Drug information of vismodegib

Basal cell cancer is associated with mutations in Hedgehog pathway components. Hedgehog regulates cell growth and differentiation in embryogenesis; while generally not active in adult tissue, Hedgehog mutations associated with basal cell cancer can activate the pathway resulting in unrestricted proliferation of skin basal cells. Vismodegib is a selective Hedgehog pathway inhibitor which binds to and inhibits Smoothened homologue (SMO), the transmembrane protein involved in Hedgehog signal transduction.

Distribution

V_d: 16.4 to 26.6 L

Males: The average vismodegib concentration in semen was 6.5% of the average steady state plasma concentration on day 8

Metabolism

Metabolized by oxidation, glucuronidation, and pyridine ring cleavage, although >98% of circulating components are as the parent drug

Excretion

Feces (82%); urine (~4%)

Time to Peak

~2.4 days (Graham 2011)

Half-Life Elimination

Continuous daily dosing: ~4 days; Single dose: ~12 days

Protein Binding

>99%; primarily to serum albumin and alpha₁ acid glycoprotein (AAG)

Basal cell carcinoma, metastatic or locally advanced: Treatment (in adults) of metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or in patients who are not candidates for surgery and not candidates for radiation therapy.

Adult

Usual Adult Dose for Basal Cell Carcinoma

150 mg orally once a day until disease progression or unacceptable toxicity

Comments:
-Withhold therapy for up to 8 weeks for intolerable adverse reactions until improvement or resolution.
-Treatment durations shorter than 8 weeks prior to interruptions have not been studied.

Oral: May be administered with or without food. Swallow capsules whole; do not open or crush.

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to vismodegib or any component of the formulation; pregnancy or females at risk of becoming pregnant; breast-feeding; male patients or female patients of childbearing potential who do not comply with the Erivedge Pregnancy Prevention Program; children and adolescents <18 years of age.

Side effects requiring immediate medical attention

Along with its needed effects, vismodegib may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking vismodegib:

Less common

• Bloody or cloudy urine
• confusion
• decreased urine output
• dizziness
• dry mouth
• fast or irregular heartbeat
• headache
• increased thirst
• loss of consciousness
• muscle pain or cramps
• nausea
• pain in the lower back or side
• seizures
• swelling of the face, ankles, or hands
• thirst
• unusual tiredness or weakness
• vomiting

Side effects not requiring immediate medical attention

Some side effects of vismodegib may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Absent, missed, or irregular menstrual periods
• change in taste
• constipation
• decreased appetite
• diarrhea
• difficulty having a bowel movement
• difficulty with moving
• hair loss or thinning of the hair
• loss of taste
• muscle spasm or stiffness
• pain in the joints
• stopping of menstrual bleeding

Do not use vismodegib if you are pregnant, or if you are a man and your sexual partner is pregnant. Vismodegib use by either parent may cause severe birth defects or death of a baby.

For Women: Use effective birth control to prevent pregnancy while you are using vismodegib and for at least 24 months after your last dose. Call your doctor at once if you quit using birth control, if your period is late, or if you think you might be pregnant.

For Men: Always use a latex condom and spermicide when having sex, even if you have had a vasectomy. Continue using condoms and spermicide for at least 3 months after you stop taking vismodegib.

You should not use vismodegib if you are allergic to it, or:

• if you are pregnant or breast-feeding.

You will need to have a negative pregnancy test within 7 days before you start taking vismodegib.

You must prevent pregnancy while you are taking vismodegib, whether you are a man or a woman. This medicine can cause severe birth defects or death of a baby.

For Women: Use effective birth control while taking vismodegib and for 24 months after your last dose. The birth control method you use must be proven highly effective (at least 99%), such as: hormonal birth control (pills, vaginal ring, implants, or injections), an intrauterine device (IUD), or a tubal ligation. Call your doctor at once if you quit using birth control, if your period is late, or if you think you might be pregnant.

For Men: While you are taking vismodegib you must not have unprotected sex with a pregnant woman, or cause a woman to become pregnant. Vismodegib can affect your sperm and may cause harm to the baby at conception or during pregnancy. Always use a latex condom and spermicide when having sex, even if you have had a vasectomy. Continue using condoms and spermicide for at 3 months after you stop taking vismodegib.

Call your doctor right away if a pregnancy occurs while either the mother or the father is using vismodegib.

Tell your doctor if you have ever had:

• liver disease; or
• kidney disease.

You should not breast-feed while you are using vismodegib and for 7 months after your last dose.

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

You may take vismodegib with or without food.

Swallow the capsule whole and do not crush, chew, break, or open it.

Store at room temperature away from moisture and heat.

Skip the missed dose and use your next dose at the regular time. Do not use two doses at one time.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep bottle closed tightly to protect from moisture.

AU TGA pregnancy category: X
US FDA pregnancy category: Not assigned.

Comments:
-A pregnancy exposure registry is available.
-Advise all patients of the risks of embryofetal death and severe birth defects and the need for contraception during and after therapy.
-A pregnancy test should be performed within 7 days prior to initiating and monthly during therapy.
-If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
-Females should use 2 methods of contraception (one highly effective and one barrier) during therapy and for 24 months after.
-Persistent lack of menses during therapy should be assumed to indicate pregnancy until medical confirmation.
-Amenorrhea can occur in females of reproductive potential. Reversibility of amenorrhea is unknown.
-This drug is present in semen. Males should use condoms with spermicide (even after a vasectomy) during sexual intercourse with females while being treated and for 3 months after.
-Advise males of the potential risk to an embryo or fetus if a female partner of reproductive potential is exposed to this drug.
-Advise males not to donate semen during therapy and for 3 months after.