Consumer medicine information

Erivedge

Vismodegib

BRAND INFORMATION

Brand name

Erivedge

Active ingredient

Vismodegib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Erivedge.

SUMMARY CMI

ERIVEDGE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ERIVEDGE?

ERIVEDGE contains the active ingredient vismodegib. ERIVEDGE is used to treat adults with a type of skin cancer called advanced basal cell carcinoma. For more information, see Section 1. Why am I using ERIVEDGE? in the full CMI.

2. What should I know before I use ERIVEDGE?

Do not use if you have ever had an allergic reaction to ERIVEDGE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use ERIVEDGE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ERIVEDGE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ERIVEDGE?

  • The recommended dose of ERIVEDGE is one capsule once a day (150mg), taken at about the same time each day.
  • Swallow the capsules whole with a full glass of water. Do not crush, open or chew the capsule.
  • ERIVEDGE can be taken with or without food.
  • More instructions can be found in Section 4. How do I use ERIVEDGE? in the full CMI.

5. What should I know while using ERIVEDGE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ERIVEDGE.
  • Tell your doctor if you have kidney problems.
  • Women able to have children need to use two acceptable forms of contraception so that a pregnancy does not happen during treatment and for 24 months after the final dose.
  • For Men, always use a condom (with spermicide, if available), when you have sex during treatment and for 2 months after your final dose of ERIVEDGE.
Things you should not do
  • You must not donate blood while taking ERIVEDGE and for 24 months after your final dose.
  • You must not donate sperm while taking ERIVEDGE and for 2 months after your final dose.
  • Do not take ERIVEDGE if you are pregnant, plan to become pregnant and/or breastfeed 24 months after your final dose.
Driving or using machines
  • Be careful driving or operating machinery until you know how ERIVEDGE affects you. It is not known if ERIVEDGE affects your ability to drive or operate machinery
Looking after your medicine
  • Keep your capsules in a cool dry place where the temperature stays below 30°C.
  • Keep your capsules in the bottle, with the cap tightly closed, until it is time to take them.
  • Do not store ERIVEDGE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

For more information, see Section 5. What should I know while using ERIVEDGE? in the full CMI.

6. Are there any side effects?

Common side effects may include nausea, diarrhoea, constipation, vomiting, indigestion, stomach pain, fatigue, unusual weakness, weight loss, decreased appetite, change in the way things taste or a loss of taste, dehydration, dry or sticky mouth, low or no urine output, dark urine, no tears, sunken eyes, muscle spasms, hair loss (alopecia), abnormal hair growth, loss of menstrual periods or pain in the chest, back, side, tendons, ligaments, joints, bones or extremities (arms and legs).

Tell your doctor or nurse immediately or go to the nearest hospital Emergency Department if you experience signs or symptoms of a serious allergic reaction such as shortness of breath, difficulty breathing, chest tightness or wheezing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ERIVEDGE® (Eh-rih-vedge)

Active ingredient(s): vismodegib (viz-mod-dee-gib)


Consumer Medicine Information (CMI)

This leaflet provides important information about using ERIVEDGE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ERIVEDGE.

Where to find information in this leaflet:

1. Why am I using ERIVEDGE?
2. What should I know before I use ERIVEDGE?
3. What if I am taking other medicines?
4. How do I use ERIVEDGE?
5. What should I know while using ERIVEDGE?
6. Are there any side effects?
7. Product details

1. Why am I using ERIVEDGE?

ERIVEDGE contains the active ingredient vismodegib. ERIVEDGE belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents.

ERIVEDGE is used to treat adults with a type of skin cancer called advanced basal cell carcinoma.

It is used when the cancer;

  • has spread to other parts of the body (called "metastatic" basal cell carcinoma) or
  • has spread to surrounding areas (called "locally advanced" basal cell carcinoma) and your doctor has decided that treatment with surgery or radiation is not appropriate.

Surgery and radiation treatment may not be appropriate because;

  • surgery will change the shape of a body part (cause deformity)
  • with surgery, you may lose the use of a body part such as an eye or ear
  • the cancer has returned after previous surgeries and further surgery isn't likely to be successful
  • radiation was previously unsuccessful or you are not suitable for radiation.

ERIVEDGE works by controlling a key protein involved in this type of cancer. ERIVEDGE may slow or stop the cancer cells from growing, or may kill them. As a result, your skin cancer may shrink.

Research undertaken in the development of ERIVEDGE utilised cell lines derived from human embryos.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have given it for another reason.

This medicine is not addictive.

  • This medicine is available only with a doctor's prescription.

