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.

What is in this leaflet

This leaflet answers some common questions about Erivedge capsules.

It does not contain all the available information. It does not take the place of talking to your pharmacist or doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Erivedge against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your pharmacist or doctor.

Keep this leaflet with the medicine. You may need to read it again.

What Erivedge is used for

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.

Before you take it

When you must not take it

Do not take Erivedge if:

  1. 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 must not take this medicine if you are pregnant or plan to become pregnant.
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.
  1. 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.
  1. you are breast-feeding or intend to breast-feed in the future
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.
  1. the package is torn or shows signs of tampering
If the package is damaged, return it to your pharmacist for disposal.
  1. 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.

Before you start to take it

Tell your doctor if:

  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.

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.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought without a prescription from a 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 be affected by Erivedge, or may affect how well it works. Your doctor will advise you about this. 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.

Ask your doctor or pharmacist if you are not sure about any medicine you are taking.

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.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

The recommended dose of Erivedge is one capsule once a day.

How to take it

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 it

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.

How long 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 it

If you forget to take Erivedge, do not to take the missed capsule but resume with the next scheduled dose.

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

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering your dose, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia - telephone 13 11 26; New Zealand - telephone 0800 764 766 or 0800 POISON) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Erivedge. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

While you are taking it

Things you must 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.

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
    - progestogen-only oral contraceptives e.g. 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).

Talk to your doctor straight away if you become pregnant or think that you may be pregnant.

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.

Talk to your doctor straight away if your partner becomes pregnant or thinks she is pregnant while you are taking Erivedge.

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.

Things you must 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.

Things to be careful of

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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Erivedge.

This medicine helps most people with advanced basal cell carcinoma but it may have unwanted side effects.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • feeling sick, also called nausea
  • diarrhoea
  • constipation
  • vomiting
  • indigestion
  • stomach pain
  • feeling tired, also called fatigue
  • unusual weakness
  • weight loss
  • decreased appetite
  • a change in the way things taste or a loss of taste
  • symptoms of dehydration, such as dry or sticky mouth, low or no urine output, urine looks dark yellow, no tears or sunken eyes
  • muscle spasms
  • pain in your chest, back, side or extremities (arms and legs)
  • muscle, tendon, ligament, joint or bone pain
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • hair loss, also called alopecia
  • loss of eyelashes
  • abnormal hair growth
  • loss of menstrual periods.

Erivedge may be associated with abnormalities in your blood test results.

The above list includes the more common side effects of this medicine.

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • 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.

These are very serious side effects. You may need urgent medical attention.

Tell your doctor if you notice anything that is making you feel unwell, even if it is not on this list.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Ask your doctor or pharmacist if you don't understand anything in this list.

After using Erivedge

Storage

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. If you take the capsules out of the bottle they may not keep well.

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. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

Availability

Erivedge is available in a bottle of 28 capsules.

What it looks like

Erivedge capsules have a pink body with "150mg" printed in black ink and a grey cap with "VISMO" printed in black ink.

Ingredients

Erivedge contains 150 mg of vismodegib as the active ingredient.

It also contains the following inactive ingredients:

  • microcrystalline cellulose(460)
  • lactose monohydrate
  • sodium lauryl sulphate
  • povidone
  • sodium starch glycollate
  • purified talc(553)
  • magnesium stearate

The capsule shell contains:

  • gelatin
  • titanium dioxide (171)
  • iron oxide red (CI77491, 172)
  • iron oxide black (CI77499, 172)
  • shellac (904)

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

Manufacturer

Erivedge is distributed in Australia by:

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

Distributed in New Zealand by:

Roche Products (New Zealand) Limited
PO Box 109113 Newmarket
Auckland 1149
NEW ZEALAND
Medical enquiries: 0800 656 464

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Number:

  • AUST R 214475

This leaflet was prepared 06 April 2020

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Erivedge

Active ingredient

Vismodegib

Schedule

S4

 

1 Name of Medicine

Vismodegib.

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.

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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX43.

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 Tables 3 and 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.

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.

4.3 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.

4.8 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 include.

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.

4.2 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).

4.7 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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes