Consumer medicine information

Odomzo

Sonidegib

BRAND INFORMATION

Brand name

Odomzo Capsules

Active ingredient

Sonidegib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Odomzo.

What is in this leaflet

This leaflet answers some common questions about ODOMZO. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

Keep this leaflet with the medicine.

You may need to read it again.

What ODOMZO is used for

ODOMZO contains the active ingredient sonidegib.

ODOMZO belongs to a group of medicines called anti-neoplastic (or anti-cancer) medicines. It works by blocking cancer cells from growing and making new cells.

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

Surgery and radiation treatment may not be appropriate because:

  • surgery will change the shape of a body part (cause deformity) e.g. face, neck
  • surgery may cause you to lose the use of a body part such as an eye or ear
  • the cancer has returned after previous surgery and further surgery may not work or is not possible
  • radiation was previously not successful or it is not suitable for you to have radiation.

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

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

Before you take ODOMZO

When you must not take it

Do not take ODOMZO if you are you are pregnant, think you may be pregnant, or are planning to become pregnant during the course of treatment and for 20 months after your final dose of the medicine.

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

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

Do not take ODOMZO if you are breast-feeding or plan to breast- feed while on treatment with ODOMZO and for 20 months after your final dose of the medicine.

It is not known if the active ingredient in ODOMZO can pass into breast milk and can cause harm to your baby.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

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:

You have a history of muscle cramps or weakness or if you are taking other medicines.

ODOMZO may cause muscle pain, cramps or weakness, some medicines (e.g. medicines used to treat high cholesterol) might increase the chance for muscle pain, cramps or weakness.

You plan to donate blood during treatment with ODOMZO or plan to do so in the future.

You should not donate blood while on treatment with ODOMZO and for 20 months after your final dose of the medicine.

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

Children and adolescents

Do not use ODOMZO in children and adolescents below the age of 18 years.

Fertility preservation

Talk to your doctor about fertility preservation if you plan to have children in the future.

ODOMZO may have an impact on fertility in men and women. Discuss with your doctor fertility preservation before starting treatment with ODOMZO.

Women with the potential to become pregnant

Discuss with your doctor if you are able to become pregnant. Even if your periods have stopped (menopause), it is important to check with your doctor whether there is a risk that you could become pregnant. If you are able to become pregnant you must:

  • use two methods of birth control (contraception) including a highly effective method and a barrier method such as a condom, so that you do not become pregnant while on treatment with ODOMZO
  • continue to use a highly effective method and barrier method of birth control (contraception) for 20 months after your final dose of the medicine.

Talk to your doctor about the most suitable method of birth control (contraception) for you.

Talk to your doctor about a pregnancy test before starting treatment with ODOMZO. During treatment and 20 months aftertreatment, tell your doctor immediately if:

  • you believe your contraception has failed for any reason
  • your periods stop
  • you stop using contraception
  • you need to change your contraception.

Men taking ODOMZO

Always use a condom (with spermicide, if available) when you have sex with a female partner, even if you have had a vasectomy. Do this during treatment and for 6 months after your final dose of the medicine.

Do not donate semen while on treatment with ODOMZO and for 6 months after your final dose of the medicine.

Taking other medicines

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

Some medicines and ODOMZO may interfere with each other. These include:

  • medicines used to treat high cholesterol; statins and fibric acid derivatives;
  • vitamin B3 also known as niacin;
  • medicines used to treat infections. These include medicines that treat certain types of bacterial infections (antibiotics such as telithromycin, rifampin, rifabutin) or treat fungal infections such as ketoconazole in formulations other than shampoo, itraconazole, posaconazole or voriconazole;
  • medicines used to treat AIDS/HIV, such as ritonavir, saquinavir or zidovudine;
  • medicines used to treat acute seizures, such as carbamazepine, phenytoin or phenobarbital;
  • chloroquine and hydroxychloroquine, medicines used to treat parasitic infections;
  • nefazodone, a medicine used to treat depression;
  • penicillamine, a medicine used to treat severe joint problems (rheumatoid arthritis);
  • St. John’s wort (a herbal medicine also known as Hypericum perforatum used to treat depression)
  • Medicines used to treat gastro- oesophageal reflux disease or gastric or duodenal ulcers (such as esomeprazole, omeprazol, ranitidine, cimetidine, famotidine).

These medicines may be affected by ODOMZO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take ODOMZO

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual recommended dose is one 200mg capsule per day.

How to take it

ODOMZO capsules are to be taken by mouth on an empty stomach.

Swallow the capsules whole with a full glass of water.

When to take it

Take ODOMZO once a day 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.

Take ODOMZO on an empty stomach, for example, 1 hour before food or 2 hours after food.

Food can interfere with the absorption of this medicine.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you have questions about how long to take ODOMZO, talk to your doctor or pharmacist.

If you forget to take it

If it is more than 6 hours since your last ODOMZO dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia or0800 POISON, 0800 764 766 inNZ) 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 ODOMZO. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Keep the telephone numbers for these places handy.

While you are using ODOMZO

Things you must do

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

Tell any other 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 become pregnant) need to take precautions so that a pregnant woman is not exposed to ODOMZO. You will need to do this for 20 months after stopping treatment if you are a woman and for 6 months after stopping treatment if you are a man.

ODOMZO may cause your baby to have severe birth defects or lead to the death of your unborn baby.

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

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some blood tests (such as checking muscle function, liver, kidney and pancreas function) from time to time to make sure the medicine is working and to prevent unwanted side effects.

Women taking ODOMZO

Women who are able to become pregnant will need to show a negative pregnancy test done byyour doctor before starting treatment with ODOMZO.

If you become pregnant while taking this medicine or suspect you could be pregnant, stop taking ODOMZO and tell your doctor immediately.

Women who are able to get pregnant must use two methods of birth control (contraception), a highly effective method and a barrier method. This applies during treatment and for 20 months after your final dose of the medicine.

Men taking ODOMZO

Always use a condom (with spermicide, if available) when you have sex with a female partner, even if you have had a vasectomy. Do this during treatment and for 6 months after your final dose of the medicine.

Do not donate semen while on treatment with ODOMZO and for 6 months after your final dose of the medicine.

Tell your doctor immediately if your partner becomes pregnant or thinks she is pregnant while you are taking ODOMZO.

Things you must not do

Do not take ODOMZO to treat any other complaints unless your doctor tells you to.

Do not give ODOMZO to anyone else, even if they have the same condition as you.

Do not stop taking ODOMZO or change the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how ODOMZO affects you.

This medicine may cause tiredness in some people. If you feel tired, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

This medicine helps most people with advanced basal cell carcinoma, but it may have unwanted side effects in a few people. 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 side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • muscle pain, weakness, spasms or cramps, pain in the bones, ligaments and tendons
  • absence of menstrual periods
  • diarrhoea, heartburn
  • decreased appetite
  • headache
  • disturbed sense of taste or strange taste in the mouth
  • stomach (abdominal) pain
  • feeling sick (nausea)
  • hair loss (alopecia)
  • tiredness (fatigue)
  • pain
  • weight loss
  • vomiting
  • upset stomach, indigestion
  • constipation
  • rash
  • itching
  • abnormal hair growth

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • unexpected muscle pain, tenderness or weakness not caused by exercise

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • symptoms of allergy such as skin rash, itching, swelling of the face, lips, mouth, tongue, throat or neck which may cause difficulty in swallowing or breathing
  • unexpected muscle pain, tenderness or weakness not caused by exercise, particularly if you also feel unwell or have a fever.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

During ODOMZO treatment, you may also have some abnormal blood test results such as high levels of creatine phosphokinase (muscle function), high levels of lipase and/or amylase (pancreas function), high level of alanine aminotransferase (ALT) and/or aspartame aminotransferase (AST) (liver function), high level of creatinine (kidney function), high level of sugar in the blood, low level of hemoglobin (needed to transport oxygen in the blood) and low level of white blood cells.

The above side effects may be serious. You may need urgentmedical attention. Serious side effects are generally rare.

After using ODOMZO

Storage

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store ODOMZO 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

What it looks like

ODOMZO capsules have an opaque pink body with "SONIDEGIB 200MG" printed in black ink and an opaque pink cap with "NVR" printed in black ink.

ODOMZO is available in blister packs of 10 and 30 capsules and bottles of 30 capsules.

Not all pack sizes may be marketed.

Ingredients

ODOMZO contains 200 mg of sonidegib (as phosphate) as the active ingredient.

It also contains the following inactive ingredients:

  • crospovidone
  • lactose monohydrate
  • magnesium stearate
  • poloxamer (188)
  • butylated hydroxytoluene
  • anhydrous colloidal silica
  • sodium lauryl sulfate.

The capsule shell containes:

  • gelatin
  • iron oxide red (E172)
  • titanium dioxide (E171)
  • ammonium hydroxide
  • iron oxide black (E172)
  • propylene glycol
  • shellac.

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

Sponsor

ODOMZO is supplied in Australia by:

Sun Pharma ANZ Pty Ltd
9-13 Waterloo Road
Macquarie Park NSW 2113
Australia

® = Registered Trademark

This leaflet was prepared in October 2017

Australian Registration Number:

ODOMZO 200mg capsules

AUST R 292262 (bottles);

AUST R 226544 (blisters)

BRAND INFORMATION

Brand name

Odomzo Capsules

Active ingredient

Sonidegib

Schedule

S4

 

1 Name of Medicine

Sonidegib.

2 Qualitative and Quantitative Composition

Each hard gelatin capsule of Odomzo contains 200 mg - sonidegib (as diphosphate).

Excipient with known effects.

Each capsule contains lactose monohydrate 38.60 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard gelatin capsule.
Size #00, Coni-snap, opaque pink capsule, cap imprinted in black ink with "NVR," body imprinted in black ink with "SONIDEGIB 200MG," containing white to practically white powder with granules.