2. What should I know before I use ERIVEDGE?

Warnings

Do not use ERIVEDGE if:

  • You are pregnant, think you may be pregnant, or are planning to become pregnant during the course of treatment or during the 24 months after your final dose of the medicine.
  • You are a woman who is able to have children but you are unable or unwilling to use two acceptable forms of birth control (contraception) during the course of treatment or during the 24 months after your final dose of the medicine.
    Women able to have children need to use two acceptable forms of contraception so that a pregnancy does not happen during treatment and for 24 months after the final dose.
  • You are breast-feeding or intend to breast-feed in the future.
  • The package is torn or shows signs of tampering.
    If the package is damaged, return it to your pharmacist for disposal.
  • The expiry date (EXP) printed on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor if you:

  1. You plan to donate blood or blood products during treatment with ERIVEDGE or you plan to do so in the future.
If a pregnant woman receives your donated blood, the baby may develop birth defects.
You must not donate blood while taking ERIVEDGE and for 24 months after your final dose.
  1. You plan to donate sperm during treatment with ERIVEDGE or you plan to do so in the future.
If a woman receives your donated sperm, the baby may develop birth defects.
You must not donate sperm while taking ERIVEDGE and for 2 months after your final dose.
  1. You have kidney problems.
  2. You are allergic (hypersensitive) to vismodegib or any of the ingredients listed at the end of this leaflet or allergic to any other medicines, foods, preservatives or dyes.
Some of the symptoms of an allergic reaction may include:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, redness or hives on the skin
  • chills and shivering
  • feeling sick (nausea) or being sick (vomiting).

If you have not told your doctor about any of the above, tell him or her before you start taking ERIVEDGE.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

You must not take this medicine if you are pregnant or plan to become pregnant.

The active ingredient in ERIVEDGE may pass into breast milk and there is a possibility that your baby may suffer serious growth defects.

You must not breast-feed while taking ERIVEDGE and for 24 months after the last dose.

ERIVEDGE may affect your developing baby if you take it during pregnancy. ERIVEDGE may cause your baby to die before it is born (stillborn) or cause your baby to have severe birth defects.

Use in Children

ERIVEDGE should not be used in children and adolescents. The safety and effectiveness in people younger than 18 years old have not been established. Premature fusion of the growth plates has been reported in paediatric patients exposed to ERIVEDGE. In some cases, fusion progressed after drug discontinuation.

Fertility preservation

If you are a female patient and want to have children after treatment with ERIVEDGE, talk to your doctor about fertility preservation.

It is not known whether ERIVEDGE causes infertility. In clinical trials, some female patients no longer experienced their menstrual period after starting treatment.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your pharmacist or doctor if you are taking antibiotics or any herbal medicines (such as St. John's wort), because they can make female birth control (contraception) less effective.

Some medicines may interfere with ERIVEDGE and affect how it works.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking ERIVEDGE.

ERIVEDGE may interfere with some medicines. These include:

  • ezetimibe and statins, such as atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin – medicines used to treat high cholesterol
  • bosentan, a medicine used to treat high blood pressure in the vessels between the heart and the lungs
  • glibenclamide, a medicine used to treat diabetes
  • valsartan and olmesartan, medicines used to treat high blood pressure and heart problems.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ERIVEDGE.

4. How do I use ERIVEDGE?

How much to take

  • The recommended dose of ERIVEDGE is one capsule once a day.
  • Follow the instructions provided and use ERIVEDGE until your doctor tells you to stop.
  • Swallow the capsules whole with a full glass of water.
  • Do not crush, open or chew the capsule.
  • ERIVEDGE can be taken with or without food.

When to take ERIVEDGE

  • Take ERIVEDGE at about the same time each day
    Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • Continue taking ERIVEDGE for as long as your doctor tells you.

How long you will be treated with ERIVEDGE depends on how you are responding to treatment. Your doctor will discuss this with you.

If you forget to take ERIVEDGE

ERIVEDGE should be taken regularly at the same time each day. If you miss your dose at the usual time and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much ERIVEDGE

If you think that you have used too much ERIVEDGE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ERIVEDGE?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ERIVEDGE.

Tell all doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Both men and women who are able to have children need to take precautions so that a pregnant woman is not exposed to ERIVEDGE. You need to do this for 24 months after stopping treatment if you are a woman and for 2 months after stopping treatment if you are a man.

ERIVEDGE may cause severe birth defects. It may also lead to the death of a baby before it is born or shortly after being born.

Talk to your doctor immediately if you have unprotected sex or if you think your contraception has failed.

Call your doctor straight away if:

  • You or your partner becomes pregnant or your partner thinks they are pregnant while taking ERIVEDGE.

Remind any doctor, dentist or pharmacist you visit that you are using ERIVEDGE.

Things you should not do

  • Do not stop taking ERIVEDGE or change the dose without first checking with your doctor.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.
  • Do not give ERIVEDGE to anyone else even if they have the same condition as you.

Women taking ERIVEDGE

  • Women who are able to have children will need to show a negative pregnancy test (conducted under medical supervision) before starting treatment with ERIVEDGE. You should then have a medically-supervised pregnancy test each month during treatment.
  • Women who are able to get pregnant must use two forms of acceptable contraception (a barrier and a non-barrier form). This applies during treatment and for 24 months after your final dose.
  • Use one non-barrier form of contraception from this list:
    - combination hormonal contraceptives e.g. Yasmin, Yaz, Levlen or vaginal ring e.g. Nuvaring
    - Microlut, Provera
    - subcutaneous hormonal implant e.g. Jadelle, Implanon NXT, Implanon
    - birth control patch
    - birth control injections e.g. Depo-Provera
    - tubal sterilisation
    - vasectomy (surgery performed on male partner)
    - intrauterine device (IUD e.g. Copper TT38 Slimline, Multiload-Cu375, Mirena).
  • In addition, use one barrier form of contraception from this list:
    - any male condom (with spermicide, if available)
    - diaphragm (with spermicide, if available).

If you have stopped menstruating during the course of treatment you must still use 2 forms of acceptable contraception during treatment and for 24 months after your last dose.

Men taking ERIVEDGE

Always use a condom (with spermicide, if available), when you have sex during treatment and for 2 months after your final dose of ERIVEDGE.

A vasectomy does not give enough protection without a condom.

Do not donate sperm while taking ERIVEDGE and for 2 months after your final dose.

Talk to your doctor about the best contraception for you.

Tell your doctor if, for any reason, you have not taken ERIVEDGE exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel ERIVEDGE is not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ERIVEDGE affects you.

It is not known if ERIVEDGE affects your ability to drive or operate machinery.

Looking after your medicine

  • Keep your capsules in a cool dry place where the temperature stays below 30°C.
  • Keep your capsules in the bottle, with the cap tightly closed, until it is time to take them.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine, your doctor tells you to stop taking this medicine or the expiry date has passed, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the following information and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • feeling sick, also called nausea
  • feeling tired, also called fatigue
  • unusual weakness
  • weight loss
  • decreased appetite
  • a change in the way things taste or a loss of taste
  • pain in your chest, back, side or extremities (arms and legs)
  • hair loss, also called alopecia
  • loss of eyelashes
  • abnormal hair growth
  • loss of menstrual periods
Signs and symptoms of gastro-intestinal problems:
  • vomiting
  • indigestion
  • stomach pain
  • diarrhoea
  • constipation
Signs and symptoms of dehydration:
  • such as dry or sticky mouth
  • low or no urine output
  • urine looks dark yellow
  • no tears or
  • sunken eyes
Signs and symptoms of muscle damage:
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • muscle, tendon, ligament, joint or bone pain
  • muscle spasms
ERIVEDGE may be associated with abnormalities in your blood test results.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs and symptoms of an allergic reaction:
  • shortness of breath
  • difficulty breathing
  • chest tightness
  • wheezing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ERIVEDGE contains

Active ingredient
(main ingredient)
vismodegib
Other ingredients
(inactive ingredients)

microcrystalline cellulose (460)

sodium lauryl sulphate

povidone

sodium starch glycollate

purified talc (553)

magnesium stearate

lactose monohydrate

Other ingredients
(capsule shell)

gelatin

titanium dioxide (171)

iron oxide red (CI77491, 172)

iron oxide black (CI77499, 172)

shellac (904)

Potential allergens

lactose

sulfites

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What ERIVEDGE looks like

ERIVEDGE capsules have a pink body with "150mg" printed in black ink and a grey cap with "VISMO" printed in black ink. (AUST R 214475).

ERIVEDGE is available in a bottle of 28 capsules.

Who distributes ERIVEDGE

Roche Products Pty Ltd
ABN 70 000 132 865
Level 8, 30 – 34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

This leaflet was prepared in November 2022

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Erivedge

Active ingredient

Vismodegib

Schedule

S4

 

1 Name of Medicine

Vismodegib.

2 Qualitative and Quantitative Composition

Erivedge 150 mg hard capsule.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Erivedge 150 mg capsules are hard gelatin capsules, with a pink opaque body with "150 mg" printed in black ink and a grey opaque cap with "VISMO" printed in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Erivedge is indicated for the treatment of adult patients with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma where surgery and/or radiation therapy are not appropriate.

4.2 Dose and Method of Administration

Dosage.

The recommended daily dose of Erivedge is 150 mg.
Erivedge should be taken once a day, with or without food. Capsules must be swallowed whole with water and must not be opened or crushed under any circumstances.
Erivedge should be continued until disease progression or until unacceptable toxicity. In patients where treatment is discontinued prior to progression, patients should be monitored for disease recurrence or worsening of disease.

Missed dose.

If a dose of Erivedge is missed, patients should be instructed not to take the missed dose but to resume dosing with the next scheduled dose.

Special populations.

Elderly patients.

No dose adjustment is required in patients > 65 year years of age (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients.

The safety and efficacy of Erivedge in children and adolescents (< 18 years) have not been established.

Patients with renal impairment.

No dose adjustment is required in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties). Very limited data is available in patients with severe renal impairment. Patients with severe renal impairment should be carefully monitored for adverse reactions.

Patients with hepatic impairment.

No dose adjustment is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Erivedge is contraindicated in:
pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation);
women of child-bearing potential, unless two reliable methods of contraception are being used during treatment and for 24 months after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation);
nursing mothers during the course of treatment and for 24 months after the last dose because of the potential to cause serious development defects in breast-fed infants and children (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

General warnings.

Blood donation.

Patients should not donate blood or blood products while on treatment and for 24 months after the last dose of Erivedge.

Paediatric use.

The safety and efficacy of Erivedge in children and adolescents (< 18 years) have not been established. Premature fusion of the epiphyses (EPF) and precocious puberty have been reported in paediatric patients exposed to Erivedge. In some cases of EPF, fusion progressed after drug discontinuation.

Use in the elderly.

Of the total number of patients in clinical studies of Erivedge with advanced basal cell carcinoma, approximately 40% of patients were ≥ 65 years old. There was an insufficient number of subjects in this older age category to rule out a lower objective response rate or to rule out an increased frequency of severe adverse events.

Use in renal impairment.

No dedicated clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vismodegib. Results of a population PK analysis demonstrated no impact of renal impairment on the pharmacokinetics of vismodegib. No dose adjustment is required in patients with renal impairment. Very limited data is available in patients with severe renal impairment. Patients with severe renal impairment should be carefully monitored for adverse reactions.

Use in hepatic impairment.

The pharmacokinetics, safety and tolerability of vismodegib were evaluated in patients with mild, moderate or severe hepatic impairment in a dedicated clinical study, following multiple doses of vismodegib. Results demonstrated no impact of hepatic impairment on the pharmacokinetics of vismodegib. No dose adjustment is required in patients with mild, moderate or severe hepatic impairment.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs) including cases of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening, have been reported during post-marketing use (see Section 4.8). If the patient has developed any of these reactions with the use of vismodegib, treatment with vismodegib must not be restarted in this patient at any time.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of vismodegib on other medicines.

Clinically significant PK interactions between vismodegib and CYP450 substrates are not expected.
Results of a drug-drug interaction study conducted in cancer patients demonstrated no clinically significant PK interaction between vismodegib and rosiglitazone (a CYP2C8 substrate). Thus, inhibition of CYP enzymes by vismodegib may be excluded.
Results of a drug-drug interaction study conducted in cancer patients demonstrated no clinically significant PK interaction between vismodegib and the oral contraceptives ethinyloestradiol and norethisterone.
Vismodegib inhibits OATP1B1 in vitro at clinically relevant concentrations. Vismodegib may increase the exposure to substrates of OATP1B1 (e.g. bosentan, ezetimibe, glibenclamide, valsartan and statins). Particular caution should be exercised if vismodegib is administered in combination with any statin. Vismodegib also inhibits OATP1B3 in vitro, but more weakly. An interaction with co-administered medicines that are substrates of OATP1B3 cannot be excluded.
Clinically significant PK interactions between vismodegib and breast cancer resistance protein (BCRP) substrates are not expected. In vitro data indicate that vismodegib is an inhibitor of the BCRP transporter. However, the in vitro concentrations at which inhibition occurred are significantly greater than the unbound vismodegib concentrations observed in patients.

Effects of other medicines on vismodegib.

Medicines that inhibit drug transport systems.

Clinically significant PK interactions between vismodegib and P-gp inhibitors are not expected. Results from a clinical study demonstrated no clinically significant PK interaction between vismodegib and itraconazole (a strong P-glycoprotein inhibitor) in healthy volunteers.

Medicines that affect gastric pH.

Clinically significant PK interactions between vismodegib and pH elevating agents are not expected. Results from a clinical study demonstrated no clinically significant PK interaction between vismodegib and rabeprazole (a proton pump inhibitor) in healthy volunteers.

Medicines that inhibit or induce drug metabolising enzymes.

Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP450 enzymes.
Clinically significant PK interactions between vismodegib and CYP450 inhibitors are not expected. Results from a clinical study demonstrated no clinically significant PK interaction between vismodegib and fluconazole (a moderate CYP2C9 inhibitor) or itraconazole (a strong CYP3A4 inhibitor) in healthy volunteers.
Inducers of CYP3A4 are not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e. carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e. erythromycin, fluconazole).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Erivedge may impair fertility. Amenorrhea has been observed in clinical trials in women of child-bearing potential (see Section 4.8). Reversibility of fertility impairment is unknown. Fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Erivedge.
In a dedicated rat fertility study, no effects on male reproductive organs or fertility endpoints were observed with treatment with vismodegib at 100 mg/kg/day for 26 weeks (corresponding to 1.3-fold of the steady-state AUC0-24h at the recommended human dose) either at the end of the dosing period or following a 15-week recovery phase. In addition, in general toxicity studies with vismodegib of up to 26 weeks duration conducted in sexually mature rats and dogs, no effects on male reproductive organs were observed. An increased number of degenerating germ cells and hypospermia in sexually immature dogs observed at ≥ 50 mg/kg/day in a 4-week general toxicity study were of undetermined relationship to vismodegib.
In a dedicated fertility study in female rats, treatment with vismodegib at 100 mg/kg/day for 27 weeks resulted in embryotoxicity immediately after treatment discontinuation, evident as decreased implantations, increased percent preimplantation loss, and decreased number of dams with viable embryos. Similar findings were not observed after a 15-week recovery period. No correlative histopathological changes were observed. The exposure in female rats at 100 mg/kg corresponds to 1.2-fold of the steady-state AUC0-24h at the recommended human dose. In addition, in a general 26-week toxicity study in rats, decreased number of corpora lutea was observed with vismodegib at 100 mg/kg/day; the effect was not reversed by the end of an 8-week recovery period.
(Category X)
Erivedge may cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Hedgehog pathway inhibitors such as Erivedge have been demonstrated to be embryotoxic and/or teratogenic in multiple animal species and can cause severe midline defects, missing digits, and other irreversible malformations in the developing embryo or foetus.
Pregnant women must not take Erivedge because of the risk of embryo-fetal death or severe birth defects caused by Erivedge (see Section 4.3 Contraindications).
There are no adequate or well controlled studies in pregnant women using Erivedge. Erivedge has been shown to be embryotoxic and teratogenic in animals. Due to the key role of the Hedgehog pathway in embryogenesis and the known effects of Erivedge on embryo-fetal development, women of childbearing potential must use two acceptable methods of contraception during treatment with Erivedge and for 24 months after the last dose (see Section 4.3 Contraindications).
Contraception in males and females.

Female patients.

Women of childbearing potential must use 2 forms of acceptable contraception (including one acceptable barrier method with spermicide, where available) during therapy and for 24 months after completing therapy. Contraceptive advice should be given to the patient.
The following are acceptable forms of primary contraception where medically appropriate: combination hormonal contraceptives (combined oral contraceptives, vaginal ring), subcutaneous hormonal implant, hormonal patch, hormonal contraceptives (progestogen only oral contraceptives, levonorgestrel releasing intrauterine system, medroxyprogesterone acetate depot), tubal sterilisation, vasectomy and intrauterine device (copper IUD). The following are acceptable forms of secondary contraception (barrier methods): any male condom (with spermicide, where available) or diaphragm (with spermicide, where available).
A pregnancy test should be performed at a medical office or laboratory within 7 days prior to initiating Erivedge treatment and monthly during treatment.
If pregnancy occurs, the patient must notify her treating physician immediately to discuss further evaluation and counselling.

Male patients.

Vismodegib is present in semen. To avoid potential embryo-fetal exposure during pregnancy, male patients must use condoms with spermicide (where available), even after a vasectomy, during sexual intercourse with women while being treated with Erivedge and for 2 months after the last dose.
Male patients should not donate semen while being treated with Erivedge and for 2 months after the final dose.
In an embryo-fetal development study in which pregnant rats were administered vismodegib daily during organogenesis, vismodegib was severely toxic to the conceptus. Malformations, including craniofacial anomalies, open perineum, and absent and/or fused digits, were observed in foetuses of dams at 10 mg/kg/day (corresponding to an AUC0-24hr exposure 20% of that at the recommended human dose). The incidence of foetal retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of cervical vertebrae, or proximal phalanges and claws) was also increased at 10 mg/kg/day. Vismodegib was embryolethal at ≥ 60 mg/kg/day (corresponding to an AUC0-24hr exposure 2.8-fold greater than that at the recommended human dose).
The extent to which vismodegib is excreted in breast milk is not known. Due to its potential to cause serious developmental defects, Erivedge is contraindicated in nursing mothers who are taking Erivedge or who have taken Erivedge within the last 24 months (see Section 4.3 Contraindications).
Irreversible adverse effects on growing teeth and premature closure of the epiphyseal plate have been observed in rats treated with vismodegib.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Erivedge on the ability to drive or operate machinery have been performed.

