Consumer medicine information

Erlyand Tablets

Apalutamide

BRAND INFORMATION

Brand name

Erlyand

Active ingredient

Apalutamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Erlyand Tablets.

SUMMARY CMI

ERLYAND® Tablets

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using ERLYAND?

ERLYAND contains the active ingredient apalutamide. ERLYAND is used to treat patients with

  • prostate cancer that has spread to other parts of the body and still responds to treatments that lower testosterone
  • prostate cancer that has not spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone.

For more information, see Section 1. Why am I using ERLYAND? in the full CMI.

2. What should I know before I use ERLYAND?

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ERLYAND? in the full CMI.

3. What if I am taking other medicines?

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

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

4. How do I use ERLYAND?

  • The recommended dose of ERLYAND is 240 mg (one 240 mg tablet or four 60 mg tablets) once a day.
  • Swallow ERLYAND tablets whole with a glass of water. Do not break or chew them.

More instructions can be found in Section 4. How do I use ERLYAND? in the full CMI.

5. What should I know while using ERLYAND?

Things you should do
  • Remind any doctor, dentist or pharmacist who are treating you that you are taking ERLYAND.
  • Use a reliable method of contraception (such as condoms) during treatment and for 3 months after your treatment with ERLYAND has finished.
Looking after your medicine
  • Store below 30°C. Keep the tablets in the original container.

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

6. Are there any side effects?

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

Common and less serious side effects are: feeling very tired, nausea, skin rash, weight loss, hot flushes, hypothyroidism, high blood pressure, decreased appetite, water retention, nausea, diarrhoea, joint pain, fractures and falls.

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

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

ERLYAND® Tablets

Active ingredient(s): apalutamide

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using ERLYAND?

ERLYAND contains the active ingredient apalutamide. ERLYAND is an anticancer medicine and belongs to a group of medicines called androgen receptor inhibitors.

ERLYAND is used to treat patients with:

  • Prostate cancer that has not spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone.
  • Prostate cancer that has spread to other parts of the body and still responds to treatments that lower testosterone.

2. What should I know before I use ERLYAND?

Warnings

Do not use ERLYAND if:

  • you are allergic (hypersensitive) to apalutamide, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you are pregnant or may be potentially pregnant.
    ERLYAND is not for use in women.

Check with your doctor if you:

  • have a history of seizure, brain injury, stroke, or brain tumours (non-cancerous or cancerous)
  • have a history of heart disease, high blood pressure, diabetes, have abnormal amounts of fat or cholesterol in your blood (dyslipidemia).
  • have ever developed a severe rash over the body, usually with fever and swollen lymph nodes, and effects on blood cells and organs (drug reaction with eosinophilia and systemic symptoms or DRESS) or a severe skin rash or skin peeling, blistering and/or mouth sores (Stevens-Johnson syndrome/toxic epidermal necrolysis).
  • have a partner who is pregnant or may become pregnant. See additional information under Pregnancy and breastfeeding.

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

Pregnancy and breastfeeding

Do not father a child while taking ERLYAND and for 3 months after stopping treatment.

Use condoms and do not donate sperm during treatment and for 3 months after your treatment has finished. Talk with your healthcare providers if you have questions about birth control. If you plan to father a child, talk to your doctor or healthcare professional before taking ERLYAND. ERLYAND may harm your unborn baby.

Children and adolescents below 18 years of age

ERLYAND should not be used by anyone under 18 years of age because it has not been studied in this age group.

3. What if I am taking other medicines?

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

Tell your doctor if you take any of the following medicines:

  • warfarin, a medicine used to prevent blood clots
  • omeprazole, a medicine used to treat heartburn or gastric and duodenal ulcers
  • midazolam, often used as a sedative
  • rosuvastatin or gemfibrozil, medicine used to lower your lipid levels
  • fexofenadine, a medicine used to treat hay fever
  • rifampin, a medicine used to treat certain infections
  • antifungal medicines like itraconazole or ketoconazole.

ERLYAND might interact with other medicines. This may result in greater or lesser effects or even side effects from these medicines.

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

4. How do I use ERLYAND?

How much to take

  • The recommended dose of ERLYAND is one 240 mg tablet or four 60 mg tablets once a day.

When to take ERLYAND

  • Try to take ERYLAND at the same time each day. You may take them with or without food.

How to take ERLYAND

  • Swallow ERLYAND tablets whole with a glass of water.
    Do not break or chew them.

If you have trouble swallowing the tablets whole:

For a 240 mg tablet, mix with one of the following non-fizzy beverages or soft foods; orange juice, green tea, applesauce, or drinkable yogurt as follows:

  • Place the whole ERLYAND 240 mg tablet in a cup. Do not crush or split the tablet.
  • Add about 2 teaspoons (10 mL) of non-fizzy water to make sure that the tablet is completely in water.
  • Wait 2 minutes until the tablet is broken up and spread out, then stir the mixture.
  • Add in 6 teaspoons or 2 tablespoons (30 mL) of one of the following non-fizzy beverages or soft foods; orange juice, green tea, applesauce, or drinkable yogurt and stir the mixture.
  • Swallow the mixture immediately.
  • Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.
  • Do not save the medicine/food mixture for later use.

For a 240 mg tablet, give through a feeding tube:

ERLYAND 240 mg tablet may also be given through certain feeding tubes. Ask your healthcare provider for specific instructions on how to properly take the tablet through a feeding tube.

For 60 mg tablets, mix with applesauce:

  • Stir your entire dose of ERLYAND 60 mg tablets in 120 mL of applesauce. Do not crush the tablets.
  • Stir after 15 minutes
  • Stir again after 30 minutes until the tablets are well mixed with no chunks remaining.
  • Using a spoon, swallow the mixture right away.
  • Rinse the empty mixture container with 60 mL of water. Drink the water mixture and repeat the rinse with 60 mL of water one more time to make sure the medicine is swallowed completely. Drink the mixture within one hour of preparation. Do not store ERLYAND that is mixed with applesauce.

If you forget to use ERLYAND

ERLYAND should be used regularly at the same time each day. If you miss your dose at the usual time, take your normal dose as soon as possible on the same day. Return to your normal schedule on the following day.

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

If you use too much ERLYAND

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

You should immediately:

  • phone the Poisons Information Centre (in Australia telephone 13 11 26. In New Zealand telephone 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

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

5. What should I know while using ERLYAND?

Things you should do

Be sure to keep all your doctor's appointments so your progress can be checked.

Be sure to follow your doctor's instructions about other medicines you should take, and other things you should do.

Remind any doctor, dentist or pharmacist who are treating you that you are taking ERLYAND.

Things you should not do

  • Do not change your dose or stop taking ERLYAND unless your doctor tells you to.

Driving or using machines

There have been no studies on the effects of ERLYAND on the ability to drive or use machines. However, it is not anticipated that ERLYAND will affect the ability to drive and use machines.

Looking after your medicine

  • Store below 30°C. Keep tablets in the original container.

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • feeling very tired
  • nausea
  • skin rash
  • weight loss
  • hot flushes
  • hypothyroidism
  • high blood pressure
  • decreased appetite
  • water retention
  • nausea
  • diarrhoea
  • joint pain
  • fractures and falls.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Falls and fractures: ERLYAND treatment can cause bones and muscles to weaken and may increase your risk for falls and fractures. Falls and fractures have happened in people during treatment with ERLYAND. Falls were not caused by loss of consciousness (fainting) or seizures.Your healthcare provider will monitor your risks for falls and fractures during treatment with ERLYAND.
Seizure: treatment with ERLYAND may increase your risk of having a seizure. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others.Tell your healthcare provider right away if you have a loss of consciousness or seizure.
Heart disease, stroke, or mini-stroke: blockage of the arteries in the heart or in part of the brain (which can lead to death) has happened in some people during treatment with ERLYAND. If you get chest pain or discomfort (whether at rest or with activity) or shortness of breath, or if you get muscle weakness/paralysis in any part of the body, or difficulty in speaking during your treatment with ERLYAND,
Severe Cutaneous Adverse Reactions (SCAR): Severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes, and genitals (Steven-Johnson syndrome)/Life threatening rash with blisters and peeling over much of the body (toxic epidermal necrolysis) and severe rash over the body, usually with fever and swollen lymph nodes, impacting blood cells and organs (drug reaction with eosinophilia and systemic symptoms)
Interstitial lung disease: inflammation within the lungs that may lead to permanent damage.
Restless leg syndrome: Uncomfortable feeling, with an irresistible urge to move your legs, and sometimes arms and other parts of your body.		Go to the nearest emergency department right away.

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

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

Reporting side effects

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

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

7. Product details

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

What ERLYAND contains

Active ingredient
(main ingredient)		Apalutamide
60 mg or 240 mg
Other ingredients
(inactive ingredients)		ERLYAND 60 mg tablet
Tablet Core:
  • croscarmellose sodium
  • microcrystalline cellulose
  • silicified microcrystalline cellulose
  • colloidal anhydrous silica
  • hypromellose acetate succinate
  • magnesium stearate Film-coat
  • Opadry® II 85F210036 Green
ERLYAND 240 mg tablet
Tablet Core:
  • Colloidal anhydrous silica
  • Croscarmellose sodium
  • Hypromellose acetate succinate
  • Magnesium stearate
  • Silicified microcrystalline cellulose
Film-coat
  • Iron oxide black
  • glyceryl mono and dicaprylocaprate
  • Polyvinyl alcohol
  • Talc
  • Titanium dioxide
  • Macrogol poly(vinyl alcohol) grafted copolymer
Potential allergensERLYAND tablets are gluten- and lactose-free.

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

What ERLYAND looks like

ERLYAND 60 mg tablets are slightly yellowish to greyish green, oblong-shaped tablets with “AR 60” on one side. ERLYAND 60 mg tablets are supplied in bottles containing 120 tablets (AUST R 299792).

ERLYAND 240 mg tablets are bluish grey to grey, oval-shaped, film-coated tablets, debossed with “E240” on one side. ERLYAND 240 mg tablets are supplied in bottles containing 30 tablets (AUST R 408373).

Not all presentations may be available.

Who distributes ERLYAND

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Rd
Macquarie Park
NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland, New Zealand
Telephone: 0800 800 806

This leaflet was prepared in February 2024.

® ERLYAND is a registered trademark of Janssen-Cilag.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Erlyand

Active ingredient

Apalutamide

Schedule

S4

 

1 Name of Medicine

Apalutamide.

2 Qualitative and Quantitative Composition

Erlyand 60 mg tablets contain 60 mg of apalutamide.
Erlyand 240 mg tablets contain 240 mg of apalutamide.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Erlyand 60 mg tablets are slightly yellowish green to greyish green, oblong-shaped, film-coated tablets, debossed with "AR 60" on one side.
Erlyand 240 mg tablets are bluish grey to grey, oval-shaped, film-coated tablets, debossed with "E240" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Erlyand (apalutamide) is indicated for the treatment of patients with: metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic, castration-resistant prostate cancer (nmCRPC).