4 Clinical Particulars

4.1 Therapeutic Indications

Odomzo is indicated for the treatment of adult patients with:
Locally advanced basal cell carcinoma (BCC) who are not amenable to curative surgery or radiation therapy;
Metastatic BCC.

4.2 Dose and Method of Administration

General target population.

The recommended dose of Odomzo is 200 mg taken orally once daily on an empty stomach, at the same time each day. Odomzo should be taken at least 1 hour before, or two hours after a meal. Odomzo capsules must be swallowed whole. They must not be chewed or crushed.
If a dose is missed, the recommended dose of Odomzo should be taken within 6 hours after the missed dose. If more than 6 hours have passed, the patient should be instructed not to take the missed dose. The patient should continue treatment with the next prescribed dose.
Continue treatment as long as clinical benefit is observed or until unacceptable toxicity develops.

Dose modifications.

Renal impairment.

Sonidegib has not been studied in patients with renal impairment. Based on the available data, sonidegib elimination via the kidney is negligible. A population pharmacokinetic analysis did not find significant influence of renal function on the apparent clearance (CL/F) of sonidegib suggesting that dose adjustment is not necessary in patients with renal impairment (see Section 5 Pharmacological Properties).

Hepatic impairment.

No dose adjustment is necessary in patients with hepatic impairment (see Section 5 Pharmacological Properties).

Creatine phosphokinase (CK) elevations and muscle related adverse events.

Temporary dose interruption and/or dose reduction of Odomzo therapy may be required for CK elevations and muscle related adverse events.
Table 1 summarizes recommendations for dose interruption and/or dose reduction of Odomzo treatment in the management of symptomatic CK elevations and muscle related adverse events (such as myalgia, myopathy, and/or spasm).

Other dose modifications.

If dose reduction is required due to any other adverse drug reaction, then the recommended dose of Odomzo should be reduced to 200 mg every other day. If the same adverse drug reaction occurs following the switch to alternate-daily dosing and does not improve, consider discontinuing treatment with Odomzo.

4.3 Contraindications

Women who are pregnant or breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation).
Women of child-bearing potential, unless two reliable methods of contraception are used during treatment and for 20 months after the last dose (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Muscle related adverse events.

Advise all patients starting therapy with Odomzo of the risk of muscle related adverse events including the potential for rhabdomyolysis. Advise all patients to report promptly any new unexplained muscle pain, tenderness or weakness occurring during treatment with Odomzo or if symptoms persist after discontinuing treatment.
Check CK levels prior to starting treatment and as clinically indicated thereafter, e.g. if muscle related symptoms are reported. If clinically notable elevation of CK is detected, renal function should be assessed (see Section 4.2 Dose and Method of Administration).
Follow dose modification or interruption guidelines (see Section 4.2 Dose and Method of Administration). Management of high grade CK elevation using supportive therapy, including proper hydration, should be considered according to local standards of medical practice and treatment guidelines.
In the phase II pivotal study, muscle spasms, myalgia, myopathy and cases of CK elevations were observed. The majority of patients treated with Odomzo 200 mg daily who had Grade 2 or higher CK elevations developed muscle symptoms prior to the CK elevations. For most patients, muscle symptoms and CK elevations resolved with appropriate proper management.
Closely monitor patients for muscle related symptoms if Odomzo is used in combination with certain medications that may increase the potential risk of developing muscle toxicity (e.g. CYP3A inhibitors, chloroquine, hydroxychloroquine, fibric acid derivatives, penicillamine, zidovudine, niacin, HMG-CoA reductase inhibitors) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Closely monitor patients with neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) due to an increased risk of muscle toxicity.

Women of child-bearing potential and sexually active men.

Odomzo may cause embryo-fetal death or severe birth defects when administered to pregnant women. Based on the mechanism of action, in animal studies, sonidegib has been shown to be teratogenic and fetotoxic. Odomzo must not be administered to women who are, or planning to become, pregnant. Women who have received Odomzo should not become pregnant for at least 20 months following their last Odomzo dose. Verify pregnancy status of women of childbearing potential within 7 days prior to the initiation of Odomzo treatment and monthly during treatment by a test performed by a healthcare professional. Women of child-bearing potential must be instructed to use two methods of contraception, including one highly effective method and a barrier method while taking Odomzo. Contraception must be continued for 20 months after ending treatment. Women whose periods are irregular or have stopped must follow all the advice on effective contraception. In case of pregnancy occurring during treatment, Odomzo must be stopped immediately.
Sexually active males being treated with Odomzo must use a condom with spermicide (if available), regardless of vasectomy status, during intercourse and for 6 months after ending treatment to prevent exposure of female partners to the drug via seminal fluid. They should not father a child or donate semen while taking Odomzo or for at least 6 months after ending treatment.
Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise female patients (and female partners of male patients) to contact their healthcare provider immediately if they suspect that they may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If Odomzo is used during pregnancy or if a patient (or the female partner of a male patient) becomes pregnant while taking Odomzo, the expectant mother should be apprised of the potential hazard to the fetus.
Encourage women who may be exposed to Odomzo during pregnancy, either directly or through seminal fluid to report this to their treating physician immediately.