4.8 Adverse Effects (Undesirable Effects)

The safety of Erivedge has been evaluated in clinical trials with 138 patients treated for advanced BCC, which includes both mBCC and laBCC. In 4 open-label phase 1 and 2 clinical trials patients were treated with at least 1 dose of Erivedge monotherapy at dosages ≥ 150 mg. Doses > 150 mg did not result in higher plasma concentrations in clinical trials and patients on doses > 150 mg have been included in the analysis. Additionally, safety was assessed in a post-approval study that included 1215 aBCC patients evaluable for safety and treated with 150 mg. In general the safety profile observed was consistent in both mBCC and laBCC patients and across studies as described below.
The most frequent (≥ 10%) adverse drug reactions (ADRs) reported from these clinical studies with Erivedge are summarised in Table 1.

Other very common (≥ 10%) adverse reactions in an at risk subset of patients.

Reproductive system and breast disorders.

Of the 138 patients with advanced BCC, 10 were women of childbearing potential. Amongst these women, amenorrhoea was observed in 3 patients (30%).

Adverse reactions in < 10% of advanced BCC patients treated with Erivedge.

Gastrointestinal disorders.

Abdominal pain (common), upper abdominal pain (common).

General disorders and administration site conditions.

Asthenia (common).

Investigations.

Hepatic enzyme increased (common)#, blood creatine phosphokinase increased (common).

Metabolism and nutrition disorders.

Dehydration (common).

Musculoskeletal disorders.

Musculoskeletal pain (common), back pain (common), musculoskeletal chest pain (common), myalgia (common), flank pain (common).

Nervous system disorders.

Hypogeusia (common).

Skin and subcutaneous tissue disorders.

Madarosis (common), abnormal hair growth (common).
#Hepatic enzyme increased includes the following reported adverse event preferred terms: hepatic enzyme increased, aspartate aminotransferase increased, liver function test abnormal, blood alkaline phosphatase increased, gamma-glutamyl transferase increased and blood bilirubin increased.
In general, the safety profile observed was consistent in both metastatic BCC and locally advanced BCC patients as described above.

Laboratory abnormalities.

Amongst 138 aBCC patients, post-baseline changes in laboratory parameters of Grade 3 were uncommon, occurring in < 5% and there were no Grade 4 laboratory abnormalities. Laboratory abnormalities (n > 1) that changed from baseline to Grade 3 were decreased sodium (n = 7), decreased potassium (n = 2), and elevated blood urea nitrogen (BUN) (n = 3).

Postmarketing experience.

The following adverse drug reactions have been identified during post-approval use of Erivedge (Table 2) based on reports from Investigator Initiated Studies and literature cases.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Erivedge has been administered at doses 3.6 times higher than the recommended 150 mg daily dose. No increases in plasma drug levels or toxicity were observed.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XJ01.

Pharmacodynamic effect.

Vismodegib is a low molecular weight, orally available inhibitor of the Hedgehog pathway. Hedgehog pathway signalling through the smoothened transmembrane protein (SMO) leads to the activation and nuclear localisation of GLI transcription factors and induction of Hedgehog target genes. Many of these genes are involved in proliferation, survival, and differentiation. Vismodegib binds to and inhibits SMO thereby preventing Hedgehog signal transduction.
Assays of Hedgehog pathway inhibition utilised the human embryonic palatal mesenchymal (HEPM) cell line, established in 1979, and HEK293 (human embryonic kidney) cell line, established in the early 1970s.

Cardiac electrophysiology.

There was no effect of therapeutic doses of Erivedge on the QTc interval. In a randomised, double-blind, placebo- and positive controlled, parallel-group QTc study, healthy subjects were administered Erivedge 150 mg every 24 hours for 7 days, placebo and a single oral dose of moxifloxacin. Similarly, Erivedge had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Clinical trials.

Pivotal study: ERIVANCE BCC (SHH4476g).