4.2 Dose and Method of Administration

Dose.

The recommended dose of Erlyand is 240 mg (one 240 mg tablet or four 60 mg tablets) administered orally once daily.
Patients should concurrently receive a gonadotropin-releasing hormone (GnRH) analogue, unless they have had a bilateral orchiectomy.

Method of administration.

Erlyand tablets should be administered orally once daily, with or without food. Swallow the tablets whole.
If the patient misses a dose, it should be taken as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose.
Alternative method of administration.

Disperse 240 mg tablet in water and administer with non fizzy beverage or soft food.

For patients who cannot swallow the tablet whole, the recommended dose of one Erlyand 240 mg tablet can be dispersed in non fizzy water and then mixed with one of the following non fizzy beverages or soft foods; orange juice, green tea, applesauce, or drinkable yogurt as follows:
1. Place the whole Erlyand 240 mg tablet in a cup. Do not crush or split the tablet.
2. Add about 2 teaspoons (10 mL) of non fizzy water to make sure that the tablet is completely in water.
3. Wait 2 minutes until the tablet is broken up and spread out, then stir the mixture.
4. Add in 6 teaspoons or 2 tablespoons (30 mL) of one of the following non fizzy beverages or soft foods; orange juice, green tea, applesauce, or drinkable yogurt and stir the mixture.
5. Swallow the mixture immediately.
6. Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.
Do not save the medicine/food mixture for later use (see Section 5.2 Pharmacokinetic Properties).

Administer 240 mg tablet through a feeding tube.

Erlyand 240 mg tablet can be administered through a polyurethane (PUR), silicone, or polyvinyl chloride (PVC) nasogastric feeding tube (NG tube) 8 French or greater as follows:
1. Place one 240 mg tablet in the barrel of the syringe (use at least a 20 mL syringe) and draw up 10 mL of non carbonated water into the syringe.
2. Wait 10 minutes and then shake vigorously to disperse contents completely.
3. Administer immediately through the NG feeding tube.
4. Refill the syringe with non carbonated water and administer. Repeat until no tablet residue is left in the syringe or feeding tube.

Administer 60 mg tablets with applesauce.

For patients who have difficulty swallowing tablets whole, the recommended dose of Erlyand 60 mg tablets may be mixed with 120 mL of applesauce. Do not crush the tablets. Stir applesauce upon introduction of whole tablets as well as at 15 minutes and 30 minutes afterwards until tablets are dispersed (well mixed with no chunks remaining). Using a spoon, swallow the mixture right away. Rinse the mixture container with 60 mL of water and immediately drink the contents. Repeat the rinse with 60 mL of water one more time to ensure the whole dose is taken. The mixture should be consumed within one hour of preparation. See Section 5.2 Pharmacokinetic Properties.
No clinical data for apalutamide is available with other food vehicles.

Dosage adjustment.

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse effect, hold dosing until symptoms improve to ≤ Grade 1 or original grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted.

4.3 Contraindications

Erlyand is contraindicated in women who are or may become pregnant, see Section 4.6, Use in pregnancy.

4.4 Special Warnings and Precautions for Use

Ischaemic cardiovascular events and ischaemic cerebrovascular disorders.

Ischaemic cardiovascular events and ischaemic cerebrovascular disorders, including events leading to death, occurred in patients receiving Erlyand. Monitor for signs and symptoms of ischaemic heart disease. Optimise management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidaemia. Consider discontinuation of Erlyand for Grade 3 and 4 events. See Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions.
In the SPARTAN study, with a median exposure of 32.9 months for Erlyand and 11.5 months for placebo, ischaemic cerebrovascular disorders occurred in 4% of patients treated with Erlyand and 1% of patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse events). In the TITAN study, ischaemic cerebrovascular disorders occurred in a similar proportion of patients in the Erlyand (1.5%) and placebo (1.5%) groups. Across the SPARTAN and TITAN studies, 2 patients (0.2%) treated with Erlyand and no patients treated with placebo died from an ischaemic cerebrovascular disorder.
Patients with clinically significant cardiovascular disease in the past 6 months including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g. pulmonary embolism, cerebrovascular accident including transient ischaemic attacks), or clinically significant ventricular arrhythmias were excluded from the clinical studies (SPARTAN and TITAN). Therefore, the safety of apalutamide in these patients has not been established.

Fractures.

Fractures occurred in patients receiving Erlyand. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. See Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions.

Falls.

Falls (including events leading to death) occurred in patients receiving Erlyand with increased frequency in the elderly. Evaluate patients for fall risk. See Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions.

Seizure.

Seizure occurred in patients receiving Erlyand. Permanently discontinue Erlyand in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with Erlyand and there is no clinical experience in re-administering Erlyand to patients who experienced a seizure. Advise patients of the risk of developing a seizure while receiving Erlyand and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. See Section 4.7 Effects on Ability to Drive and Use Machines; Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions.

Hypothyroidism.

Hypothyroidism occurred in patients receiving Erlyand, more commonly in patients who were already receiving thyroid replacement therapy. Initiation or adjustment of thyroid replacement therapy may be required. As levothyroxine exposure may be reduced when it is co-administered with apalutamide, evaluate for loss of levothyroxine efficacy and need for dose adjustment. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of Erlyand on other medicines; Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions.

Severe cutaneous adverse reactions (SCAR).

Rare postmarketing cases of SCAR (including drug reaction with eosinophilia and systemic symptoms [DRESS] and Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN]), which can be life-threatening or may lead to death, have been reported with androgen receptor inhibitors including Erlyand. SCAR was not reported in clinical trials TITAN and SPARTAN. Discontinue Erlyand immediately if signs or symptoms of SCAR develop.

