Vismodegib

Keep all appointments with your doctor.

Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Vismodegib is usually taken once per day. You may take the medicine with or without food.

Do not crush, chew, break, or open a vismodegib capsule. Swallow it whole.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Skip the missed dose and wait until your next scheduled dose to take the medication. Do not take extra medicine to make up the missed dose.

Vismodegib is an inhibitor of the hedgehog (Hh) signaling pathway, which is described chemically as 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. The molecular formula is C19H14Cl2N2O3S. The molecular weight is 421.30 g/mol and the structural formula is:

Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan powder. The solubility of vismodegib is pH dependent with 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1. The partition coefficient (log P) is 2.7.

Each ERIVEDGE (vismodegib) capsule for oral administration contains 150 mg vismodegib and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycolate, talc, and magnesium stearate (non-bovine). The capsule shell contains gelatin, titanium dioxide, red iron oxide, and black iron oxide. The black printing ink contains shellac and black iron oxide.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. It has been shown that use of vismodegib in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Absorption

Bioavailability

Absolute bioavailability: 31.8%.1

Saturable absorption; increase in exposure not observed with doses >150 mg.1 3 5

Food

Steady-state exposure not affected by food.1

Special Populations

Pharmacokinetics not studied in renal or hepatic impairment.1

Population pharmacokinetic analyses indicate that weight (41–140 kg), age (26–89 years), Clcr (30–80 mL/min), and gender do not have clinically meaningful effects on systemic exposure.1

Distribution

Extent

Not known if distributed into milk.1

Plasma Protein Binding

>99%; binds albumin and α1-acid glycoprotein (saturable).1 4

Elimination

Metabolism

Undergoes oxidation, glucuronidation, and pyridine ring cleavage; oxidative metabolites produced by CYP2C9 and 3A4/5.1

Elimination Route

Excreted unchanged and as metabolites primarily in feces (82%) and to a lesser extent in urine (4.4%).1

Half-life

4 days following continuous once-daily dosing.1

12 days following a single dose.1

• Importance of patients reading medication guide before initiation of therapy and each time prescription is refilled.2

• Importance of women informing their clinician if they are or plan to become pregnant.1 2 Advise patients to contact their clinician immediately if pregnancy is confirmed or suspected; advise pregnant women of risk to the fetus.1 2

• Importance of both women and men using effective contraception during therapy. 1 2 Advise women to avoid pregnancy during and for at least 7 months after therapy with the drug.1 2 Advise men to use condoms with spermicide during and for at least 2 months after therapy with the drug.1 2

• Importance of women informing clinicians immediately if they are breast-feeding or plan to breast-feed.1 2 Advise women of the potential for serious adverse reactions from the drug in nursing infants.1

• Importance of patients not donating blood or blood components while receiving vismodegib and for at least 7 months after discontinuance.1 2

• Advise patients to swallow capsules whole and not to crush or open capsules.1 2

• Advise patients not to replace any missed doses and to resume regular dosing schedule after a missed dose.1 2

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 2

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Use vismodegib as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Swallow whole. Do not chew, open, or crush.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep lid tightly closed.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

No dosage adjustment necessary.

Applies to vismodegib: oral capsule

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:

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

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:

• Absent, missed, or irregular menstrual periods
• change in taste
• decreased appetite
• diarrhea
• difficulty having a bowel movement (stool)
• 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
• weight loss

Applies to vismodegib: oral capsule

Dermatologic

Very common (10% or more): Alopecia (63.8%), pruritus
Common (1% to 10%): Rash, madarosis, abnormal hair growth[Ref]

Gastrointestinal

Very common (10% or more): Nausea (30.4%), diarrhea (29.0%), constipation (21.0%), vomiting (13.8%)
Common (1% to 10%): Dyspepsia, upper abdominal pain, abdominal pain[Ref]

General

The most frequent adverse drug reactions reported were muscle spasms (74.6%), alopecia (65.2%), dysgeusia (57.2%), weight loss (48.6%), fatigue (44.9%), and nausea (34.8%).[Ref]

Genitourinary

Very common (10% or more): Amenorrhea[Ref]

Metabolic

Very common (10% or more): Weight loss (44.9%), decreased appetite (25.4%)
Common (1% to 10%): Dehydration, hyponatremia, azotemia, and hypokalemia[Ref]

Musculoskeletal

Very common (10% or more): Muscle spasms (71.7%), arthralgia (15.9%)
Common (1% to 10%): Pain in extremity, back pain, musculoskeletal chest pain, myalgia, flank pain, musculoskeletal pain[Ref]

Nervous system

Very common (10% or more): Dysgeusia (55.1%), ageusia (10.9%)
Common (1% to 10%): Hypogeusia[Ref]

Hepatic

Common (1% to 10%): Hepatic enzymes increased[Ref]

Other

Very common (10% or more): Fatigue (39.9%)
Common (1% to 10%): Pain, asthenia[Ref]

Renal

Common (1% to 10%): Elevated blood urea nitrogen[Ref]

Some side effects of vismodegib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual adult dose: 150 mg orally once a day

Duration of therapy: Until disease progression or until unacceptable toxicity.

Use: Treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Data not available

Administration advice:
-May be taken with or without food.
-Swallow capsules whole; do not open or crush capsules.
-If a dose of is missed, do not make up that dose; resume dosing with the next scheduled dose.

Monitoring:
-Pregnancy

Patient advice:
-Advise patients that exposure during pregnancy can cause embryo-fetal death or severe birth defects.