An international, single arm, multicentre, open-label, 2 cohort pivotal study (ERIVANCE BCC) was conducted in 104 patients with advanced basal cell carcinoma (BCC), including metastatic BCC (n = 33) and locally advanced BCC (n = 71). Metastatic BCC (mBCC) was defined as BCC that had spread beyond the skin to other parts of the body, including the lymph nodes, lung, bones and/or internal organs. Locally advanced BCC (laBCC) patients had cutaneous lesions that were inappropriate for surgery (inoperable, multiply recurrent where curative resection deemed to be unlikely or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. Prior to study enrolment, diagnosis of BCC was confirmed by histology. Patients with Gorlin syndrome who had at least one advanced BCC (aBCC) lesion and met inclusion criteria were eligible to participate in the study. Patients were treated with oral daily dosing of Erivedge at 150 mg.
The median age was 62 years for all patients with 45% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (100%), 32% of patients had mBCC and 68% of patients had laBCC. For the metastatic cohort, nearly all patients had prior therapies (97%) including surgery (97%), radiotherapy (58%), and systemic therapies (30%). For the locally advanced cohort, nearly all patients had prior therapies (94%) including surgery (89%), radiotherapy (27%), and systemic/ topical therapies (11%). The median duration of treatment for all patients was 12.9 months (range, 0.7 to 47.8).
The primary endpoint was objective response rate (ORR) as assessed by an independent review facility (IRF). Results from the primary analysis (9 months after last patient enrolment) and further 12 month follow-up are summarised in Table 3.
Investigator assessment of ORR was a secondary endpoint. Results from the primary analysis (9 months after last patient enrolment) and further 30 month follow-up are summarised in Table 4.
Objective response was defined as a complete or partial response determined on two consecutive assessments separated by at least 4 weeks. In the mBCC cohort, tumour response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the laBCC cohort, tumour response was assessed based on visual assessment of external tumour and ulceration, tumour imaging (if appropriate), and tumour biopsy. A patient was considered a responder if at least one of the following criteria was met and the patient did not experience progression: (1) ≥ 30% reduction in lesion size [sum of the longest diameter (SLD)], from baseline in target lesions by radiography; (2) ≥ 30% reduction in SLD from baseline in externally visible dimension of target lesions; (3) complete resolution of ulceration in all target lesions.
Additional secondary endpoints include duration of response (DoR), progression free survival (PFS), histopathologic response and overall survival (OS). Results are shown in Table 3 and Table 4.
The waterfall plots in Figures 1 and 2 represent IRF assessment at 12 month follow-up by charting the maximum reduction in target lesion(s) size for each patient. The majority of patients in both cohorts experienced tumour shrinkage.
At the time of the primary analysis for mBCC the majority of IRF assessed responses (6 of 10 responders) occurred by week 8 and additional responses were observed at later assessments. For laBCC the majority of IRF assessed responses (14 of 27 responders) occurred by week 8 and additional responses were observed at later assessments. 54% of laBCC patients (n = 63) had a histopathologic response with no evidence of BCC at 24 weeks.

Post-approval study: STEVIE (MO25616).

A post-approval, open-label, non-comparative, multicentre, phase II clinical trial (STEVIE) was conducted in 1232 patients with advanced BCC, of whom 1215 were evaluable for efficacy and safety. laBCC was defined as cutaneous lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. mBCC was defined as histologically confirmed distant metastasis. Prior to study enrolment, diagnosis of BCC was confirmed by histology. Patients were treated with oral daily dosing of Erivedge at 150 mg.
The median age was 72 years for all patients. The majority of patients were male (57%), 8% had mBCC whereas 92% had laBCC. For the metastatic cohort, the majority of patients had prior therapies, including surgery (91%), radiotherapy (62%) and systemic therapy (16%). For the locally advanced cohort, the majority of patients had prior therapies, including surgery (85%), radiotherapy (28%) and systemic therapy (7%). The median duration of treatment for all patients was 8.6 months (range 0 to 44.1).
Among patients in the efficacy-evaluable population with measurable and histologically confirmed disease (n = 1161; laBCC n = 1077; mBCC n = 84), 68.5% and 36.9% responded to treatment (complete or partial response by RECIST v1.1) in the laBCC and mBCC cohorts, respectively. Of patients who had a confirmed response, the median Duration of Response was 23.0 months (95% CI: 20.4, 26.7) in the laBCC cohort and 13.9 months (95% CI: 9.2, NE) in the mBCC cohort. Complete response was achieved in 4.8% of patients in the mBCC cohort and 33.4% in the laBCC cohort.

5.2 Pharmacokinetic Properties

Absorption.

Single dose absolute bioavailability of vismodegib is 31.8%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg and 540 mg vismodegib. Under clinically relevant conditions (steady state), the pharmacokinetics (PK) of vismodegib is not affected by food. Therefore, vismodegib may be taken without regard to meals.

Distribution.

The volume of distribution for vismodegib is low, ranging from 16.4 to 26.6 L. In vitro binding of vismodegib to human plasma proteins is high (97%) at clinically relevant concentrations. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG). In vitro binding to AAG is saturable at clinically relevant concentrations. Ex vivo plasma protein binding in human patients is > 99%. Vismodegib concentrations are strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low unbound drug levels.

Metabolism.

Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug. Vismodegib is predominant in plasma, with concentrations representing greater than 98% of the total circulating drug related components. Metabolic pathways of vismodegib in human include oxidation, glucuronidation, and an uncommon pyridine ring cleavage. The two most abundant oxidative metabolites recovered in faeces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.

Excretion.

