Overview:
Certain kinds of melanoma involve a specific type of skin cancer with an aberrant "BRAF" (B-Raf proto-oncogene) gene that has migrated to other areas of the body, or that cannot be removed surgically; Vemurafenib is a prescription drug. Melanoma with a healthy BRAF gene does not respond to Vemurafenib therapy. Additionally, one specific form of Erdheim-Chester sickness, a disorder in which overproduction of a type of white blood cells occurs, can be treated with it. Vemurafenib belongs to the group of drugs known as kinase inhibitors. It functions by preventing the action of a complex protein that instructs cancer cells to proliferate. This aids in containing or halting the spread of cancer cells. Vemurafenib's safety and effectiveness in children under 18 are unknown.
Indications for Vemurafenib:
Metastatic or unresectable melanoma - Vermurafenib is recommended for treating individuals with metastatic or incurable melanoma identified as having the BRAF V600E mutation food and drug administration, United States (FDA) approved test. The limitation of Vemurafenib is that it is not recommended for treating patients with wild-type BRAF melanoma.
The Erdheim-Chester Condition- The use of Vemurafenib is recommended for the treatment of Erdheim-Chester Disease (ECD) patients who have the BRAF V600 mutation.
How Does Vemurafenib Work?
The BRAF gene is altered in about 50 percent of all melanomas, causing the cells to overproduce BRAF protein. This protein promotes the growth and division of cancer cells. By concentrating on this protein, Vemurafenib slows or halts the growth of cancer cells. The oral medication vemurafenib inhibits mutant BRAF-serine-threonine kinase. Vemurafenib interacts with the mutant species of BRAF as a competitive inhibitor, particularly effective against the BRAF V600E mutation. Vemurafenib inhibits the growth of tumors by blocking downstream pathways, which eventually results in apoptosis. When used against melanoma cell lines that carry the wild-type BRAF mutation, Vemurafenib has no anti-tumor effects.
Warnings and Precautions:
Skin Malignancies:
Patients who took Vemurafenib in Trial 1 had a greater incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma than those in the control group. In the Vemurafenib arm, there were 24 % more cases of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas than in the dacarbazine arm. Age (65 years and above), past skin cancer, and prolonged sun exposure were all possible risk factors for cutaneous squamous cell carcinoma seen in clinical studies utilizing Vemurafenib.
It is advised to utilize dermatopathology analysis and excision to manage problematic skin lesions. Following the cessation of Vemurafenib, patients should consider undergoing dermatologic monitoring for six months. Patients using Vemurafenib may develop non-cutaneous squamous cell carcinomas of the head and neck. Patients on Vemurafenib should be cautiously watched for any new non-cutaneous squamous cell carcinoma.
Tumor Promotion in Melanoma of the BRAF Wild-Type:
In vitro tests have shown that BRAF wild-type cells treated with BRAF inhibitors paradoxically activate MAP (mitogen-activated protein)-kinase signaling and promote cell proliferation. Before beginning treatment with Vemurafenib, confirming the presence of the BRAF V600E mutation in tumor samples is essential.
Reactions from Hypersensitivity:
Vemurafenib can cause anaphylaxis and other severe hypersensitivity reactions both during therapy and after resuming it. Hypotension, medication reaction with eosinophilia and systemic symptoms, broad rash, erythema, and severe hypersensitivity reactions were also reported (DRESS syndrome). Patients who have a severe hypersensitivity reaction should permanently stop taking Vemurafenib.
Dermatologic Reactions:
Patients on Vemurafenib may experience severe dermatologic reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients who have a severe dermatologic reaction should permanently stop taking Vemurafenib.
QT Prolongation:
In a previously treated patient with metastatic melanoma who also had the BRAF V600E mutation, concentration-dependent QT prolongation was seen. The likelihood of ventricular arrhythmias, such as Torsade de Pointes, may increase as QT prolongation occurs. Patients with irreversible electrolyte imbalances, QTc values more than 500 ms, long QT syndrome, or on medications known to prolong the QT interval should not begin treatment. Evaluate ECG (electrocardiogram) and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly for the first three months of the treatment, then every three months after that, or more frequently as clinically necessary, before and after treatment commencement or after dose change of Vemurafenib for QTc prolongation.
Patients who experience a QTc > 500 ms should stop using Vemurafenib. Upon return to QTc, 500 milliseconds which is Grade 2, recommence at a lower dose. Immediately stop taking Vemurafenib if the QTc interval appears and remains more significant than 500 milliseconds and has grown by more than 60 milliseconds compared to pretreatment readings. QT prolongation can induce cardiac problems such as bradyarrhythmia, congestive cardiac failure, and abnormal electrolytes.
Hepatotoxicity:
Injuries to the liver that result in functional hepatic impairment, such as coagulopathy or other organ failures, can occur when using Vemurafenib. Alkaline phosphatase, transaminases, and bilirubin should be given before starting treatment, monthly while receiving treatment, or as clinically necessary. Manage inconsistency in the laboratory with dosage reduction, treatment stoppage, or treatment cessation. Ipilimumab and Vemurafenib together have not been proven to be safe and effective. In a dose-finding trial, most patients who received concurrent Ipilimumab and Vemurafenib experienced Grade 3 elevations in transaminases and bilirubin.
Photosensitivity:
Patients on Vemurafenib may experience mild to severe photosensitivity. Encourage patients to use lip balm with an SPF of at least 30 and a broad-spectrum UVA and UVB sunscreen whenever they are outside.
Ophthalmologic Reactions:
In patients receiving Vemurafenib, uveitis, blurred vision, and photophobia have all been reported. In a clinical trial of the patients receiving Vemurafenib, they reported experiencing uveitis, including iritis, as opposed to individuals in the Dacarbazine group. To treat uveitis, steroid and mydriatic ophthalmic drops may be necessary. Keep an eye out for uveitis symptoms in the patients.
Toxicity to the Fetus:
When given to a pregnant woman, Vemurafenib has the potential to harm the fetus due to its mode of action. Information should be given to the expectant mothers about the potential fetal risk. Females with the ability to procreate should be advised to use effective contraception while receiving Vemurafenib medication and for two weeks following the last dosage.
Radiation Recall and Radiation Sensitization:
Patients who had radiation before, during, or after receiving Vemurafenib treatment have reported radiation sensitivity and recall. In some cases, there was severe involvement of cutaneous and visceral organs. Patients with visceral organ involvement have experienced fatal situations, according to reports. When Vemurafenib is given concurrently or after radiation therapy, patients should be watched closely.
Renal Failure:
Vemurafenib can cause renal failure, including acute interstitial nephritis and acute tubular necrosis. Patients in a clinical trial with metastatic melanoma experienced Grade 1 to 2 creatinine in 26 % of Vemurafenib-treated patients and 5 % of Dacarbazine-treated patients; Grade 3 to 4 creatinine elevations occurred in 1.2 % of Vemurafenib-treated patients and 1.1 % of Dacarbazine-treated patients. Before beginning Vemurafenib medication and at regular intervals afterward, check serum creatinine levels.
Plantar Fasciitis Fibromatosis and Dupuytren's Contracture:
With Vemurafenib, reports of Dupuytren's contracture and plantar fascial fibromatosis have been made. Most cases of Dupuytren's contracture were mild to moderate, but there have also been reports of severe, incapacitating cases.
For Patients:
What Is Melanoma?
The melanocytes, which make melanin, the pigment responsible for our skin's color, grow into melanoma, the most dangerous type of skin cancer. Additionally, melanoma can develop in our eyes and, very rarely, inside our body, like in the throat or nose.
What Causes Melanoma?
Most medical professionals concur that excessive sun exposure, especially sunburns, is a significant risk factor for melanoma. UV (ultraviolet) exposure can alter specific genes that control how cells grow and divide by damaging a cell's DNA. When the skin's DNA is harmed, and those cells begin to divide, issues could arise.
Although anyone can get melanoma, those who have the following risk factors are more likely to do so:
-
A personal history of having melanoma.
-
A melanoma family history.
-
Blue eyes, blond or red hair, and fair skin with freckles.
-
Excessive sun exposure can result in painful sunburns.
-
A residence near the equator or at a high elevation may expose you to more UV or ultraviolet radiation.
-
A background in using tanning beds.