Use in the elderly.

The safety and effectiveness data of Odomzo in patients aged 65 years and older do not suggest that a dosage adjustment is required in elderly patients (see Section 5 Pharmacological Properties).

Paediatric use.

The safety and efficacy of Odomzo in children and adolescents aged below 18 years with basal cell carcinoma have not been established. No data are available.

Effects on laboratory tests.

No data available.

Other toxicological findings.

Cardiovascular studies in dogs receiving a daily dose of sonidegib for 26 weeks showed only a mild increase (approx. 7%) in QTc interval at plasma concentrations at least 15-fold higher than those anticipated at steady-state in patients taking 200 mg daily. Other safety pharmacology studies indicate that sonidegib is unlikely to interfere with the vital functions of the respiratory and CNS systems.
The safety of sonidegib was evaluated on an oral daily dosing schedule for up to 6 months in rats and dogs. The majority of adverse effects of sonidegib observed in toxicity studies in rats and dogs can be attributed to its pharmacologic mechanism of action on developmental pathways and effects in rats and dogs were similar. The most significant effects were on growing bone and consisted of thinning or closure of growth plates in the sternum and femur and decreasing proliferating chondrocytes in the chostochondral junction of ribs. Effects on growing teeth in rats were also seen, including dentine dysplasia of the incisors and loss of incisors. Neither effects on bone or teeth are expected to occur in adult cancer patients due to the maturity of the dental and skeletal systems.
Other drug-related effects, likely associated with the pharmacology of sonidegib, included effects on the male and female reproductive tract (see Section 4.6, Effects on fertility). Atrophy of the hair follicles and hair thinning is also a pharmacologic effect of sonidegib. Gastrointestinal (GI) toxicity with body weight loss was dose limiting in rats and dogs. In rats, distention of stomach and duodenum, haemorrhage in the stomach wall, loss of mucosa with inflammation, and ulcerations of the non-glandular mucosa occurred. Emesis and diarrhea with single cell necrosis of intestinal epithelium and thinning of the epithelium with erosion were also seen in dogs.
An additional target organ was the kidney with acute tubular necrosis and mineralization of tubular epithelium seen in rats. Lymphoid depletion in thymus and spleen and lymphocytolysis/lymphophagocytes in lymph nodes and gut associated lymphoid tissue (GALT) were also seen in both rats and dogs.
In a juvenile rat study effects were seen in bone, teeth, reproductive tissues, GI tract, and lymphoid tissues similar to the effects in adult rats. In addition, a minimal to slight degeneration of nerve fibers was found in the sciatic nerve and, less commonly, in the thoracic spinal cord, but not in the cervical or lumbar spinal cord or optic nerve. These effects might be secondary to spinal cord and nerve compression resulting from sonidegib induced cessation of bone growth, but a direct effect of sonidegib cannot be excluded. Effects on nerves were not seen in any of the toxicity studies on more mature rats or dogs.

Blood donation.

Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months after ending treatment.

Premature fusion of the epiphyses.

Premature fusion of the epiphyses has been reported in paediatric patients exposed to Hedgehog (Hh) pathway inhibitors. In some cases, fusion progressed after drug discontinuation (see Section 4.8 Adverse Effects (Undesirable Effects)).

Advice to handler.

Do not open capsules due to risk of teratogenicity.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sonidegib undergoes metabolism primarily by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease sonidegib concentrations significantly.

Agents that may increase sonidegib plasma concentration.

In healthy subjects, co-administration of a single 800 mg dose of Odomzo with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A inhibitor, resulted in a 2.25-fold and a 1.49-fold increase in sonidegib AUC and Cmax, respectively, compared to when Odomzo was given alone. Co-administration of Odomzo with strong CYP3A inhibitors increases sonidegib plasma concentration. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Patients should be carefully monitored for adverse events if one of these agents is used together with sonidegib. Recommended dose reductions should be considered if muscle-related symptoms develop.

Agents that may decrease sonidegib plasma concentration.

In healthy subjects, co-administration of a single dose of 800 mg Odomzo with rifampicin (600 mg daily for 14 days), a strong CYP3A inducer, resulted in 72% and 54% decreases in sonidegib AUC and Cmax respectively, compared with when Odomzo was given alone. Co-administration of Odomzo with strong CYP3A inducers decreases sonidegib plasma concentration. Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin and St. John's wort (Hypericum perforatum). If a strong CYP3A inducer must be used concomitantly with sonidegib, consider increasing the dose of sonidegib by 200 mg increments to a maximum daily dose of 800 mg. This dose of sonidegib is predicted to adjust the AUC to the range observed without inducers based on pharmacokinetic data. The dose of Odomzo used prior to initiation of the strong inducer should be resumed if the strong inducer is discontinued.
Results from a clinical study demonstrated a change in sonidegib exposure (32% and 38% decrease in AUC and Cmax) after co-administration of a single dose of Odomzo 200 mg with esomeprazole (a proton pump inhibitor) at 40 mg daily for 6 days in healthy subjects. The effect of this interaction upon clinical efficacy has not been determined.