After a single oral dose, vismodegib demonstrates a unique PK profile with sustained plasma levels and an estimated terminal half-life of 12 days.
After continuous once daily dosing, the pharmacokinetics of vismodegib appear to be nonlinear. Considering the single dose half-life, steady-state plasma concentrations in patients are achieved faster than expected (typically within approximately 7 days of continuous daily dosing), with lower than expected accumulation. The apparent half-life of vismodegib at steady state is estimated to be 4 days with continuous daily dosing.
After oral administration of radiolabeled drug, vismodegib is absorbed and slowly eliminated by a combination of metabolism and excretion of parent drug, the majority of which is recovered in the faeces (82% of the administered dose), with 4.4% of the administered dose recovered in urine. Vismodegib and associated metabolic products are eliminated primarily by the hepatic route.

Pharmacokinetics in special populations.

Population PK analyses showed that weight (range: 41-140 kg) and sex do not have a clinically meaningful influence on the systemic exposure of vismodegib.

Renal impairment.

Renal excretion of orally administered vismodegib is low (< 5%). Therefore, renal impairment is unlikely to have a clinically significant effect on the pharmacokinetics of vismodegib. Based on a population PK analysis in patients with mild (BSA indexed CrCl 50 to 80 mL/min, n = 58), moderate (BSA indexed CrCl 30 to 50 mL/min, n = 16) and severe (BSA indexed CrCl < 30 mL/min, n = 1) renal impairment, impaired renal function had no clinically significant effect on the pharmacokinetics of vismodegib.

Hepatic impairment.

The major elimination pathways of vismodegib involve hepatic metabolism and biliary/ intestinal secretion. In a clinical study of subjects with degrees of hepatic impairment, results demonstrated that in patients with mild (n = 8), moderate (n = 6), and severe (n = 3) hepatic impairment the pharmacokinetics of vismodegib was comparable to that of subjects with normal hepatic function (n = 9). The subjects' degree of hepatic impairment was based on the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria: mild (TB ≤ ULN, AST > ULN or ULN < TB ≤ 1.5 x ULN, AST any); moderate (1.5 x ULN < TB < 3 x ULN, AST any); severe (3 x ULN < TB < 10 x ULN, AST any).

Elderly patients.

There is limited data in elderly patients. Population PK analysis suggests that age did not have a clinically significant impact on steady-state concentration of vismodegib.

Paediatric patients.

There is no data in paediatric patients.

5.3 Preclinical Safety Data

Genotoxicity.

Vismodegib was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and Escherichia coli and chromosomal aberrations assay in human peripheral blood lymphocytes) in the presence or absence of metabolic activation systems.
Vismodegib was not genotoxic in an in vivo rat bone marrow micronucleus assay when tested at a single dose up to 2000 mg/kg (corresponding to > 5 times the Cmax in patients at the recommended human dose).

Carcinogenicity.

Carcinogenicity studies were performed in mice and rats. Carcinogenic potential was identified in rats only and was limited to benign hair follicle tumours, including pilomatricomas and keratoacanthomas respectively at ≥ 0.1 fold and ≥ 0.6 fold of the steady-state AUC0-24h of the recommended human dose. No malignant tumours were identified in either species tested. Benign hair follicle tumours have not been reported in clinical trials with vismodegib. The relevance of this finding to patients is uncertain.

Other toxicological findings.

Findings in toxicity studies with vismodegib indicated a risk of adverse effects during postnatal development. Administration of vismodegib to rats resulted in irreversible changes in growing teeth (degeneration/ necrosis of odontoblasts, formation of fluid filled cysts in the dental pulp, ossification of the root canal, and haemorrhage) and closure of the epiphyseal growth plate.
Neurologic effects characterised as twitching, or limb or body tremors were observed at a high frequency in rat toxicity studies with vismodegib. These observations completely resolved upon discontinuation of dosing and were not associated with microscopic findings. It was not determined if these effects were centrally or peripherally mediated; however, in a rat whole body autoradiography study the penetration of vismodegib into central nervous system tissues was low. No corresponding clinical signs were observed in dogs.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, sodium lauryl sulfate, povidone, sodium starch glycollate, purified talc, magnesium stearate.

Capsule shell.

Gelatin, titanium dioxide, iron oxide red (CI77491), iron oxide black (CI77499).

Printing ink.

Shellac, iron oxide black (CI77499).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. The bottle should be kept tightly closed in order to protect from moisture.

6.5 Nature and Contents of Container

Erivedge 150 mg hard capsules are available in high-density polyethylene (HDPE) bottles of 28 capsules.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

879085-55-9.
Vismodegib 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.
Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan solid. The solubility of vismodegib is pH dependent; the solubility in water at pH 7 is 0.1 microgram/mL and is 0.99 mg/mL at pH 1.

7 Medicine Schedule (Poisons Standard)

Schedule 4. Prescription Only Medicine.

Summary Table of Changes