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A - Drug Name

apalutamide

COMMON TRADE NAME(S):   Erleada® ()

 
B - Mechanism of Action and Pharmacokinetics

Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the AR ligand-binding domain to inhibit nuclear translocation, DNA binding, and AR-mediated transcription resulting in tumor growth inhibition and regression.



Absorption
Bioavailability

100%.  Apalutamide is completely absorbed after oral administration.

Time to reach steady state

2 hours

Effects with food

Food administration has no significant effect on apalutamide exposure, however the median time to reach tmax was delayed approximately 2 hours with food. 

 

Time to reach steady state

4 weeks; accumulates approximately 5x relative to a single dose.


Distribution
Cross blood brain barrier?

Apalutamide and N-desmethyl apalutamide has been observed to cross the blood brain barrier in animal studies.

PPB

96% Apalutamide; 95% N-desmethyl apalutamide

Metabolism
Active metabolites

44% N-desmethyl apalutamide

Elimination

Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form the active metabolite N-desmethyl apalutamide.

Urine

65%; 1.2% as apalutamide and 2.7% as N-desmethyl apalutamide

Feces

24%; 1.5% as apalutamide and 2% as N-desmethyl apalutamide

Half-life

~ 3 days

 
C - Indications and Status
Health Canada Approvals:

For the treatment of patients with non-metastatic castration-resistant prostate cancer (NM-CRPC).



 
D - Adverse Effects

Extravasation Potential:   Not applicable

The following adverse effects were reported in ≥ 10% of patients in the phase III trial comparing apalutamide with androgen deprivation therapy (ADT) to placebo with ADT, where incidence was at least 2% or more compared to placebo. Severe adverse effects from other studies or post-marketing may also be included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism (4%) E
Cardiotoxicity (2%) E
Hypertension (25%) E
QT interval prolonged (rare) E
Dermatological Rash (24%) (5% severe) D
Gastrointestinal Anorexia, weight loss (16%) E
Diarrhea (20%) E
Nausea (18%) E
General Edema (11%) E
Fall (16%) E  D
Fatigue (39%) E
Hematological Anemia (70%) (mild) E  D
Myelosuppression (47%) (mild) E
Metabolic / Endocrine ↑ Cholesterol (76%) (non-fasting) E
Hyperglycemia (70%) (non-fasting) E
Hypothyroidism (8%) E  D
↑ K (32%) E
Musculoskeletal Arthralgia (16%) E
Fracture (12%) D
Nervous System Seizure (<1%) E
Syncope (2%) E
Reproductive and breast disorders Androgen deprivation symptoms (14%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for apalutamide include ↑ cholesterol, anemia, hyperglycemia, myelosuppression, fatigue, ↑ K, hypertension, rash, diarrhea and nausea.

Rash (usually macular or maculopapular) onset typically occurred at a median of 82 days with resolution within a median of 60 days in most patients. Rash recurred in approximately half of patients who were re-challenged with apalutamide.

Hypothyroidism has been reported with apalutamide. Interactions between apalutamide and thyroxine have been reported.

Fall and fractures have been observed in patients receiving apalutamide. The median time to onset of fracture was approximately 10 months. Patients at risk for fractures should be monitored and managed according to established management guidelines. Consider the use of bone targeted agents.

Seizures were observed and may be related to off target effects on GABAA gated channels.

 
E - Dosing

Refer to protocol by which patient is being treated. 



Adults:

  • Patients should also receive a gonadotropin-releasing hormone (GnRH) analog unless they have had a bilateral orchiectomy.

  • Patients should be assessed for the risk of fracture and fall and managed according to guidelines.


Oral: 240 mg (4 x 60mg tablets) Daily

Dosage with Toxicity:

Dose Level Apalutamide Dose (mg/day)
0 240
-1 180
-2 120
-3 Discontinue 

 

Toxicity Action
Intolerable or ≥ Grade 3 Hold until recover to ≤ Grade 1, resume at the same dose or at ↓ 1 dose level.
If the toxicity recurs at ≥ Grade 3, ↓ 1 dose level.

Seizure

Permanently discontinue.

 



Dosage with Hepatic Impairment:

Hepatic Impairment Action
Mild or moderate No adjustment required
Severe No data


Dosage with Renal Impairment:

Renal Impairment Action
 Mild to moderate (CrCL ≥ 30 mL/min) No adjustment required
Severe (CrCL ≤ 29 mL/min) No data


Dosage in the elderly:

No dose adjustment is necessary for elderly patients. Patients ≥ 65 years treated with apalutamide experienced higher toxicity and lower tolerance. Monitor elderly patients more closely for toxicity and adjust dose when needed.



Dosage based on ethnicity:

There is no clinically relevant difference in exposure between White (Caucasian or Hispanic or Latino), Black (of African heritage or African American), Asian (non-Japanese), or Japanese patients. No dose adjustments are necessary.



Children:

Safety and effectiveness of apalutamide in pediatric patients have not been evaluated.



 
F - Administration Guidelines
  • Tablets should be swallowed whole with a glass of water.

  • Tables can be taken with or without food.

  • Take the dose at around the same time each day.

  • A missed dose 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.

  • Store at 15°C to 30°C, in the original package to protect from light and moisture.

  • If tablets are provided in a bottle, do not remove the silica gel desiccant from the bottle.

 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

  • Women who are or may become pregnant.

Other Warnings/Precautions:

Exercise caution in patients with:

  • Cardiac disorders. 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 or clinically significant ventricular arrhythmias were excluded from clinically trials.

  • Seizures. Patients with a history of seizures or predisposing factors for seizures were excluded from clinical studies; patients on medications known to lower seizure threshold were prohibited while receiving apalutamide.

  • QT prolongation, risk factors for Torsade de pointes or on medications known to prolong QTc.


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Abortifacient effects: Probable
  • Genotoxicity: No
  • Embryotoxicity: Likely

    Apalutamide is not recommended for use in pregnancy. Adequate contraception should be used by both sexes of childbearing potential during treatment, and for at least 3 months after the last dose.

  • Breastfeeding: Unknown

    Apalutamide is not indicated for use in females. There are no data on the presence of apalutamide or its metabolites in human milk.

  • Fertility effects: Documented in animals
 
H - Interactions

  • In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP2B6 inducers and moderate inhibitors of CYP2B6.

  • Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl apalutamide cannot be excluded.

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

AGENT EFFECT MECHANISM MANAGEMENT
CYP 2C8 strong inhibitors (i.e. gemfibrozil) ↑ apalutamide concentration ↓ metabolism of apalutamide Caution; consider dose adjustment for apalutamide based on tolerability.
CYP3A4 strong inhibitors (i.e. itraconazole, clarithromycin, ritonavir, nelfinavir, etc.) ↑ apalutamide concentration ↓ metabolism of apalutamide Caution; consider dose adjustment for apalutamide based on tolerability.
CYP3A4 strong inducers (i.e. phenytoin, rifampin, carbamazepine, phenobarbital, St. John’s Wort, etc.) ↓ apalutamide concentration ↑ metabolism of apalutamide Caution, no adjustment needed.
CYP 2C8 strong inducers (i.e. rifampicin, phenobarbital) ↓ apalutamide concentration ↓ metabolism of apalutamide Caution, no adjustment needed.
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Avoid or substitute if possible. Evaluate for loss of efficacy if medication is continued.
CYP 2C19 substrates (e.g. omeprazole) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Avoid or substitute if possible. Evaluate for loss of efficacy if medication is continued.
CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Avoid or substitute if possible; if not possible monitor closely (e.g. INR).
CYP 2C8 substrates (i.e. paclitaxel, sorafenib, amiodarone) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution; no adjustment needed.
P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution; evaluate for loss of efficacy if medication is continued.
BCRP substrates (i.e. topotecan) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution; evaluate for loss of efficacy if medication is continued.
OATP1B1 substrates (i.e. rosuvastatin) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution; evaluate for loss of efficacy if medication is continued.
UGT substrates (i.e. estradiol, irinotecan, levothyroxine, thyroxine) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution; evaluate for loss of efficacy if medication is continued.
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc.) ↑ risk of QT prolongation and arrhythmias Additive Caution
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

TSH

Baseline and as clinically indicated

ECG

Baseline and as clinically indicated; more frequent in patients at risk of QTc increase

INR

If warfarin cannot be discontinued; baseline and during apalutamide treatment

Clinical toxicity assessment for androgen withdrawal effects, fatigue, infection, active cardiac disease, seizure, dermatologic toxicity and risk of fracture and falls

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

Erleada™ (apalutamide) product monograph. Toronto, Ontario, Canada: Janssen Inc; July 2018.


 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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