Interstitial lung disease (ILD).

Postmarketing cases of ILD, including fatal cases, have been observed in patients treated with anti-androgens, including apalutamide. In case of acute onset and/or unexplained worsening of pulmonary symptoms, treatment with apalutamide should be interrupted pending further investigation of these symptoms. If ILD is diagnosed, apalutamide should be discontinued and further treatment with anti-androgens should be withheld (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing data).

QT interval prolongation.

In patients with a history of QT prolongation, who are taking concomitant medications that may prolong the QT interval, or who have other risk factors for torsades de pointes, consider electrocardiogram (ECG) and electrolyte monitoring. See Section 5.1, Pharmacodynamic effects.

Use in hepatic impairment.

Erlyand has not been studied in patients with severe hepatic impairment (Child-Pugh class C), see Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

Erlyand has not been studied in patients with severe renal impairment or end-stage renal disease (eGFR ≤ 29 mL/min/1.73 m2), see Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

Of the 1327 patients who received Erlyand in clinical studies 19% of patients were less than 65 years of age, 41% of patients were 65 to 74 years, and 40% were 75 years and over. Adverse events of all categories (including events that led to discontinuation, serious, severe (Grade 3 or 4) and fatal events) and deaths occurred more frequently in the oldest age group (75 years and over) compared to the younger age groups (≤ 65 years and 65 to 74 years). No overall differences in effectiveness between older patients and younger patients were observed, and age had no significant effect on pharmacokinetics (see Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric use.

The safety and efficacy of Erlyand in patients aged less than 18 years have not been established. No data are available.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on Erlyand.

CYP2C8 inhibitors.

Apalutamide Cmax decreased by 21% while AUC increased by 68% following co-administration of Erlyand as a 240 mg single dose with gemfibrozil (a strong CYP2C8 inhibitor). Gemfibrozil is predicted to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state Cmax increased by 19% and AUC by 23%.
No initial dose adjustment is necessary however, reduce the Erlyand dose based on tolerability (see Section 4.2 Dose and Method of Administration, Dosage adjustment). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide.

CYP3A4 inhibitors.

Apalutamide Cmax decreased by 22% while AUC was similar following co-administration of Erlyand as a 240 mg single dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the steady-state apalutamide Cmax by 38% and AUC by 51%. For the active moieties, the predicted steady-state Cmax increased by 23% and AUC by 28%.
No initial dose adjustment is necessary however, reduce the Erlyand dose based on tolerability (see Section 4.2 Dose and Method of Administration, Dosage adjustment). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide.

CYP3A4/CYP2C8 inducers.

Rifampin (a strong CYP3A4 and moderate CYP2C8 inducer) is predicted to decrease the steady-state apalutamide Cmax by 25% and AUC by 34%. For the active moieties, the predicted steady-state Cmax decreased by 15% and AUC by 19%.

Acid lowering agents.

Apalutamide is not ionisable under relevant physiological pH conditions, therefore acid lowering agents (e.g. proton pump inhibitors, H2-receptor antagonists, antacids) are not expected to affect the solubility and bioavailability of apalutamide.

Medications that affect transporters.

In vitro, apalutamide and its N-desmethyl metabolite are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.

Effects of Erlyand on other medicines.

Effect of Erlyand on drug metabolising enzymes.

CYP enzymes.

In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.
In humans, Erlyand is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. Co-administration of Erlyand with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate). Erlyand did not cause clinically meaningful changes in exposure to pioglitazone (a CYP2C8 substrate).
Concomitant use of Erlyand with medications that are primarily metabolised by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of efficacy if medication is continued. If given with warfarin, monitor International Normalised Ratio (INR) during Erlyand treatment.

UGT.

Apalutamide may induce UDP-glucuronosyl transferase (UGT).
Concomitant administration of Erlyand with medications that are substrates of UGT can result in lower exposure to these medications. Use caution if substrates of UGT must be co-administered with Erlyand and evaluate for loss of efficacy (see Section 4.4 Special Warnings and Precautions for Use, Hypothyroidism).
Effect of apalutamide on drug transporters.

P-gp, BCRP and OATP1B1.

Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Co-administration of Erlyand with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate) but had no impact on Cmax.
Concomitant use of Erlyand with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with Erlyand and evaluate for loss of efficacy if medication is continued.

OCT2, OAT1, OAT3 and MATEs.

In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs), and do not inhibit organic anion transporter 1. Apalutamide is not predicted to cause clinically significant changes in exposure to OAT3 substrates.
Gonadotropin-releasing hormone (GnRH) analogue. In subjects with mCSPC receiving leuprolide acetate (a GnRH analogue), co-administration of apalutamide had no apparent effect on the steady-state exposure of leuprolide.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on animal studies, apalutamide may impair fertility in males of reproductive potential.
Male fertility is likely to be impaired by treatment with apalutamide based on findings in repeat-dose toxicology studies which were consistent with the pharmacological activity of apalutamide. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy, aspermia/hypospermia, degeneration and/or hyperplasia or hypertrophy in the reproductive system were observed at ≥ 25 mg/kg/day in rats (0.5 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.5 times the human exposure based on AUC).
In a fertility study in male rats, a decrease in sperm concentration and motility, copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.5 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.
(Category D)
Erlyand is contraindicated in women who are or may become pregnant. Based on its mechanism of action, Erlyand may cause fetal harm when administered during pregnancy. There are no data available with the use of Erlyand during pregnancy in humans.
Erlyand may be harmful to a developing fetus. Patients having sex with female partners of reproductive potential should use a condom along with another highly effective contraceptive method during treatment and for 3 months after the last dose of Erlyand.
In a development toxicity study in the rat, early embryonic loss was seen with apalutamide at 50 and 100 mg/kg/day (equivalent to 4 and 5 times the human exposure based on AUC). In addition, a disturbance of the normal embryofetal development was observed at ≥ 25 mg/kg/day (2 times the human exposure based on AUC), evidenced by a shortening of anogenital distance, misshapen (rounded) pituitary gland, severely dilated and/or convoluted ureter, and skeletal abnormalities (misshapen/small hyoid, incomplete/unossified bones).
 Erlyand is not indicated for use in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed infant, or the effect on milk production.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Erlyand on the ability to drive or use machines have been performed. Patients with a history of seizures or other predisposing factors should be advised of the risk of driving or operating machines (see Section 4.4 Special Warnings and Precautions for Use, Seizure).

4.8 Adverse Effects (Undesirable Effects)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions (≥ 10%) that occurred more frequently in Erlyand-treated patients (≥ 2% over placebo) in two randomised clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhoea, and fracture.
TITAN and SPARTAN were double-blind, placebo-controlled, multi-centre clinical studies in which patients with mCSPC (TITAN) or nmCRPC (SPARTAN) were randomised (1:1 and 2:1, respectively) to receive either Erlyand 240 mg daily or placebo. All patients received a concomitant gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy.
The median duration of exposure in TITAN was 20 months (range: 0 to 34 months) in patients who received Erlyand and 18 months (range: 0.1 to 34 months) in patients who received placebo.
The median duration of exposure in SPARTAN was 16.9 months (range: 0.1 to 42 months) in patients who received Erlyand and 11.2 months (range: 0.1 to 37 months) in patients who received placebo.
In TITAN, ten patients (2%) who were treated with Erlyand died from adverse reactions. The reasons for death were ischaemic cardiovascular events (n=3), acute kidney injury (n=2), cardiorespiratory arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal ulcer perforation (n=1). Erlyand was discontinued due to adverse reactions in 8% of patients, most commonly from rash (2%). Adverse reactions leading to dose interruption or reduction of Erlyand occurred in 23% of patients; the most frequent (> 1%) were rash, fatigue, and hypertension. Serious adverse reactions occurred in 20% of Erlyand-treated patients and 20% in patients receiving placebo.
In SPARTAN, 8 patients (1%) who were treated with Erlyand died from adverse reactions. The reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral haemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). Erlyand was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or reduction of Erlyand occurred in 33% of patients; the most common (> 1%) were rash, diarrhoea, fatigue, nausea, vomiting, hypertension, and haematuria. Serious adverse reactions occurred in 25% of Erlyand-treated patients and 23% in patients receiving placebo. The most common serious adverse reactions (≥ 2%) were fracture (3%) in the Erlyand arm and urinary retention (4%) in the placebo arm.
Table 1 shows adverse reactions commonly (≥ 1/100 to < 1/10) occurring in Erlyand-treated patients in TITAN and SPARTAN that occurred with a ≥ 2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥ 15% of patients, and more frequently (> 5%) in the Erlyand arm compared to placebo.
Additional clinically significant adverse reactions occurring in at least 2% of patients treated with Erlyand in the SPARTAN study included:
Depression - 3.9% versus 2.0% on placebo (includes depression, major depression and suicidal ideation).
Heart failure - 2.2% versus 1.0% on placebo.
White blood cell count decrease and hypertriglyceridaemia were also more common in the Erlyand arm compared to placebo in the TITAN study.

Description of selected adverse reactions.

Ischaemic cardiovascular events.

In a randomised study in patients with nmCRPC (SPARTAN), ischaemic cardiovascular events occurred in 4% of patients treated with Erlyand and 3% of patients treated with placebo. In a randomised study in patients with mCSPC (TITAN), ischaemic cardiovascular events occurred in 4% of patients treated with Erlyand and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with Erlyand and 2 patients (0.2%) treated with placebo died from an ischaemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomisation were excluded from the SPARTAN and TITAN studies.
See Section 4.4 Special Warnings and Precautions for Use.

Fractures.

In a randomised study in patients with nmCRPC (SPARTAN), fractures occurred in 12% of patients treated with Erlyand and in 7% of patients treated with placebo. Grade 3-4 fractures occurred in 3% of patients treated with Erlyand and in 1% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with Erlyand.
In a randomised study in patients with mCSPC (TITAN), fractures occurred in 9% of patients treated with Erlyand and in 6% of patients treated with placebo. Grade 3-4 fractures were similar in both arms at 2%. The median time to onset of fracture was 56 days (range: 2 to 111 days) for patients treated with Erlyand.
Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN or TITAN studies.
See Section 4.4 Special Warnings and Precautions for Use.

Falls.

In a randomised study in patients with nmCRPC (SPARTAN), falls were reported for 16% of subjects treated with Erlyand versus 9% of subjects treated with placebo, and were not associated with loss of consciousness or seizure. Falls in patients receiving Erlyand with androgen deprivation therapy were more frequent in the elderly, occurring across the SPARTAN and TITAN studies in 8% of patients younger than 65 years, 10% of patients 65-74 years, and 19% of patients 75 years or older.
In a randomised study in patients with mCSPC (TITAN), rates of falls were similar between the Erlyand arm (7.4%) and placebo arm (7.0%).
See Section 4.4 Special Warnings and Precautions for Use.

Seizure.

In two randomised studies (SPARTAN and TITAN), five patients (0.4%) treated with Erlyand and one patient (0.1%) treated with placebo experienced a seizure. Seizure occurred from 159 to 650 days after initiation of Erlyand. Patients with a history of seizure, with predisposing factors for seizure, or receiving drugs known to decrease seizure threshold or induce seizures were excluded from both studies.
See Section 4.4 Special Warnings and Precautions for Use.

Hypothyroidism.

In the combined data of two randomised, placebo-controlled studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of subjects treated with Erlyand and 2% of subjects treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. The median onset was Day 113. There were no grade 3 or 4 adverse reactions.
In patients who were already receiving thyroid replacement therapy, hypothyroidism occurred in 30% of subjects in the apalutamide arm and in 3% of subjects in the placebo arm. In subjects not previously receiving thyroid replacement therapy, hypothyroidism occurred in 7% of subjects treated with apalutamide and in 2% of subjects treated with placebo.
Thyroid replacement therapy was initiated in 7% of patients treated with Erlyand. In patients who discontinued Erlyand and had a reported event of hypothyroidism (n=14), the event resolved in 5 patients (36%). In patients who discontinued Erlyand and had increased laboratory values for TSH (> 5.5 mIU/L) (n=45), TSH levels returned to normal in 27 patients (60%).
See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effect of Erlyand on drug metabolising enzymes.

Skin rash.

In the combined data of two randomised, placebo-controlled clinical studies (SPARTAN and TITAN), skin rash associated with Erlyand was most commonly described as macular or maculo-papular. Adverse reactions of skin rash were reported for 26% of subjects treated with Erlyand versus 8% of subjects treated with placebo. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) were reported with Erlyand treatment (6%) versus placebo (0.5%). Drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (SJS) were not seen in these trials (n=1327), but cases consistent with severe cutaneous adverse reactions have been reported post-marketing.
The onset of skin rash occurred at a median of 83 days of Erlyand treatment and resolved in 78% of patients, within a median of 78 days from onset (range: 2 to 709 days). Rash was commonly managed with oral antihistamines, topical corticosteroids and 19% of subjects received systemic corticosteroids. Rash led to dose interruption in 28%, dose reduction in 14% and treatment discontinuation in 7% of cases. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of Erlyand.

Post-marketing data.

Adverse events identified during post-marketing experience are presented below with frequency category estimated from spontaneous reporting rates. The frequencies are provided according to the following convention:
Very common: ≥ 1/10; Common: ≥ 1/100 and < 1/10; Uncommon: ≥ 1/1,000 and < 1/100; Rare: ≥ 1/10,000 and < 1/1,000; Very rare: < 1/10,000; Not known: Cannot be estimated from the available data.

Metabolism and nutrition disorders.

Decreased appetite: Uncommon.

Nervous system disorder.

Restless leg syndrome: Very rare.

Respiratory, thoracic and mediastinal disorders.

Interstitial lung diseasea: Uncommon.

Skin and subcutaneous tissue disorders.

Drug reaction with eosinophilia and systemic symptomsa,b: Rare.
Toxic epidermal necrolysisa,b: Rare.
Stevens-Johnson syndromea,b: Rare.
a The adverse reaction was not identified from clinical trials.
b See Section 4.4 Special Warnings and Precautions for Use.

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

4.9 Overdose

Treatment.

There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop Erlyand, undertake general supportive measures until clinical toxicity has been diminished or resolved. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Apalutamide is an orally administered, Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide prevents AR nuclear translocation, inhibits DNA binding, impedes AR-mediated transcription, and lacks androgen receptor agonist activity in preclinical studies. A major metabolite, N-desmethyl apalutamide, exhibited one-third the in vitro activity of apalutamide in an in vitro transcriptional reporter assay. In mouse models of prostate cancer, apalutamide administration causes decreased tumour cell proliferation and increased apoptosis leading to tumour growth inhibition and regression.

Pharmacodynamic effects.

Effect on GABAA-gated chloride channel.

GABAA inhibition is an off-target activity of both apalutamide and N-desmethyl apalutamide. This is considered the mechanism for the seizures/convulsions observed at high doses in toxicology studies in animals.

Effect on QT/QTc interval and cardiac electrophysiology.

Apalutamide and N-desmethyl apalutamide inhibit the hERG K+ channel with an IC50 below steady-state Cmax at the recommended dose. In a dedicated QT study in men with CRPC administered apalutamide 240 mg once daily plus ADT, based on the longest QTcF change at any time for each patient at steady-state, the mean maximum QTcF change from baseline (ΔQTcF) was 20.2 msec (upper 90% CI bound 23.7 msec). Pharmacokinetic and pharmacodynamic analysis showed a concentration-dependent increase in QTcF with apalutamide and N-desmethyl apalutamide. See Section 4.4 Special Warnings and Precautions for Use.

Clinical trials.

The efficacy of Erlyand was established in two randomised placebo-controlled multicentre clinical studies of subjects with mCSPC (TITAN) or nmCRPC (SPARTAN). All subjects in these studies received concomitant GnRH analogue or had prior bilateral orchiectomy.

TITAN: metastatic castration-sensitive prostate cancer (mCSPC).

TITAN (56021927PCR3002) was a randomised, double-blind, placebo-controlled, multinational, multicentre clinical trial in which 1052 subjects with mCSPC were randomised (1:1) to receive either Erlyand orally at a dose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All subjects in the TITAN trial received concomitant GnRH analogue or had prior bilateral orchiectomy. Subjects were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Subjects with both high- and low-volume mCSPC were eligible for the study. High volume of disease was defined as metastases involving the viscera with 1 bone lesion or the presence of 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bones.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 68 years (range 43-94) and 23% of subjects were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent of subjects had high-volume disease and 37% had low-volume disease. Sixteen percent of subjects had prior surgery, radiotherapy of the prostate or both. A majority of subjects had a Gleason score of 8 or higher (67%). Sixty-eight percent of subjects received prior treatment with an anti-androgen (bicalutamide, flutamide, or nilutamide). All subjects except one in the placebo group, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry.
The major efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (rPFS). An updated OS analysis was conducted at the time of final study analysis when 405 deaths were observed with a median follow-up of 44 months. Results from this updated analysis were consistent with those from the pre specified interim analysis. Radiographic progression-free survival was based on investigator assessment and was defined as time from randomisation to radiographic disease progression or death. Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease.
A statistically significant improvement in OS and rPFS was demonstrated in subjects randomised to receive Erlyand compared with subjects randomised to receive placebo. The improvement in OS was demonstrated even though 39% of subjects in the placebo arm crossed over to receive Erlyand, with a median treatment duration of 15 months after crossover to Erlyand. Efficacy results of TITAN are summarised in Table 3 and Figures 1 and 2.
Consistent improvement in rPFS and OS was observed between subgroups based on disease volume (high vs low) and Gleason score at diagnosis (≤ 7 vs. > 7).
Treatment with Erlyand statistically significantly delayed the initiation of cytotoxic chemotherapy (HR = 0.47, 95% CI = 0.35, 0.63; p < 0.0001).

SPARTAN: non-metastatic, castration-resistant prostate cancer (nmCRPC).

SPARTAN (Study ARN 509-003) was a multicentre, double-blind, randomised, placebo-controlled clinical trial in which 1207 subjects with nmCRPC were randomised 2:1 to receive either Erlyand orally at a dose of 240 mg once daily (n=806) or placebo once daily (n=401). All patients received a concomitant gonadotropin-releasing hormone (GnRH) analogue, or had a bilateral orchiectomy. Patients were required to have a Prostate Specific Antigen (PSA) Doubling Time (PSADT) ≤ 10 months and confirmation of non-metastatic disease by blinded independent central review (BICR). Patients with pelvic lymph nodes < 2 cm in short axis (N1) located below the iliac bifurcation could enter the SPARTAN study. Patients were stratified by PSADT (> 6 months vs ≤ 6 months), the use of bone-sparing agents, and presence of locoregional disease. Systemic corticosteroids were not allowed at study entry. PSA results were blinded and were not used for treatment discontinuation. Subjects randomised to either arm discontinued treatment for disease progression confirmed by BICR, initiation of new treatment, unacceptable toxicity or withdrawal. Upon development of distant metastatic disease, subjects were offered abiraterone acetate as an option for the first subsequent treatment after study treatment discontinuation.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years (range 48-97) and 26% of subjects were 80 years of age or older. The racial distribution was 66% Caucasian, 5.6% Black, 12% Asian, and 0.2% Other. Seventy-seven percent (77%) of subjects in both treatment arms had prior surgery or radiotherapy of the prostate. A majority of subjects had a Gleason score of 7 or higher (81%). Fifteen percent (15%) of subjects had < 2 cm pelvic lymph nodes at study entry. In the SPARTAN study, metastases were detected by technetium-99m bone scan, CT or MRI of the chest, abdomen and pelvis. Seventy-three percent (73%) of subjects had received prior treatment with a first-generation anti-androgen; 69% of subjects had received bicalutamide and 10% of subjects had received flutamide. All subjects enrolled had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) performance status score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 279 for placebo and N = 314 for Erlyand), a greater proportion (80%) of patients treated with placebo received subsequent therapy compared to patients treated with Erlyand (56%). Locoregional-only progression occurred in 2% of patients overall.
The primary efficacy outcome was metastasis-free survival (MFS), defined as the time from randomisation to the time of first evidence of BICR-confirmed distant metastasis (defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation) or death due to any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS) which also includes locoregional progression, and overall survival (OS).
A statistically significant improvement in MFS was demonstrated in patients randomised to receive Erlyand compared with patients randomised to receive placebo. Consistent results were observed across patient subgroups including PSADT (≤ 6 months or > 6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1). The primary efficacy outcome was supported by statistically significant improvements in TTM, PFS, and time to symptomatic progression. In addition, overall survival (OS) and time to initiation of cytotoxic chemotherapy were also significantly improved. (See Table 4 for final analysis).
Efficacy results of SPARTAN are summarised in Table 4 and Figures 3 and 4.
The final analysis corroborated that treatment with Erlyand decreased the risk of symptomatic progression by 43% compared with placebo. The observed p-value (0.00000356) crossed the Obrien-Fleming (OBF) efficacy boundary (p=0.00008) for significance (see Table 4).
At the final analysis, with median follow-up time of 52.0 months, results showed that treatment with Erlyand significantly decreased the risk of death by 22% compared with placebo (HR=0.784; 95% CI: 0.643, 0.956; 2 sided p=0.0161). The median OS was 73.9 months for the Erlyand arm and 59.9 months for the placebo arm. The pre specified alpha boundary (p ≤ 0.046) for this final analysis was crossed and statistical significance was achieved.
At the final analysis, treatment with Erlyand significantly decreased the risk of initiating cytotoxic chemotherapy by 37% compared with placebo (HR=0.629; 95% CI: 0.489, 0.808; p=0.0002) demonstrating statistically significant improvement for Erlyand versus placebo. The median time to the initiation of cytotoxic chemotherapy was not reached for either treatment arm.
If eligible and without evidence of disease progression, subjects treated with placebo were given the opportunity to cross-over to treatment with Erlyand at time of unblinding. After unblinding, 19% of the randomized placebo population crossed over to Erlyand. Of all the randomized subjects, a greater proportion of subjects in the placebo arm received subsequent therapy (285/401, 71%) compared with the Erlyand arm (386/806, 48%).
Final analysis of PFS-2 confirmed a 44% reduction in risk of PFS-2 with Erlyand versus placebo (HR=0.565; 95% CI: 0.471, 0.677; p < 0.0001).
There were no detrimental effects to overall health-related quality of life with the addition of Erlyand to placebo and a small but not clinically meaningful difference in change from baseline in favor of Erlyand observed in the analysis of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score and subscales.

5.2 Pharmacokinetic Properties

Apalutamide pharmacokinetic parameters are presented as the mean (coefficient of variation; CV%) unless otherwise specified. Following repeat once-daily dosing, apalutamide exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 30 mg to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. At steady-state, apalutamide Cmax was 6 microgram/mL (28%) and AUC was 100 microgram.h/mL (32%). Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism.
At steady-state, the major active metabolite (N-desmethyl apalutamide) Cmax and was 5.9 microgram/mL (18%) and AUC was 124 microgram.h/mL (19%). N-desmethyl apalutamide is characterised by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. The AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat dose administration was about 1.3 (21%). Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributes to the clinical activity of apalutamide.

Absorption.

Mean absolute oral bioavailability is approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours).
Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal resulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayed about 2 hours with food.
Following oral administration of 4 x 60 mg apalutamide tablets dispersed in applesauce, Cmax and AUC were 28% and 5% higher, respectively, when compared to administration of 4 intact 60 mg tablets under fasting condition, see Section 4.2 Dose and Method of Administration.

Distribution.

The mean apparent volume of distribution at steady-state of apalutamide is about 276 L (greater than the volume of total body water, indicative of extensive extravascular distribution).
Apalutamide is 96% (and N-desmethyl apalutamide is 95%) bound to plasma proteins, with no concentration dependency. Studies in rodents and dogs indicate that apalutamide and N-desmethyl apalutamide can cross the blood brain barrier.

Metabolism.

Metabolism is the main route of elimination of apalutamide. It is metabolised primarily by CYP2C8 and CYP3A4 to form N-desmethyl apalutamide. Apalutamide and N-desmethyl apalutamide are further metabolised by carboxylesterase to form an inactive carboxylic acid metabolite. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
Apalutamide (45%), N-desmethyl apalutamide (44%), and an inactive carboxylic acid metabolite (3%) represented most of the total 14C-AUC following a single oral administration of 14C-labeled apalutamide 240 mg.

Excretion.

Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in faeces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide).
The CL/F of apalutamide is 1.3 L/h after single dosing and increases to 2.0 L/h at steady-state after once-daily dosing. The mean effective half-life for apalutamide in subjects is about 3 days at steady-state.

Special populations.

No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18-94 years), race (Black, non-Japanese Asian, Japanese), mild to moderate renal impairment (eGFR 30-89 mL/min/1.73 m2, estimated by the modification of diet in renal disease [MDRD] equation) or mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment.
The effect of severe renal impairment or end stage renal disease (eGFR ≤ 29 mL/min/1.73 m2) or severe hepatic impairment (Child-Pugh Class C) on apalutamide pharmacokinetics is unknown.

5.3 Preclinical Safety Data

Genotoxicity.

Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration test in human lymphocytes, the in vivo rat micronucleus assay or the in vivo rat Comet assay.

Carcinogenicity.

Apalutamide was not carcinogenic in a 6-month study in the male transgenic (Tg.rasH2) mouse at oral doses up to 30 mg/kg/day. However, maximum tested exposures were low for apalutamide and subclinical for the metabolite M3 (up to 1 and 0.4 times the human exposure based on AUC respectively). Results of a 24-month carcinogenicity study in the male rat are not yet available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Erlyand 60 mg film-coated tablets contain the following excipients.

Tablet core.

Colloidal anhydrous silica, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, silicified microcrystalline cellulose.

Film-coat.

Opadry II 85F210036 Green.

Erlyand 240 mg film-coated tablets contain the following excipients.

Tablet core.

Colloidal anhydrous silica, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, silicified microcrystalline cellulose.

Film-coat.

Iron oxide black, glyceryl mono and dicaprylocaprate, polyvinyl alcohol, purified talc, titanium dioxide, macrogol poly(vinyl alcohol) grafted copolymer.

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. Keep out of the sight and reach of children. Protect from moisture.

6.5 Nature and Contents of Container

Erlyand 60 mg tablets are available in opaque, high-density polyethylene bottles with child-resistant polypropylene closure and induction seal liner. Each bottle contains 120 tablets and a desiccant.
Erlyand 240 mg tablets are available in opaque, high-density polyethylene bottles with child-resistant polypropylene closure and induction seal liner. Each bottle contains 30 tablets and a desiccant.
Not all presentations may be available.

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 structure.


CAS number.

956104-40-8.
The drug substance has a dissociation constant pKa of 9.7 (acidic carboxamide moiety) and is practically insoluble in aqueous media over a wide range of pH values and practically insoluble to very soluble in organic solvents. The Log P at 20°C between 1-octanol and an aqueous buffered solution (pH 7.0) is 2.89. The Log D at 20°C between 1-octanol and aqueous buffered solutions (pH 1.0, 4.0 and 7.0) is 2.86, 2.80 and 2.89 respectively. Molecular formula: C21H15F4N5O2S. Molecular weight: 477.43.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine.

Summary Table of Changes