Anticipated interactions to be considered.

Sonidegib is a competitive inhibitor of CYP2B6 and CYP2C9 in vitro. However, results of a drug-drug interaction study in cancer patients demonstrate that the systemic exposure of bupropion (a CYP2B6 substrate) and warfarin (a CYP2C9 substrate) is not altered when co-administered with sonidegib. Sonidegib is also a breast cancer resistance protein (BCRP) inhibitor. Patients should be carefully monitored for adverse drug reactions with concomitant use of substrates of BCRP transporter, especially those with a narrow therapeutic range.

Agents that are substrates of transporters.

Based on in vitro data, sonidegib did not inhibit apical efflux transporters, P-gp or MRP2, hepatic uptake transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations. Therefore, clinical drug-drug interactions as a result of sonidegib-mediated inhibition of substrates for these transporters are unlikely to occur.

Agents that may increase muscle related adverse events.

Due to overlapping toxicities, patients taking Odomzo who are also taking medications known to increase the risk of muscle related toxicity may be at increased risk of developing muscle related adverse events. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.
In the phase II pivotal study, 12 (15.2%) patients treated with Odomzo 200 mg took concomitant HMG-CoA reductase inhibitors. Of the patients on HMG-CoA reductase inhibitors, 7 (58.3%) had up to Grade 1 muscle symptoms while 43 (64.2%) patients not taking HMG-CoA reductase inhibitors experienced up to Grade 3 symptoms. No patient taking HMG-CoA reductase inhibitors experienced Grade 3/4 CK elevations, as opposed to 6 (9.0%) patients not taking HMG-CoA reductase inhibitors.

Drug-food interaction.

The bioavailability of Odomzo is increased in the presence of food (see Section 5 Pharmacological Properties). Odomzo should be taken at least 1 hour before, or two hours after a meal.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The potential for Odomzo to cause infertility in male and female patients is unknown. Based on findings from animal studies, male and female fertility may be compromised by Odomzo. Fertility preservation strategies should be discussed prior to starting treatment with Odomzo.
In a fertility study in rats, sonidegib administered to female rats at 20 mg/kg resulted in a complete lack of fertility even though estrous cycling was within normal ranges and the precoital interval was comparable to concurrent controls. There was also a reduction of the number of pregnant females and a decrease in the number of viable fetuses at 2 mg/kg/day (exposure below the clinical exposure based on AUC). The no observed effect level (NOEL) for female fertility was 0.2 mg/kg. For sonidegib-treated males, the 20 mg/kg/day (high) dose (exposure approx. 3 times the clinical exposure based on AUC) did not impact the ability of the male rat to impregnate the untreated females and therefore, the 20 mg/kg/day dose is considered the NOEL for fertility and reproduction in the male rat. Repeat dose toxicity studies in rats and dogs at around clinical exposure levels showed various reproductive tract changes such as delayed or arrested maturation as well as atrophy of testes, seminal vesicles, prostate, ovary and uterus.
(Category X)
Odomzo may cause embryo-foetal death or severe birth defects when administered to pregnant women. Based on the mechanism of action, in animal studies, sonidegib has been shown to be teratogenic and foetotoxic. Odomzo must not be administered to women who are, or planning to become, pregnant. Women who have received Odomzo should not become pregnant for at least 20 months following their last Odomzo dose.
Sonidegib was shown to be feto-toxic in rabbits as evidenced by abortion and/or complete resorption of fetuses and teratogenic resulting in severe malformations at ≥ 5 mg/kg/day (approx. 0.05 times the clinical exposure based on AUC). Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations and other severe midline defects. Feto-toxicity in rabbits was seen at low maternal doses (0.01 mg/kg/day) where maternal exposure was below the limit of detection.
It is unknown whether Odomzo is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse drug reactions in breastfed newborns/infants from Odomzo, women must not breast feed while taking Odomzo or for at least 20 months after ending treatment.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The phase II pivotal study evaluated the safety of Odomzo in a total of 229 adult patients with locally advanced or metastatic BCC. Patients were treated with Odomzo 200 mg daily (n = 79) or with Odomzo 800 mg daily (n = 150). The following safety analysis is based on data collected after all patients were followed for at least 30 months unless discontinued earlier. The median duration of treatment was 11.0 months for patients treated with Odomzo at the recommended dose of 200 mg (range 1.3 to 41.3 months). Thirteen (13) (16.5%) patients had a dose reduction and 23 (29.1%) discontinued treatment due to adverse events. One death occurred while on treatment or within 30 days of the last dose taken in either the metastatic BCC or locally advanced BCC patients taking Odomzo 200 mg.
The most common adverse drug reactions occurring in ≥ 10% in patients treated with Odomzo 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhoea, weight decreased, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting and pruritus.
The most common Grade 3/4 adverse drug reactions occurring in > 2% of patients treated with Odomzo 200 mg were fatigue, weight decreased and muscle spasms.
Among adverse drug reactions reported, the frequency was greater in patients taking Odomzo 800 mg than in patients taking Odomzo than 200 mg except musculoskeletal pain, diarrhea, abdominal pain, headache and pruritus. This was also true for Grade 3/4 adverse reactions, except fatigue.

