ERLEADA SIDE EFFECTS
- Generic Name: apalutamide tablets
- Brand Name: Erleada
- Drug Class: Antineoplastics, Antiandrogen, Antiandrogens
SIDE EFFECTS
The following are discussed in more detail in other sections of the labeling:
- Cerebrovascular and Ischemic Cardiovascular Events
- Fractures
- Falls
- Seizure
Clinical Trial Experience
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 the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.
Metastatic Castration-Sensitive Prostate Cancer (mCSPC)
TITAN, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had mCSPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or placebo. All patients in the TITAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. The median duration of exposure was 20 months (range: 0 to 34 months) in patients who received ERLEADA and 18 months (range: 0.1 to 34 months) in patients who received placebo.
Ten patients (2%) who were treated with ERLEADA died from adverse reactions. The reasons for death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardio-respiratory arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal ulcer perforation (n=1). ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly from rash (2%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 23% of patients; the most frequent (>1%) were rash, fatigue, and hypertension. Serious adverse reactions occurred in 20% of ERLEADA-treated patients and 20% in patients receiving placebo.
Table 1 shows adverse reactions occurring in ≥10% on the ERLEADA arm in TITAN 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 ERLEADA arm compared to placebo.
Table 1: Adverse Reactions in TITAN (mCSPC)
| System/Organ Class | ERLEADA N=524 |
Placebo N=527 |
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| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| Adverse reaction | % | % | % | % |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgiaa | 17 | 0.4 | 15 | 0.9 |
| Skin and subcutaneous tissue disorders | ||||
| Rashb | 28 | 6 | 9 | 0.6 |
| Pruritus | 11 | <1 | 5 | <1 |
| Vascular disorders | ||||
| Hot flush | 23 | 0 | 16 | 0 |
| Hypertension | 18 | 8 | 16 | 9 |
| aPer the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 bIncludes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular |
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Additional adverse reactions of interest occurring in 2%, but less than 10% of patients treated with ERLEADA included diarrhea (9% versus 6% on placebo), muscle spasm (3% versus 2% on placebo), dysgeusia (3% versus 1% on placebo), and hypothyroidism (4% versus 1% on placebo).
Table 2: Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in TITAN (mCSPC)
| ERLEADA N=524 |
Placebo N=527 |
|||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| Laboratory Abnormality | % | % | % | % |
| Hematology | ||||
| White blood cell decreased | 27 | 0.4 | 19 | 0.6 |
| Chemistry | ||||
| Hypertriglyceridemiaa | 17 | 3 | 12 | 2 |
| aDoes not reflect fasting values | ||||
Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)
SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had nmCRPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 33 months (range: 0.1 to 75 months) in patients who received ERLEADA and 11 months (range: 0.1 to 37 months) in patients who received placebo.
Twenty-four patients (3%) who were treated with ERLEADA died from adverse reactions. The reasons for death with ≥ 2 patients included infection (n=7), myocardial infarction (n=3), cerebrovascular event (n=2), and unknown reason (n=3). ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of ERLEADA-treated patients and 23% in patients receiving placebo. The most frequent serious adverse reactions (>2%) were fracture (3%) in the ERLEADA arm and urinary retention (4%) in the placebo arm.
Table 3 shows adverse reactions occurring in ≥10% on the ERLEADA arm in SPARTAN that occurred with a ≥2% absolute increase in frequency compared to placebo. Table 4 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the ERLEADA arm compared to placebo.
Table 3:Adverse Reactions in SPARTAN (nmCRPC)
| ERLEADA N=803 |
Placebo N=398 |
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| System/Organ Class | All Grades | Grade 3-4 | All Grades | Grade 3-4 |
| Adverse reaction | % | % | % | % |
| General disorders and administration site conditions | ||||
| Fatiguea,b | 39 | 1 | 28 | 0.3 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgiab | 16 | 0 | 8 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rashc | 25 | 5 | 6 | 0.3 |
| Metabolism and nutrition disorders | ||||
| Decreased appetited | 12 | 0.1 | 9 | 0 |
| Peripheral edemae | 11 | 0 | 9 | 0 |
| Injury, poisoning and procedural complications | ||||
| Fallb | 16 | 2 | 9 | 0.8 |
| Fracturef | 12 | 3 | 7 | 0.8 |
| Investigations | ||||
| Weight decreasedb | 16 | 1 | 6 | 0.3 |
| Vascular disorders | ||||
| Hypertension | 25 | 14 | 20 | 12 |
| Hot flush | 14 | 0 | 9 | 0 |
| Gastrointestinal disorders | ||||
| Diarrhea | 20 | 1 | 15 | 0.5 |
| Nausea | 18 | 0 | 16 | 0 |
| aIncludes fatigue and asthenia bPer the Common Terminology Criteria for Adverse Reactions (CTCAE), the highest severity for these events is Grade 3 cIncludes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, dermatitis, and rash vesicular dIncludes appetite disorder, decreased appetite, early satiety, and hypophagia eIncludes peripheral edema, generalized edema, edema, edema genital, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema fIncludes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebral fracture, upper limb fracture, fractured sacrum, hand fracture, pubis fracture, acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bones fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibula fracture, fractured coccyx, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture, and tibia fracture |
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Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ERLEADA included hypothyroidism (8% versus 2% on placebo), pruritus (6% versus 2% on placebo), and heart failure (2% versus 1% on placebo).
Table 4: Laboratory Abnormalities Occurring in ≥ 15% of ERLEADA-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in SPARTAN (nmCRPC)
| ERLEADA N=803 |
Placebo N=398 |
|||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| Laboratory Abnormality | % | % | % | % |
| Hematology | ||||
| Anemia | 70 | 0.4 | 64 | 0.5 |
| Leukopenia | 47 | 0.3 | 29 | 0 |
| Lymphopenia | 41 | 2 | 21 | 2 |
| Chemistry | ||||
| Hypercholesterolemiaa | 76 | 0.1 | 46 | 0 |
| Hyperglycemiaa | 70 | 2 | 59 | 1 |
| Hypertriglyceridemiaa | 67 | 2 | 49 | 0.8 |
| Hyperkalemia | 32 | 2 | 22 | 0.5 |
| a Does not reflect fasting values | ||||
Rash
In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, rash associated with ERLEADA was most commonly described as macular or maculopapular. Adverse reactions of rash were reported for 26% of patients treated with ERLEADA versus 8% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (6%) versus placebo (0.5%).
The onset of rash occurred at a median of 83 days of ERLEADA treatment. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA.
Hypothyroidism
In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 5% of patients treated with ERLEADA. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.
Post-Marketing Experience
The following additional adverse reactions have been identified during post-approval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis.
SRC: NLM .