Vismodegib: The Shining Hope Against Basal Cell Carcinoma

Overview:

The drug Vismodegib is an oral medication prescribed typically for treating basal cell carcinoma. Basal cell carcinoma is a type of skin cancer that generally begins in the basal cells, the cells responsible for producing new cells when the old ones die. So, Vismodegib is indicated for treating basal cell carcinomas that have metastasized (spread) to adjacent body parts. It is also used for treating basal cell carcinomas that have relapsed following the surgery or those that cannot be treated with radiation therapy or surgery.

The drug Vismodegib was approved by the Food and Drug Administration (FDA) on January 30, 2012, as the first hedgehog signaling pathway targeting agent. This drug is under study and clinical trials for its use and efficacy in metastatic colorectal cancer, advanced stomach cancer, pancreatic cancer, small-cell lung cancer, chondrosarcoma (cancerous condition of bone and soft tissue), and medulloblastoma (a type of primary brain cancer in younger children).

Available Doses and Dosage Forms:

• Vismodegib medication comes in capsule form to be taken orally.

• The strength of each tablet is 150 mg.

• The Vismodegib capsules come in bottles containing about 28 capsules.

For Patients,

What Is Basal Cell Carcinoma?

Basal cell carcinoma is a kind of skin cancer that typically begins in the basal cells. The basal cell is a cell that processes new cells when the old cells are eliminated. This cancer results when certain basal cells of the skin develop a genetic mutation in its Deoxyribonucleic acid (DNA). However, most basal cell carcinomas are known to develop from long-term exposure to ultraviolet rays from the sunlight. Basal cell carcinoma generally manifests as a white waxy lump form or a brown scaly patch on the skin that is exposed to the sun. So, this type of cancer can be significantly seen in the skin covering the face and neck.

How Serious Is Basal Cell Carcinoma?

Basal cell carcinoma is known to be the most frequent form of skin cancer. This is also considered the most common form of all cancerous conditions. Basal cell carcinomas grow at slower rates in most cases. They do not spread through the bloodstream and lymph nodes. So, they are generally not a profound threat, even if they are unrecognized. This cancer usually damages adjacent skin tissues. Basal cell carcinoma and its deterioration can get progressive over time, requiring medical attention. The treatment for basal cell carcinoma includes medicated creams or surgery to eliminate the cancer. Some cases of this skin cancer might require radiation therapy.

How Does Vismodegib Work?

Vismodegib is prescribed for treating a type of skin cancer called basal cell carcinoma, where the cancer has spread to various body parts. This drug is also used for treating basal cell carcinoma that could not be treated with radiation or surgery or cancer that has come back following the surgical treatment. Vismodegib belongs to a group of medicines called the hedgehog pathway inhibitors. So, this functions by adhering to and blocking the action of specific proteins that signal cancerous cells to multiply in the hedgehog signaling pathway. This helps with either slowing down or stopping the progression of cancer cells, shrinking the cancer.

What Is the Dosage of Vismodegib?

• Basal Cell Carcinoma: The dosage of Vismodegib for treating basal cell carcinoma is 150 mg orally once daily in adults. The safety and efficacy of Vismodegib have not been determined in children.

What Are the Things to Inform the Doctor Before Taking the Drug Vismodegib?

• Inform the healthcare provider if one is allergic to Vismodegib or any other ingredients contained in the prescribed medication.

• Inform the doctor if one has an allergy to other medicines in general.

• One must inform the doctor about the prescription and non-prescription medication one takes or has a plan to take. This typically includes pharmaceutical drugs, nutritional supplements, herbal products, and vitamin supplements.

• Be certain to mention any of the drugs, including antibiotics like Clarithromycin, Azithromycin, and Erythromycin. Also, inform if one takes the medication for ulcers, heartburn, or indigestion, such as Ranitidine, Famotidine, and Cimetidine. Inform without fail if one takes proton-pump inhibitor drugs like Lansoprazole, Omeprazole, Dexlansoprazole, Rabeprazole, and Pantoprazole. The doctors might consider changing the dosage of the medication Vismodegib while conscientiously monitoring for the side effects.

• Inform the healthcare provider regarding the medical conditions one has both in the past and present.

• Inform the doctor about the pregnancy status. So, inform if one is pregnant or has a plan to become pregnant. This drug is not usually prescribed for females who are pregnant.

• Inform the doctor if one is breastfeeding. The doctors advise not to breastfeed during the treatment and for about 24 months following the last dose of Vismodegib.

How Is Vismodegib Administered?

The doctors prescribe the dosage and frequency of Vismodegib according to the condition and severity of the condition.

• One should follow the doctor’s prescription and manufacturer’s labeled information for administering Vismodegib.

• One should take the Vismodegib medication exactly as prescribed by the healthcare professional.

• One can take Vismodegib with or without food intake.

• Swallow the Vismodegib capsule as a whole. So, one must neither open nor crush the capsules.

• Take Vismodegib medication one time and the same time every day.

What Are the Side Effects of Vismodegib?

Vismodegib is a safe and effective medicine for the treatment of skin cancer called basal cell carcinoma. However, it can induce adverse or unwanted reactions in several people. So, not every individual experiences the potential side effects of Vismodegib.

The common side effects of the drug Vismodegib include the following:

• Nausea.

• Diarrhea.

• Muscle spasms.

• Hair loss.

• Decreased appetite.

• Weight loss.

• Changes in taste sensation.

• Loss of taste.

• Constipation.

• Tiredness.

• Vomiting.

• Joint and muscle pain.

Serious Side Effects

Vismodegib can induce certain serious side effects. The serious unwanted effects of Vismodegib include the following.

Severe Skin Reactions:

Serious skin reactions have been reported in some people taking Vismodegib. This must be taken into consideration and treated effectively since these severe skin reactions can turn out to be life-threatening or sometimes fatal. So, inform the healthcare professionals straight away if one encounters any of the following signs and symptoms of severe skin reaction. So, the doctors might stop the Vismodegib treatment permanently.

• Blisters and peeling of the skin.

• Fever.

• Flu-related symptoms.

• Blisters around the lips and eyes.

• Enlarged lymph nodes.

• Mouth sores.

• Genital sores.

• Burning sensation.

• Pain.

Muscle Problems:

Muscle problems occur commonly with Vismodegib treatment. But, this can turn out to be serious sometimes. The reports say that Vismodegib could increase one’s risk of muscle pain and spasms. So, one should inform the doctor correctly in case one develops any new severe muscle pain, weakness, or tenderness during or after the Vismodegib treatment. The healthcare providers will perform certain blood tests and kidney function tests before and during the treatment to check for muscle concerns.

Bone Growth Problems:

Bone growth problems have been reported in children exposed to Vismodegib treatment. Such bone growth problems could persist even after the cessation of therapy. So, this drug is not indicated for use in children.

Amenorrhea:

Amenorrhea refers to the absence of menstrual periods. The drug Vismodegib is known to cause amenorrhea in female patients with the ability to become pregnant. However, the severity of the side effects is not fully determined. Discuss with the healthcare provider if one has any concerns about the menstrual cycle.

Dietary Considerations:

One can continue the routine diet unless the healthcare professionals utter any restrictions. But, one should be focused on a well-balanced nutritious diet.

Significant Considerations:

One should not donate blood and blood products during Vismodegib treatment and for about 24 months following the final dosage.

Other Cautions and Considerations:

For Females of Reproductive Ability:

• Discuss with the healthcare providers regarding the potential risk of Vismodegib to the unborn infant.

• The doctor might advise a pregnancy test about seven days before the initiation of Vismodegib therapy.

• The doctors recommend using effective virtual control aids during the Vismodegib treatment and for about 24 months following the final dose. Discuss with the healthcare provider which birth control method to follow.

• Inform the doctor if one has become pregnant or is about to get conceived during the treatment.

• Inform the doctor if one has had unprotected sex or when the birth control method has failed.

For Males:

• Vismodegib is present in semen. So, one should not donate semen during the treatment and for about three months following the final dose of Vismodegib.

• Males should always use effective contraception, even if they have had a vasectomy. So, use them when at sex with female partners during the treatment and for about three months following the last dose. This is to protect the female partner from being exposed to Vismodegib.

• Inform the doctors if one’s partner has become pregnant or is about to become pregnant while one is taking Vismodegib.

Missed Dose:

In case of a missed dosage of Vismodegib, skip the missed one and go for the regular dosing schedule. One must not take a double dose of Vismodegib to make up for the missed one.

Overdose:

Seek emergency medical services in the case of an overdose of Vismodegib. Report to the healthcare services at the earliest because the overdose of Vismodegib can be potentially life-threatening.

Storage:

• Store the Vismodegib medication at a room temperature of 20 to 25 degrees Celsius.

• Keep the bottle firmly closed to protect the unused Vismodegib medication from heat, light, and moisture.

• Any medication should be kept away from the reach of children.

For Doctors,

Clinical Data of Vismodegib:

• Generic Name: Vismodegib.

• Other Names: GDC-0449, RG-3616

• Route of Administration: Oral.

• Drug Class: Hedgehog signaling pathway inhibitors.

• Chemical Formula: C19H14Cl2N2O3S

• Molar Mass: 421.29 g·mol−1

Indication:

Vismodegib is typically indicated for the treatment of adult patients with metastatic basal cell carcinoma or those with a locally advanced form of basal cell carcinoma, which has recurred after surgery. Visomodegib is also indicated for treating locally advanced basal cell carcinoma in adults who are not regarded as a candidate for radiation and surgery.

Associated Conditions:

• Metastatic basal cell carcinoma.

• Locally advanced basal cell carcinoma.

Dosage Modifications:

• Hepatic Impairment: No dosage adjustment is required in hepatic Impairment cases.

• Renal Impairment: No dosage modification is needed in the case of renal impairment.

• Intolerable Adverse Reactions: If intolerable adverse reactions are detected, Consider withholding Vismodegib treatment for about eight weeks until there is an improvement or resolution.

• Musculoskeletal Adverse Reactions: Discontinue the Vismodegib therapy in case of intolerable or severe musculoskeletal adverse reactions. Consider permanent discontinuation of the treatment when there is a recurrence of musculoskeletal reactions.

• Severe Cutaneous Adverse Reactions: Consider permanent discontinuation of Vismodegib treatment in case of severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis (TEN) (a painful and life-threatening skin condition characterized by blisters and peeling), Stevens-Johnson syndrome (SJS) (a rare and serious disorder of the skin and mucous membrane), and drug reaction with eosinophilia and systemic symptoms (DRESS).

What Are the Pharmacological Aspects of Vismodegib?

• Pharmacodynamics: The drug Vismodegib is typically an inhibitor of the hedgehog signaling pathway. So, it selectively binds to and inhibits the transmembrane protein involved in the hedgehog signaling pathway called the smoothened homolog (SMO). Following the use of Vismodegib once-daily dosing of 150 mg for seven days, there were no clinically relevant QT interval prolongation changes. Vismodegib can result in severe birth defects and even embryo-fetal death. It can also induce severe musculoskeletal adverse reactions and intense cutaneous adverse reactions in adult patients. In the pediatric population, clinical reports say that Vismodegib might cause premature fusion of the epiphysis.

• Mechanism of Action: The hedgehog signaling pathway has a pivotal role in cell growth, cell differentiation, apoptosis, and self-renewal during embryogenesis. The hedgehog signaling pathway then remains silent in the cells and tissues following the developmental stage. The hedgehog signaling pathway remains silenced except for skin, hair, and stem cells. Hence, genetic mutation on the elements associated with the hedgehog signaling pathway might lead to uncontrolled basal cell proliferation. Moreover, aberrant or dysregulated hedgehog signaling is attributable to any pathogenesis of basal cell carcinoma. Therefore, Vismodegib treats the condition of basal cell carcinoma by targeting and blocking the hedgehog pathway. Vismodegib binds to the transmembrane protein smoothened homolog (SMO) and inhibits them. This is a protein that induces activation and nuclear translocation of the significant factors contributing to the hedgehog signaling pathway.

Absorption:

• Following daily oral dosing, Vismodegib is known to undergo a nonlinear pharmacokinetic state.

• The steady state of Vismodegib is generally achieved within seven days.

• The dosage increase of 150 mg (milligrams) of Vismodegib to 540 mg does not result in a raised steady-state plasma concentration.

• The once-daily dosage of 150 mg of Vismodegib shows an average plasma concentration at a steady state of about 23 μm (microns).

• The total oral bioavailability of the single dosage of Vismodegib is about 31.8 percent.

• The absorption of Vismodegib is saturable while not affected by blood.

Distribution:

• The range of volume of distribution of the drug Vismodegib is from 16.4 liters to 26.6 liters.

• Vismodegib possesses a significantly high plasma protein binding capacity of about greater than 99 percent.

• Vismodegib binds to the protein plasma albumin as well as alpha-1-acid glycoprotein.

Metabolism:

• Vismodegib is chiefly metabolized by the enzymes CYP3A4 and CYP2C9 in the liver.

• Nevertheless, it has been determined that more than 98 percent of the absolute systemic Vismodegib does not undergo metabolization.