Tabulated summary of adverse drug reactions.

Adverse drug reactions for the recommended dose from the phase II pivotal clinical study (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Clinically relevant laboratory abnormalities.

The most commonly reported Grade 3/4 laboratory abnormalities with an incidence of ≥ 5% occurring in patients treated with Odomzo 200 mg were lipase increase and blood CK increase (Table 3).

Description of selected adverse drug reactions.

Muscle-related adverse events including CK elevation.

Muscle-related adverse reactions are the most clinically relevant side effect reported in patients receiving Odomzo therapy, and are a class effect of inhibitors of the Hh signaling pathway. In the phase II pivotal study muscle spasms were the most common 'muscle-related' adverse events, and were reported in fewer patients in the Odomzo 200 mg group (54%) than in the Odomzo 800 mg group (69%).
Grade 3/4 increase in blood CK was reported in 8% of patients taking Odomzo 200 mg. The majority of patients who had Grade 2 or higher CK elevations developed muscle symptoms prior to the CK elevations. In these patients, increases in laboratory values of CK to Grade 2 and higher severity had a median time to onset of 12.9 weeks (range 2 to 39 weeks) after initiating Odomzo therapy and a median time to resolution (to normalization or Grade 1) of 12 days (95% confidence interval 8 to 14 days).
One patient receiving Odomzo 200 mg experienced muscle symptoms and CK elevations above 10 x ULN and required intravenous fluids, compared to 6 patients receiving Odomzo 800 mg.
After at least 30 months follow up for all patients unless discontinued earlier, the phase II pivotal study had no reported cases of rhabdomyolysis confirmed (defined as CK levels > 10-fold above the pre-treatment or baseline level or > 10 x ULN if no baseline level reported plus a 1.5-fold increase in serum creatinine from the pre-treatment or baseline level). However, 1 reported case in a patient treated with Odomzo 800 mg in a non-pivotal study was confirmed.

Amenorrhea.

In the phase II pivotal study, 2 out of 14 (14.3%) women of either childbearing potential or of childbearing age sterilized by tubal ligation, developed amenorrhea while on treatment with Odomzo 200 mg or 800 mg once daily.

Premature fusion of epiphyses.

Three cases (one case of cartilage injury, one case of epiphyseal disorder and one case of epiphyseal fracture) of epiphyseal growth plate disorders were reported in paediatric patients with sonidegib g clinical study but causal association with sonidegib cannot be ascertained conclusively. Premature fusion of the epiphyses has been reported in paediatric patients exposed to Hh (Hedgehog) pathway inhibitors. Odomzo (sonidegib) should not be used in these paediatric patients as safety and effectiveness is not established in paediatric patients.

Reporting suspected adverse effects.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

In dose escalation studies, Odomzo was administered up to 3000 mg orally once daily. Patients should be monitored closely for adverse events and given appropriate supportive measures in all cases of overdose.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or 0800 POISON, 0800 764 766 in NZ for advice on management.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Sonidegib is a selective and orally bioavailable Smoothened (Smo) antagonist. Smo is a G protein-coupled receptor-like molecule that positively regulates the Hedgehog (Hh) signal transduction pathway. Hh pathway activation of Smo leads to activation and nuclear localization of Glioma-Associated Oncogene (GLI) transcription factors, and is linked to the pathogenesis of several types of cancer including basal cell carcinoma (BCC). Sonidegib binds Smo with high affinity to inhibit GLI mediated target gene activation thereby inhibiting Hh signaling.

Pharmacodynamics.

The sonidegib plasma concentration-QTc analysis showed that the upper bound of one-sided 95% confidence interval for QTc increase was below 5 msec at steady-state Cmax for 800 mg daily doses, which provide 2.3-fold plasma exposure compared with the recommended 200 mg dose. Further, sonidegib plasma concentrations above those achieved with the therapeutic doses were not associated with life threatening arrhythmias or Torsades de pointes.
In the pivotal study A2201, a postbaseline QTcF > 500 ms was reported for one patient in the sonidegib 200 mg group. This patient had prolonged QTcF intervals at baseline which present consistently throughout the study; there were no associated cardiac-related AEs. Increases from baseline of > 30 ms were reported for 7.6% of patients in the sonidegib 200 mg group. No increases from baseline in QTcF of > 60 ms were observed.
Tumor response was independent of sonidegib dose or plasma concentration in the dose range of 200 mg to 800 mg.

