurafenib should be permanently discontinued.
• Patients with uncorrectable electrolyte abnormalities, long QT syndrome, or those taking medications known to prolong the QT interval should not initiate treatment with vemurafenib.
• These precautions and monitoring measures are important to minimize the risk of serious heart rhythm abnormalities associated with QT prolongation.

Radiation sensitization/recall

• In some cases, patients treated with radiation therapy prior to, during, or after vemurafenib treatment have experienced radiation sensitization and recall.
• This phenomenon can lead to severe reactions affecting the skin and internal organs.
• There have been reports of fatal cases where vital organs were involved.
• Therefore, it is crucial to closely monitor patients who are receiving radiation therapy in conjunction with vemurafenib or sequentially.
• Monitoring helps to detect any potential complications or adverse reactions that may arise from the combined treatment.

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Vemurafenib: Drug Interaction

Risk Factor C (Monitor therapy)
Aminolevulinic Acid (Topical)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
ARIPiprazole	CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Brentuximab Vedotin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Celiprolol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	CYP1A2 Inhibitors (Moderate) may increase the serum concentration of CloZAPine.
CloZAPine	CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine.
CYP1A2 Substrates (High risk with Inhibitors)	CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Everolimus	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Haloperidol	QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Larotrectinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.
Naldemedine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Naloxegol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
NiMODipine	CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine.
Ondansetron	May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Pentamidine (Systemic)	May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Perhexiline	CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Substrates:	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide.
Porfimer	Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.
Prucalopride	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
QT-prolonging Antidepressants (Moderate Risk)	May enhance the QTc-prolonging effect of QTprolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
QT-prolonging Antipsychotics (Moderate Risk)	May enhance the QTc-prolonging effect of QTprolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide.
QT-prolonging Class IC Antiarrhythmics (Moderate Risk)	May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
QT-prolonging Kinase Inhibitors (Moderate Risk)	May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
QT-prolonging Miscellaneous Agents (Moderate Risk)	QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Domperidone.
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk)	May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk).
QT-prolonging Quinolone Antibiotics (Moderate Risk)	May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Ranolazine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
RifAXIMin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Silodosin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Talazoparib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs.
Tegaserod	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Verteporfin	Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.
Warfarin	Vemurafenib may increase the serum concentration of Warfarin.
Risk Factor D (Consider therapy modification)
Afatinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
Betrixaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor.
Bilastine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors.
Colchicine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
CYP1A2 Substrates (High risk with Inhibitors)	Vemurafenib may increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Exceptions: CloZAPine; OLANZapine.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. Consider use of an alternative that is not a strong inhibitor of CYP3A4 as clinically appropriate. Exceptions are discussed in separate monographs. Exceptions: Clarithromycin; Saquinavir; Voriconazole.
Dabigatran Etexilate	P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Digoxin	Vemurafenib may increase the serum concentration of Digoxin. Management: Avoid coadministration of vemurafenib and digoxin when possible. If concomitant use cannot be avoided, consider digoxin dose reduction.
Domperidone	QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk.
DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Edoxaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation.
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
Ipilimumab	May enhance the hepatotoxic effect of Vemurafenib. Management: Consider alternatives to this combination when possible. Use of this combination should only be undertaken with extra close monitoring of liver function (hepatic transaminases and bilirubin) and signs/symptoms of hepatotoxicity.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Pirfenidone	CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug).
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
QT-prolonging Agents (Highest Risk)	May enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities.
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk)	Vemurafenib may enhance the QTcprolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP.
Rasagiline	CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking moderate CYP1A2 inhibitors.
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
TiZANidine	CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions.
Venetoclax	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors.
Risk Factor X (Avoid combination)
Alosetron	CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Alosetron.
Aminolevulinic Acid (Systemic)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
PAZOPanib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
Pimozide	May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk).
Topotecan	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
VinCRIStine (Liposomal)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).

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Monitor:

Confirm BRAF V600 Mutation Status:

• Essential for patients with melanoma to ensure targeted treatment effectiveness.

Liver Function Tests:

• Measure liver transaminases, alkaline phosphatase, and bilirubin levels at baseline and monthly during treatment or as clinically appropriate.

Kidney Function:

• Monitor serum creatinine levels at baseline and periodically during treatment to assess kidney function.

Electrolyte Levels:

• Evaluate calcium, magnesium, and potassium levels at baseline and after any dosage modifications to maintain proper electrolyte balance.

Electrocardiogram (ECG):

• Perform baseline ECG, followed by another ECG 15 days after starting treatment, then monthly for the first 3 months.
• Conduct subsequent ECGs every 3 months unless a more frequent evaluation is clinically necessary.
• ECGs should also be done when adjusting the dosage.

Dermatology Evaluation:

• Conduct a dermatology evaluation at the beginning of treatment and every 2 months to check for new skin lesions.
• Consider continued monitoring for 6 months after completing treatment.

Signs and Symptoms to Monitor:

• Stay vigilant for signs and symptoms of hypersensitivity reactions, uveitis (eye inflammation), and malignancies (including new skin lesions).
• Monitor for signs of radiation sensitization and recall if the patient receives radiation therapy alongside vemurafenib.

Adherence Monitoring:

• Ensure patients are adhering to the prescribed treatment regimen.

Regular monitoring and prompt reporting of any concerning symptoms or abnormalities are essential for the effective and safe management of patients receiving vemurafenib treatment. These monitoring recommendations can help patient's to detect any potential adverse effects, and make necessary adjustments to ensure the best possible outcomes.

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How to administer Vemurafenib (Zelboraf)?

Timing and Frequency:

• Take doses orally in the morning and evening, approximately 12 hours apart.
• It can be taken with or without a meal.

Vomiting After Dose:

• If vomiting occurs after taking a dose, do not take an additional dose.
• Continue with the next scheduled dose.

Swallowing Instructions:

• Take the tablets whole with a glass of water.
• Do not crush or chew the tablets.

Important Note on Crushing Tablets:

• Although there have been case reports of vemurafenib administration after crushing, it's important to note that vemurafenib is nearly insoluble in water.
• Vemurafenib is manufactured as a microprecipitated bulk powder core within a film-coated tablet to enhance solubility and bioavailability.
• The pharmacokinetics (how the drug is absorbed, distributed, metabolized, and excreted) and efficacy of crushed or altered administration methods have not been determined.

It is crucial to follow the prescribed administration instructions for vemurafenib to ensure optimal absorption and effectiveness of the medication. Swallowing the tablets whole with water, as instructed, is the recommended method of administration. Crushing or altering the tablets may affect the drug's solubility and bioavailability, potentially impacting its effectiveness.

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Mechanism of action of Vemurafenib (Zelboraf):

• Vemurafenib is an oral medication that belongs to the class of drugs called BRAF kinase inhibitors.
• It is specifically designed to inhibit the activity of mutated forms of the BRAF protein, such as the BRAF V600E mutation, which is commonly found in about 50% of melanoma cases.
• By blocking the kinase activity of mutated BRAF, vemurafenib helps to slow down the growth of melanoma tumors by preventing the proliferation of melanoma cells carrying the mutation.
• It is important to note that vemurafenib is not effective against melanoma cells that have the normal, or wild-type, form of the BRAF protein.
• The BRAF V600E mutation involves a specific change in the genetic code, substituting valine with glutamic acid at position 600 of the BRAF protein.

Distribution:

• Volume of distribution (V): Approximately 106 liters.

Protein Binding:

• Vemurafenib is highly bound to proteins in the blood, with over 99% binding to albumin and α -acid glycoprotein.

Elimination Half-life:

• The elimination half-life of vemurafenib is around 57 hours, but it can vary between 30 to 120 hours in different individuals.
• This means that it takes approximately 57 hours for half of the drug to be eliminated from the body.

Time to Peak:

• Vemurafenib reaches its peak concentration in the blood approximately 3 hours after administration.

Excretion:

• The majority of vemurafenib is eliminated through the feces, accounting for approximately 94% of the drug.
• Only a small amount, around 1%, is excreted in the urine.

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International Brands of Vemurafenib:

• Zelboraf

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Vemurafenib (Zelboraf) is not Available in Pakistan.

No Brands Available in Pakistan.