• The potential metabolic pathways of Vismodegib are glucuronidation, oxidation, and pyridine ring cleavage.

• There can be two most abundant oxidative metabolites recovered in the feces. They are generally produced by recombinant enzymes CYP3A4/5 and CYP2C9 in vitro.

Elimination:

• Vismodegib is generally excreted in an unchanged form.

• The primary route of elimination for Vismodegib and its metabolites is through feces.

• The administered dose of Vismodegib is recovered about 82 percent and 4.4 percent in the feces and urine, respectively.

Half-life and Clearance:

• The half-life period of Vismodegib following a single dosage is about 12 days.

• In addition, the half-life following continuous daily dosing is about four days.

Toxicity:

The information on the toxicity of Vismodegib is not available. Nevertheless, people encountering an overdose have an increased risk of serious complications, including severe musculoskeletal adverse effects and severe cutaneous adverse reactions. Vismodegib therapy induces severe birth defects and even embryo-fetal death. So, supportive and preventive measures are recommended in Vismodegib therapy.

Vismodegib is not known to be mutagenic, according to the results conducted in vivo and in vitro. The animal study conducted on rats and mice with Vismodegib administration showed no evidence of carcinogenicity. Fertility studies on male rats with 100 mg/kg/day of Vismodegib showed no effects on fertility and reproductive organs. The same study on female rats determined that Vismodegib administration can be associated with a raised percentage of preimplantation loss, decreased implantations, and reduced viable embryos.

Contraindications:

None.

Adverse Effects:

Vismodegib can induce significant adverse reactions.

• Muscle spasms.

• Dysgeusia (taste disorder).

• Alopecia (a chronic and immune-mediated skin disorder characterized by significant hair loss).

• Fatigue.

• Nausea.

• Vomiting.

• Diarrhea.

• Decreased appetite.

• Weight loss.

• Ageusia (total loss of taste).

• Constipation.

• Arthralgia (joint pain).

• Azotemia (abnormal high nitrogen concentration in the blood).

• Hypokalemia.

• Hyponatremia.

• Amenorrhea (absence of menstruation).

• Increased blood creatinine phosphokinase.

• Premature fusion of epiphyses.

Post-marketing Experience

• Drug-induced liver injury.

• Subcutaneous tissue adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Warnings and Precautions:

• Embryo-fetal Toxicity: Vismodegib can induce severe birth defects and embryo-fetal death when administered to pregnant women. The animal reproduction studies also determine that Vismodegib is fetotoxic, embryotoxic, and teratogenic in case of maternal exposures less than human exposures of the standard dosage of 150 mg once daily.

• Females of Reproductive Potential: The females of reproductive potential should get their organ act status verified within seven days before the initiation of Vismodegib treatment. Advise the pregnant women about the potential risk to the fetus. Inform the females of reproductive potential to follow effective contraception during Vismodegib treatment and about 24 months following the final dose.

• Males of Reproductive Potential: The studies show that Vismodegib can be present in semen. However, it is not determined whether the amount of Vismodegib detected in semen can induce embryo-fetal harm. So, advise males of reproductive potential to follow effective contraception even after a vasectomy to prevent possible Vismodegib exposure in pregnant partners during the therapy and for about three months following the final dosage. Subsequently, advise male patients of reproductive potential to not donate semen during the treatment and for about three months following the final dosage.

• Blood Donation: Advise the individuals treated with Vismodegib not to donate blood and blood products during the therapy and for about 24 months following the last dose.

• Premature Fusion of Epiphyses: Premature fusion of epiphyses turned up with Vismodegib exposure in the pediatric population. The clinical depots also show evidence of the progression of fusion right after the discontinuation of the drug. Therefore, Vismodegib is not indicated for children.

Specific Considerations:

• Pregnancy: The limited studies show that Vismodegib increases the risk of loss of pregnancy and even harms the fetus.

• Lactation: No clinical data states the presence of Vismodegib in human milk, its effects on milk production, and the infant. Nevertheless, advise the patient that breastfeeding is strictly not recommended during the treatment and for about 24 months following the final dose due to the drug's potential for severe adverse reactions.

• Pediatric Use: The safety and efficacy of the drug Vismodegib has not been determined. The pediatric population.

• Geriatric Use: The clinical research of Vismodegib does not study adequate numbers of older patients of 65 years and over to conclude whether the geriatric population responds differently from the younger population.

• Hepatic Impairment: No dosage modification is required in people with hepatic impairment.

• Renal Impairment: No dosage modification is required in people with renal impairment.