Clinical trials.

A phase II, randomized double-blind study of two dose levels (200 mg or 800 mg) of Odomzo was conducted in 230 patients with either locally advanced basal cell carcinoma (laBCC) (n = 194) or metastatic basal cell carcinoma (mBCC) (n = 36). Of the 230 patients, 16 had a diagnosis of Gorlin Syndrome (15 laBCC and 1 mBCC). Adult patients with laBCC or mBCC (≥ 18 years of age) who were not candidates for radiotherapy, surgery or other local therapies, were randomized to receive either Odomzo 200 mg or 800 mg daily until disease progression or unacceptable toxicity.
The primary efficacy endpoint of the trial was objective response rate (ORR) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with laBCC and RECIST 1.1 in patients with mBCC as determined by central review. The secondary endpoints included duration of response (DoR), time to tumor response (TTR) and progression free survival (PFS) according to mRECIST in patients with laBCC and RECIST 1.1 in patients with mBCC as determined by central review.
For patients with laBCC, the Independent Review Committee (IRC) Composite Overall Response was integrated from centrally evaluated MRI scans, digital clinical photographs, and histopathology according to mRECIST. For laBCC, multiple punch biopsies of target lesions were taken to confirm a complete response (CR) or each time a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. MRI tumor response was evaluated by RECIST 1.1. Response by digital clinical photograph was evaluated by World Health Organization (WHO) adapted criteria [partial response (PR): ≥ 50% decrease in the sum of the product of perpendicular diameters (SPD) of lesions, complete response (CR): disappearance of all lesions, progressive disease (PD): ≥ 25% increase in the SPD of lesions]. The criteria for CR were highly stringent for mRECIST. Negative biopsy alone was not sufficient for a composite overall response of CR; all modalities used for assessment must have demonstrated absence of tumor.
Of the 230 patients randomized, 79 patients were assigned to Odomzo 200 mg. Of these 79 patients, 66 (83.5%) were laBCC patients (37 [46.8%] with aggressive histology and 29 [36.7%] with non-aggressive histology) and 13 (16.5%) were mBCC patients. The median age of all patients receiving Odomzo 200 mg was 67 years (59.5% were > 65 years of age), 60.8% were male and 89.9% Caucasian. The majority of patients (laBCC 74%, mBCC 92%) had undergone prior therapies including surgery (laBCC 73%, mBCC 85%), radiotherapy (laBCC 18%, mBCC 54%), and antineoplastic therapies (laBCC 23%, mBCC 23%).
The following efficacy analysis includes data collected after all patients were followed for at least 30 months unless discontinued earlier. The key efficacy results per central review and local investigator assessment are presented in Table 4.
Figures 1 and 2 show the best change in target lesion size for each patient with laBCC (Figure 1) and mBCC (Figure 2) at the dose of 200 mg per central review.
The estimated PFS rate at 12 months was 82% for laBCC and 59% for mBCC patients taking Odomzo 200 mg based on central review (Figure 3).
Patient-reported outcomes were evaluated as an exploratory endpoint to evaluate changes in disease-related symptoms (e.g. pain, fatigue, and weight loss), functioning (e.g. physical function, social function, trouble with social contact), and health status/quality of life (QoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and its associated head and neck cancer specific module (H and N35).
Results, from 18 months follow up data for all patients unless discontinued earlier, confirmed the consistency of the observed treatment effect in patients with laBCC or mBCC. The majority of patients experienced maintenance and/or improvement in their disease-related symptoms, functioning, and health status. Time to deterioration in the prespecified PRO scales (corresponding to > 10-point worsenings without subsequent improvement) essentially mirrored the estimated PFS, reflecting durable clinical benefit.

5.2 Pharmacokinetic Properties

Absorption.

Following the administration of a single dose of Odomzo (100 mg to 3000 mg) without food in patients with cancer, the median time-to-peak concentration (Tmax) was 2-4 hours. Sonidegib is poorly absorbed following oral administration (6% to 7% of the administered dose at 800 mg in the fasting state). The oral absorption of sonidegib 200 mg is expected to be higher based on the nonlinear dose-exposure relationship, but is unlikely to exceed 14%. An absolute oral bioavailability study in humans has not been conducted due to the insolubility of sonidegib in a large number of potential vehicles. Sonidegib exhibited approximate dose-proportional increases in AUC and Cmax over the dose range from 100 mg to 400 mg, but less than dose-proportional increases above 400 mg. There was no evidence of clearance change with repeated dosing based on the population PK analysis and estimated accumulation based on steady state AUC (0-24h) was 19-fold irrespective of dose (200 mg QD or 800 mg QD). Steady state was reached approximately 4 months after starting sonidegib. The average steady state Ctrough for 200 mg was 810 nanogram/mL (range 182 to 2810 nanogram/mL) in cancer patients. Compared to the fasted state, the Cmax and AUC of sonidegib 800 mg was increased 7.8- and 7.4-fold, respectively when the single dose of sonidegib was given with a high-fat meal in healthy subjects.