-
A lot of moles, particularly unusual moles.
-
A compromised immune system.
Melanoma can affect anyone; however, it is more prevalent in white people. Melanoma most frequently develops on the palms, soles, and nails of those with darker skin.
What Are the Symptoms and Signs of Melanoma?
Because early melanomas can often be successfully treated, it is crucial to recognize them. Moles, open sores, scaly patches, and elevated bumps can all be symptoms of melanoma.
The "ABCDE" memory aid from the American academy of dermatology will help one remember the indicators that a lesion on their skin can be melanoma:
Asymmetry: One half is different from the other.
Border: The borders are not straight.
Color: There are varying hues of brown, black, gray, red, and white that are speckled and irregular.
Diameter: The spot's diameter is larger than the diameter of a pencil eraser.
Evolving: The spot changes in size, shape, or color or is new.
Tell the doctor if you see any sores that would not heal, odd bumps or rashes, skin changes, or moles you already have because not all melanomas follow the ABCDE rule. The ugly duckling sign is another method for detecting melanoma. The ugly duckling mole stands out from the rest and needs to be examined by a dermatologist.
How to Diagnose Melanoma?
The following tests and techniques are used to identify melanoma:
Examination of the Body- Your doctor will inquire about your medical history and look for potential melanoma warning signals on your skin.
Removing a Tissue Sample for Analysis or Biopsy- Your doctor could advise taking a sample of skin for testing to identify whether a suspicious skin lesion is a melanoma. The sample is delivered to a lab for analysis.
Their doctor may propose a particular biopsy operation depending on a patient's unique circumstances. When it is feasible, doctors almost always advise removing the entire tumor. A punch biopsy typically involves pressing a circular blade into the skin near the suspicious mole. Another method, an excisional biopsy, involves using a knife to remove the whole mole and a small margin of the surrounding healthy tissue.
The next step is to establish if the melanoma has spread when the doctor receives the skin biopsy findings indicating evidence of melanoma cells. Staging describes this. Once identified, melanoma will be classified according to several criteria, including the extent of its spread and how it appears under a microscope. The most crucial factor in outcome prediction is tumor thickness.
The following phases are used to categorize melanomas:
Stage 0 (Melanoma in Situ): Only the top layer of skin is affected by melanoma, which is the epidermis.
Stage I: Primary melanoma that is low-risk and has not spread. Surgery can typically cure this stage.
Stage II: Some characteristics point to a higher likelihood of recurrence, but there is no proof that it has spread.
Stage III: The melanoma has affected local lymph nodes or surrounding skin.
Stage IV: The melanoma has migrated to internal organs, distant lymph nodes, or skin.
How to Treat Melanoma?
The stage of melanoma and overall general health will determine how the patient will be treated. The main form of treatment for melanoma is typically surgery. The technique entails removing the malignancy and some of the surrounding healthy skin. The location and size of the skin cancer will determine how much healthy skin needs to be removed. Melanomas can typically be surgically removed under local anesthetic in a dermatologist's clinic. Advanced conditions could call for alternative forms of care in addition to or instead of surgery.
Melanoma Treatments:
Melanoma Surgery: If performed in the early stages, surgery has a good chance of curing melanoma. A dermatologist usually performs this procedure in their clinic, using a local anesthetic to numb the skin before removing the melanoma and its borders which are the healthy surrounding skin.
Lymphadenectomy: When melanoma has spread, it may be necessary to remove the lymph nodes close to the location of the initial diagnosis. This may stop the disease from spreading to other parts of your body.
Metastasectomy: This procedure removes little pieces of melanoma from organs.
Targeted Cancer Therapy: Cancer therapy that targets particular cancer cells employs medications to kill those cells. This "targeted" strategy only affects cancer cells while sparing healthy cells.
Radiation Therapy: Radiation therapy uses high-energy radiation to treat tumors and kill cancer cells.
Immunotherapy: To combat cancer, immunotherapy activates your body's own immune system.
What Specific Safety Measures Should a Patient Take?
-
If a patient has an allergy to Vemurafenib, any other medications, or any of the ingredients in Vemurafenib tablets, they should tell their doctor and pharmacist before using Vemurafenib.
-
Patients should inform their doctor and pharmacist about any additional prescription and over-the-counter drugs, vitamins, dietary supplements, and herbal products they are now taking or intend to use. Incorporate any of the following: antifungal drugs, HIV (human immunodeficiency virus) or AIDS (acquired immunodeficiency syndrome) drugs, a number of seizure drugs, Tizanidine, and Warfarin. The physician might need to adjust the dosage of the drugs or keep a close eye on the patients for side effects. Patients should inform their doctor about all the drugs they are taking, even any not on this list, as many other drugs may also interact with Vemurafenib.
-
A prolonged QT interval (a rare heart condition that can result in an erratic heartbeat, fainting, or sudden death); heart failure; a low level of calcium, magnesium, or potassium in your blood; or heart, kidney, or liver problems should all be disclosed to your doctor.
-
Tell your doctor whether you have ever received radiation therapy or if you have any plans to do so.
-
If one is pregnant or plans to become pregnant, they should inform their doctor. Pregnancy should be avoided while taking Vemurafenib. Throughout Vemurafenib treatment and two weeks following your last dose, you should take birth control to prevent getting pregnant. Discuss effective birth control options with your doctor. If a patient is pregnant, they should discuss it with their doctor, as the drug can adversely affect the fetus.
-
Let the doctor know if you are nursing a baby. While using Vemurafenib and for two weeks following your last dosage, one should not breastfeed.
-
Do not undergo surgery, including oral surgery, if you take Vemurafenib unless your physician or dentist directs otherwise.
-
Make a plan to limit your time in the sun, and wear sunscreen, protective clothing, sunglasses, and lip balm (SPF 30 or higher). Your skin could become sun-sensitive if you take Vemurafenib.
For Doctors:
Administration and Dosage:
Melanoma Patient Selection for Treatment- Before beginning Vemurafenib therapy, confirm the existence of the BRAF V600E mutation in melanoma tumor samples.
Vemurafenib should be taken orally, with or without food, at doses of 960 milligrams every 12 hours. One can take a missed dose up to 4 hours before the next dose. Vemurafenib should be given to patients until the onset of unacceptable side effects or disease progression. If vomiting happens after taking Vemurafenib, patients should not take a second dose; instead, they should take the next dose as scheduled. It should not be chewed or crushed.
Modifications to the Dose for Fresh Primary Cutaneous Malignancies: No dosage adjustments are advised in such cases.
Vemurafenib Should No Longer Be Used for Any of the Following Reasons:
Grade 4 adverse response, first or second manifestation (if clinically indicated).
A QTc prolongation of more than 500 ms and a rise of more than 60 ms from baseline. Withhold Vemurafenib for severe grade 2 or higher adverse reactions.
After reaching Grade 0-1, reintroduce Vemurafenib at a lower dosage as follows:
For the initial occurrence of unacceptable Grade 2 or Grade 3 adverse effects, 720 milligrams twice daily. 480 milligrams twice daily for the recurrence of adverse reactions of Grade 2 (if unbearable), Grade 3, or Grade 4, or the onset of Grade 4 adverse reactions if clinically appropriate. Never lower the dose to less than 480 mg twice daily.
Modifying Doses for Potent CYP3A4 Inducers - Avoid concurrent use of potent CYP3A4 inducers when taking Vemurafenib. If a potent CYP3A4 inducer is used simultaneously, 240 mg or one more tablet of Vemurafenib should be administered if it is unavoidable. After ceasing use, restart the Vemurafenib dose taken before beginning the potent CYP3A4 inducer for two weeks.
Pharmacodynamics:
Patients who received vemurafenib 960 mg orally twice daily did not suffer significant changes in mean QTc interval, which is more than 20 ms from baseline, in a multi-center, open-label, single-arm study in 132 patients with metastatic melanoma harboring the BRAF V600E mutant. Vemurafenib is linked to a concentration-dependent lengthening of the QTc interval. At 2 hours post-dose on day 15, an increase of 12.8 ms (within the upper border of the two-sided 90 percent confidence interval of 14.9 milliseconds) represented the most significant mean change from baseline throughout the first month of treatment. Pre-dose time points showed the greatest observed mean change from baseline over the first six months of treatment, increasing by 15.1 ms (upper bound of the two-sided 90 % confidence range of 17.7 ms).
Pharmacokinetics:
Patients with metastatic BRAF mutation-positive cancer were studied to establish the pharmacokinetics of Vemurafenib. After 15 days of taking 960 mg twice daily, melanoma is spaced around 12 hours apart. The 458 patients' data were combined for the population pharmacokinetic analysis. Vemurafenib demonstrates steady-state within the dose range of 240 mg to 960 mg, linear pharmacokinetics.
Mechanism of Action:
Vemurafenib is a low molecular weight, an orally absorbable inhibitor of some mutant BRAF serine-threonine kinases, such as BRAF V600E. In vitro, Vemurafenib inhibits CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at comparable doses. BRAF proteins that are constitutively activated due to mutations in the BRAF gene, such as V600E, can cause cell proliferation without growth factors, which are typically necessary for expansion. In animal models and cellular models of melanomas with mutant BRAF V600E, Vemurafenib shows anti-tumor effects.
Absorption:
Vemurafenib's bioavailability has not been established. After multiple doses, the median Tmax (time to peak drug concentration) was almost three hours. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice-daily regimen is 7.4, and steady-state is reached between 15 and 22 days. Vemurafenib was given without attention to diet during clinical trials. A single dosage of Vemurafenib with a high-fat meal increased AUC by about 5-fold, Cmax (maximum concentration) by approximately 2.5-fold, and Tmax by about 4 hours compared to the fasting state, according to a food effect study. Increased exposures could prolong QTc since vemurafenib is linked to concentration-dependent QTc interval lengthening.
Distribution:
Human albumin and plasma alpha-1 acid glycoprotein proteins are substantially bound (> 99 %) to Vemurafenib. With a 66 % inter-patient variability, the population's apparent volume of distribution is calculated to be 106 L.
Metabolism:
The mean data showed that Vemurafenib and its metabolites made up 95 % and 5 % of the components in plasma over 48 hours following oral administration of 960 mg of 14C-Vemurafenib, respectively.
Elimination:
Approximately 94 percent of the radioactive dose of 960 mg of 14C-Vemurafenib taken orally was retrieved in the feces, and just 1 % was recovered in the urine. With a 32 % inter-patient variability, the estimated apparent population clearance is 31 L/day. Vemurafenib's estimated median elimination half-life is 57 hours (the 5th and 95th percentile range are 30 to 120 hours).
Non-clinical Toxicology:Mutagenesis, Carcinogenesis, and Fertility Impairment:
Vemurafenib's potential to cause cancer has not been officially investigated. In clinical trials, Vemurafenib caused more patients to develop cutaneous squamous cell carcinomas. In vitro experiments and the in vivo rat bone marrow micronucleus test, Vemurafenib did not result in genetic harm when examined. There have not been any specific studies with Vemurafenib in animals to assess the impact on fertility, but repeat-dose toxicology studies in rats at doses up to 450 mg/kg/day (roughly 0.6 and 1.6 times the human exposure and dogs at doses up to 450 mg/kg/day which is about 0.3 times the human therapeutic exposure.
Animal Pharmacology or Toxicology - Vemurafenib treatment in mice implanted with human cutaneous squamous cell carcinoma (cuSCC) cells resulted in a dose-dependent acceleration of the growth of the implanted tumors, which is consistent with the higher frequency of cutaneous squamous cell carcinomas in patients treated with the drug.
Interaction With Other Drugs:
Vemurafenib's Response to Strong CYP3A4 Inhibitors or Inducers:
Since Vemurafenib is a CYP3A4 substrate, Vemurafenib plasma concentrations and toxicity may increase when potent CYP3A4 inhibitors are also used. Avoid taking Vemurafenib simultaneously as potent CYP3A4 inhibitors, such as Voriconazole, Ketoconazole, Itraconazole, Clarithromycin, Saquinavir, Ritonavir, Indinavir, or Nelfinavir, and wherever possible, switch to an alternative medication.
Vemurafenib plasma concentrations were lowered when Vemurafenib was administered along with Rifampin, a potent CYP3A4 inducer, which may have impacted efficacy. Strong CYP3A4 inducers, such as Phenytoin, Carbamazepine, and Rifampin, should not be administered with Vemurafenib; instead, substitute an alternative medication wherever practical. Increase the dose of Vemurafenib by 240 mg (one tablet) as tolerated if coadministration of a potent CYP3A4 inducer is necessary.
Vemurafenib's Impact on CYP1A2 Substrates- Tizanidine's systemic exposure was enhanced by 4.7 times when Vemurafenib and Tizanidine, a sensitive CYP1A2 substrate, were administered together. Avoid using Vemurafenib concurrently with medications with a limited therapeutic window and metabolized mainly by CYP1A2. If coadministration cannot be prevented, watch out for toxicities and consider lowering the dose of any concurrent CYP1A2 substrates.
Ipilimumab Concurrent:
Most patients who got Ipilimumab and Vemurafenib simultaneously saw an increase in transaminases and bilirubin.
Vemurafenib's Impact on P-gp Substrates- Digoxin is a sensitive P-glycoprotein (P-gp) substrate, and coadministration of Vemurafenib enhanced Digoxin systemic exposure by 1.8 times. Avoid using P-gp substrates simultaneously; those are known to have limited therapeutic indices. If you must take these medications, consider lowering the dose of P-gp substrates.
Usage of Vemurafenib in a Specific Population:
Use in Patients With Hepatic Impairment:
The pharmacokinetics of vemurafenib are affected by hepatic impairment, but this has not been examined in formal clinical research. Based on a population pharmacokinetic analysis, no dosage change is advised for patients with mild and moderate hepatic impairment. The right dose of Vemurafenib has not yet been determined in individuals with severe hepatic impairment.
Usage in Patients With Renal Impairment:
Evaluation of the impact of renal impairment on the pharmacokinetics of vemurafenib has not been done in formal clinical research. Based on a population pharmacokinetic analysis, no dosage change is advised for patients with mild and moderate renal impairment. There is no defined Vemurafenib dosage for patients with severe renal impairment.
Usage in Pregnant Patients:
When given to a pregnant woman, Vemurafenib has the potential to harm the fetus due to its mode of action. Vemurafenib has been reported to pass through the placenta to a fetus, but there is no data on the usage of Vemurafenib in pregnant women to assess the drug's risk. Vemurafenib exposure at levels high enough to completely address its potential toxicity in pregnant women could not be accomplished in animals. Inform expectant mothers of the possibility of fetal damage.
For the indicated population(s), it is unknown what the baseline risks are for severe birth abnormalities and miscarriage. In rat fetuses at a dosage up to 250 mg/kg/day (roughly 1.3 times the clinical exposure at 960 milligrams twice daily based on AUC) and rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the clinical exposure at 960 mg twice daily found on AUC), Vemurafenib showed no evidence of developmental toxicity. Vemurafenib has the potential to be passed from the mother to the developing baby because fetal drug levels were 3 to 5 % of maternal levels.
Usage in Children:
Vemurafenib has not been proven to be safe or effective in pediatric patients. Six adolescents (15–17 years old) with metastatic or incurable melanoma and the BRAF V600 mutation were investigated with Vemurafenib. Vemurafenib dosages up to 960 mg twice daily were not enough to attain the maximum tolerable dose. There were no new warning signs of safety. These six teenage patients had steady-state vemurafenib exposures that were usually comparable to adults.
Usage in Geriatric Patients:
There were insufficient elderly participants in Vemurafenib clinical investigations to ascertain whether their responses differed from those of younger participants.
Usage in Lactating Patients:
There is no information on Vemurafenib's presence in human milk, its effects on nursing infants, or its impact on milk production. Encourage women not to breastfeed during treatment with Vemurafenib and for two weeks following the final dosage due to the risk of serious adverse reactions in a breastfed infant, including severe dermatologic reactions, QT prolongation, malignancy, hepatotoxicity, photosensitivity, and ophthalmologic toxicity.
Usage in Sexually Reproductive Females and Males:
When given to a pregnant woman, Vemurafenib has the potential to harm the fetus due to its mode of action. Encourage women who are sexually active to use reliable contraception while taking Vemurafenib and for two weeks following the final dose.