Distribution.

Based on a population pharmacokinetic analysis of 351 patients who received oral doses of Odomzo in the dose range of 100 mg to 3000 mg, the apparent steady-state volume of distribution (Vss/F) was 9170 L. Steady-state level of sonidegib in the skin was 6-fold higher than in plasma.
Sonidegib was highly bound to human plasma proteins (human serum albumin and alpha-1 acid glycoprotein) in vitro (> 97%), and binding was not concentration-dependent from 1 nanogram/mL to 2500 nanogram/mL.
Sonidegib is not a substrate of P-gp, BCRP or multi-resistance protein 2 (MRP2).

Metabolism.

Sonidegib is primarily metabolized by CYP3A4. Unchanged sonidegib represented 36% of circulating radioactivity. The major circulating metabolite (45% of parent exposure) identified in plasma is the hydrolysis product of sonidegib and is pharmacologically inactive. The metabolites tested were at least 4-fold less potent than sonidegib.

Excretion.

Sonidegib and its metabolites are eliminated primarily by the hepatic route with 93.4% of the administered dose recovered in the feces and 1.95% recovered in urine. Unchanged sonidegib in feces represented 88.7% of the administered dose and was not detectable in urine. The elimination half-life (t1/2) of sonidegib estimated from population PK modeling was approximately 28 days.

Pharmacokinetics in special patient groups.

Patients with hepatic impairment.

The pharmacokinetics of sonidegib were examined in subjects with mild (Child-Pugh class A; N = 8), moderate (Child-Pugh class B; N = 8), or severe (Child-Pugh class C; N = 9) hepatic impairment and in 8 healthy subjects with normal hepatic function. Cmax of sonidegib after a single oral 800 mg dose was 20%, 21%, and 60% lower in mild, moderate, and severe hepatic impairment, respectively, compared to normal hepatic function. AUCinf of sonidegib was 40%, 22%, and 8% lower, respectively. AUClast was 35% lower in mild hepatic impairment, 14% higher in moderate hepatic impairment, and 23% lower in severe hepatic impairment. No dose adjustment is necessary in patients with hepatic impairment.

Patients with renal impairment.

The effect of renal impairment on the systemic exposure of sonidegib has not been studied. Since sonidegib is not renally excreted, no change in systemic exposure is anticipated in patients with renal impairment. A population pharmacokinetic analysis did not find significant influence of renal function (creatinine clearance > 27 mL/min) on the apparent clearance (CL/F) of sonidegib suggesting that dose adjustment is not necessary in patients with renal impairment.

Effect of age, weight and gender.

Population PK analyses showed that there are no clinically relevant effects of age, body weight, gender, or creatinine clearance on the systemic exposure of sonidegib.

Effect of ethnicity.

The Cmax and AUCinf of sonidegib in Japanese healthy subjects were 1.56 and 1.68-fold higher respectively of those seen in Western healthy subjects for a single dose of 200 mg.

5.3 Preclinical Safety Data

Genotoxicity.

Sonidegib was not genotoxic in studies conducted in vitro in bacteria (gene mutation) and in human lymphocytes and lymphoblastoid cells (chromosome aberration) and in vivo in rats (chromosome aberration).

Carcinogenicity.

Carcinogenicity studies have not been performed with sonidegib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Crospovidone, lactose monohydrate, magnesium stearate, poloxamer , butylated hydroxytoluene, colloidal anhydrous silica and sodium lauryl sulfate. The capsule shell contains: gelatin, iron oxide red, and titanium dioxide. Opacode manogramming ink S-1-277002 Black (PI 107581).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 25°C. Protect from moisture. Store in the original package.
Odomzo capsules must be kept out of the reach and sight of children.

6.5 Nature and Contents of Container

Blister [PVC/PCTFE (Aclar)/Al] in pack sizes of 10 and 30 capsules or bottle (HDPE) with child-resistant closure (CRC) in pack size of 30 capsules.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name (IUPAC).

N-{6-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl}-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamide diphosphate.

INN.

Sonidegib.

Chemical structure.


CAS number.

Free base: 956697-53-3.
Salt Form: 1218778-77-8.
Biopharmaceutics Classification System (BCS): Class II.

Molecular formula.

Salt form on anhydrous basis: C26H26F3N3O3.2H3PO4.
Salt/base ratio on anhydrous basis: 1.404.

Molecular weight.

Free base: 485.50. Diphosphate salt: 681.49.
The compound is a white to off-white powder obtained by a standard synthetic organic chemistry synthesis. Sonidegib free base is practically insoluble, with < 10 microgram/mL solubility across the pH range (pH 1-10). The diphosphate salt has a similar solubility profile to the free base, but shows increased solubility at pH 2 (0.018 mg/mL). The diphosphate salt also shows improved solubility in fed state simulated intestinal fluid (0.275 mg/mL). Dissolution profiles of the free base and diphosphate salt were similar in fed and fasted state simulated intestinal fluid.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes