Erleada, 60 mg 120 pcs

Pharmacotherapeutic group: antitumor agent, antiandrogen.

The ATX code: L02BB05

Pharmacological properties

Mechanism of action

Apalutamide is an orally taken selective androgen receptor inhibitor that binds directly to the ligand-binding domain of the androgen receptor. Apalutamide inhibits nuclear translocation of the androgen receptor, inhibits DNA binding, disrupts androgen receptor-mediated transcription and has no activity as an androgen receptor agonist – noted in preclinical studies.

In murine models of prostate cancer, administration of apalutamide led to a decrease in proliferation of tumor cells and an increase in apoptosis, which was accompanied by significant antitumor activity. The activity of the main metabolite, N-desmethylapalutamide, was one third of the in vitro activity of apalutamide.

Pharmacodynamics

Heart electrophysiology

The effect of apalutamide at a dose of 240 mg once daily on the QTc interval was studied in an open, uncontrolled, multicenter QT interval study in one group of 45 participants with castration-resistant PPH. The maximum mean change in the QTcF interval from baseline was 12.4 ms (upper limit of two-sided 90% CI: 16.0 ms). Analysis of the relationship between systemic exposure and the QT interval suggested a concentration-dependent prolongation of the QTcF interval of apalutamide and its active metabolite.

Pharmacokinetics

An increase in systemic apalutamide levels (C_max and area under the concentration-time curve [AUC [AUC]) within the dose range of 30 to 480 mg. After using the drug at a dose of 240 mg once daily, equilibrium levels of apalutamide were reached after 4 weeks, and the average cumulation ratio compared with a single application was 5.

At equilibrium, the mean (CV%) C_max and AUC values for apalutamide were 6 µg/mL (28%) and 100 µg×h/mL (32%), respectively. Daily fluctuations in plasma concentrations of apalutamide were small, with a mean ratio between peak and minimum concentrations of 1.63. There was an increase in apparent clearance (CL/F) with repeated administration, which is probably due to the induction by apalutamide of its own metabolism.

At equilibrium, the mean (CV%) C_max and AUC values for the major active metabolite, N-desmethylapalutamide, were 5.9 µg/mL (18%) and 124 µg×h/mL (19%), respectively. N-desmethylapalutamide was characterized by a horizontal concentration-time dependence profile at equilibrium with an average peak-to-minimum concentration ratio of 1.27. The mean (CV%) metabolite/source drug AUC ratio for N-desmethylapalutamide after multiple administration was approximately 1.3 (21%). Based on systemic levels, relative activity, and pharmacokinetic properties, it is likely that N-desmethylapalutamide contributes to the clinical activity of apalutamide.

Intake

After oral administration, the median time to peak plasma concentration (t_max) was 2 hours (range: 1 to 5 hours). Mean absolute bioavailability with oral administration was approximately 100%, which corresponds to complete absorption of apalutamide after oral administration.

The administration of apalutamide to healthy volunteers on an empty stomach and after a high-fat meal was not accompanied by clinically relevant changes in C_max and AUC. There was an increase in median time to reach t_max by approximately 2 hours after ingestion of the drug with food.

Distribution

The mean apparent volume of distribution of apalutamide at equilibrium is approximately 276 L. The distribution volume of apalutamide exceeds the total fluid volume, indicating significant extravascular distribution.

The apalutamide and N-desmethylapalutamide are 96% and 95% bound to plasma proteins, respectively; binding is predominantly to plasma albumin and is independent of concentration.

Metabolism

After a single oral dose of 240 mg of labeled ¹⁴C-apalutamide, most of the ¹⁴C-radioactivity in plasma was due to apalutamide, the active metabolite N-desmethylapalutamide and the inactive carboxylic acid derivative, which were associated with 45%, 44% and 3% of the total ¹⁴C-AUC, respectively.

Metabolism is the major route of elimination of apalutamide. Metabolism is predominantly carried out by CYP2C8 and CYP3A4 isoenzymes with the formation of N-desmethylapalutamide. Further metabolism of apalutamide and N-desmethylapalutamide occurs with the formation of an inactive carboxylic acid derivative under the action of carboxylesterase. The contribution of CYP2C8 and CYP3A4 isoenzymes to the metabolism of apalutamide is 58% and 13% after single use, and it is 40% and 37% respectively when used repeatedly at equilibrium.

Apalutamide is excreted, primarily as metabolites, mainly in the urine. After a single oral administration of radiolabeled apalutamide, 89% of the dose was excreted up to 70 days after drug administration. 65% of the dose was excreted in the urine (1.2% as the parent substance, 2.7% as N-desmethylapalutamide) and 24% in the feces (1.5% as the parent substance, 2% as N-desmethylapalutamide).

After a single dose, the CL/F value of apalutamide was 1.3 L/h, with an increase in this value to 2 L/h at equilibrium with once-daily administration. The average effective half-life of apalutamide at equilibrium is approximately 3 days.

Particular patient populations

Patients with impaired renal and hepatic function

No significant differences in the pharmacokinetics of apalutamide and N-desmethylapalutamide were observed in patients with mild renal impairment (estimated glomerular filtration rate (pSCF) 60-89 mL/min/1.73 m²) or moderate renal impairment (rGFR 30-59 mL/min/1.73 m²), mild renal impairment (Child-Pugh class A) or moderate renal impairment (Child-Pugh class B), for ages ranging from 18 to 94 years and for various races.

The potential effect of severe renal dysfunction or end-stage renal failure (rCF ≤ 29 mL/min/1.73 m²) has not been established due to insufficient data. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh class C).

Indications

The drug Erleada is indicated for the treatment of adult men with:

– nonmetastatic castration-resistant prostate cancer (CRPC) with high risk of metastases;

– metastatic hormone-sensitive CRPC in combination with androgen deprivation therapy (ADT).

Active ingredient

Composition

1 tablet contains:

The core

The active ingredient: apalutamide 60 mg.

Hypromellose acetate succinate, colloidal silicon dioxide, croscarmellose sodium, microcrystalline cellulose type 101, microcrystalline cellulose (silanized), magnesium stearate.

The film coating

Opadray® II 85F210036 green (polyvinyl alcohol, partially hydrolyzed, titanium dioxide, macrogol, talc, iron oxide yellow dye, iron oxide black dye).

How to take, the dosage

The drug should be prescribed and used under the regular supervision of a physician experienced in the treatment of cancer and in specialized departments.

The recommended dose of Erleada is 240 mg (4 tablets of 60 mg), taken orally once a day. The tablets should be swallowed whole. The drug Erleada can be taken regardless of meals. During treatment, patients who have not undergone surgical castration should undergo medical castration with a gonadotropin-releasing hormone analog (GnRH).

Dose adjustment

If a patient has grade 3 toxicity or intolerance, suspend administration until symptoms improve to grade ≤ 1 or baseline, then resume at the same dose or, if necessary, at a reduced dose (180 or 120 mg).

Dose skipping

If a patient misses a dose, it should be taken as soon as possible on the same day; the next day, the normal dosing regimen should be followed. The patient should not take extra pills to make up for the missed dose.

Particular patient groups

Children under 18 years of age

The safety and effectiveness of Erleada in children has not been established.

There are no significant data on the use of Erleada in patients under 18 years of age.

Elderly patients (65 years and older)

Of the 1327 patients who received Erleada in clinical trials, 19% were younger than 65 years, 41% were 65 to 74 years, and 40% were 75 years or older. No significant differences in safety or efficacy were found between these patients and younger patients.

Kidney dysfunction

There has been no specific study of Erlead in patients with impaired renal function. Based on data from pharmacokinetic analyses in clinical trials in subjects with castration-resistant PPH and healthy subjects, no significant differences were observed with respect to systemic levels in subjects with initially observed mild to moderate impaired renal function (FFR of 30 to 89 mL/min/1.73 m2) compared with subjects with normal renal function (SCF ≥90 mL/min/1.73 m2). No dose adjustment is required for patients with mild to moderate renal dysfunction. No data for patients with severe renal dysfunction or terminal renal failure (FFR £ 29 ml/min/1.73 m2).

Liver dysfunction

The Liver Dysfunction Special Study compared systemic levels of apalutamide and N-desmethylapalutamide in subjects with baseline mild to moderate liver dysfunction (Child-Pugh Class A or B, respectively) compared to healthy participants with normal liver function. Systemic levels of apalutamide and N-desmethylapalutamide were similar in patients with mild to moderate hepatic impairment compared to patients with normal liver function. No dose adjustment is required in patients with mild to moderate hepatic impairment. No data are available for patients with severe hepatic impairment (Child-Pugh class C).

Interaction

Metabolism of apalutamide and formation of its active metabolite, N-desmethylapalutamide, is mediated in equilibrium by both CYP2C8 and CYP3A4 isoenzymes to the same extent. No clinically significant changes in their total exposure are expected as a result of drug interaction with CYP2C8 or CYP3A4 isoenzyme inhibitors or inducers. Apalutamide is an enzyme and transporter inducer and may be responsible for increased excretion of many commonly used drugs.

The effect of other drugs on apalutamide exposure

CYP2C8 isoenzyme inhibitors

The CYP2C8 isoenzyme plays a role in the excretion of apalutamide and in the formation of its active metabolite. In a drug interaction study, there was a 21% decrease in Cmax of apalutamide and a 68% increase in AUC when a single 240 mg dose of Erlead was coadministered with gemfibrozil (a potent CYP2C8 isoenzyme inhibitor). For the active ingredient (total for apalutamide and adjusted for active metabolite potency), Cmax decreased by 21%, while AUC increased by 45%. There is no need for initial dose adjustment in case of co-administration of Erleada with potent CYP2C8 isoenzyme inhibitor (e.g. gemfibrozil, clopidogrel), however, Erleada dose reduction should be considered based on its tolerability (see Dosage and Administration – Dose Adjustment). Weak or moderate CYP2C8 isoenzyme inhibitors are not expected to affect the pharmacokinetics of apalutamide.

CYP3A4 isoenzyme inhibitors

The CYP3A4 isoenzyme plays a role in the excretion of apalutamide and in the formation of its active metabolite. In a drug interaction study, there was a 22% reduction in Cmax of apalutamide while maintaining AUC at the same levels when a single 240 mg dose of Erlead was co-administered with itraconazole (a potent CYP3A4 inhibitor). For the active ingredient (total for apalutamide and adjusted for active metabolite potency), Cmax decreased by 22% while maintaining AUC at the same level. There is no need for initial dose adjustment in case of Erleada co-administration with potent CYP3A4 isoenzyme inhibitor (e.g. ketoconazole, ritonavir, clarithromycin), however Erleada dose reduction should be considered based on its tolerability (see Dosage and Administration – Dose Adjustment). Weak or moderate CYP3A4 isoenzyme inhibitors are not expected to affect the pharmacokinetics of apalutamide.

CYP3A4 or CYP2C8 isoenzyme inducers

The effects of CYP3A4 or CYP2C8 isoenzyme inducers on the pharmacokinetics of apalutamide have not been evaluated in in vivo studies. Based on the results of interaction studies with potent CYP3A4 and CYP2C8 isoenzyme inhibitors, CYP3A4 or CYP2C8 inducers are not expected to have clinically significant effects on the pharmacokinetics of apalutamide and the active substance, so no dose adjustment is required when Erleada is used together with CYP3A4 or CYP2C8 inducers.

The effect of apalutamide on exposure to other drugs

Apalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, an interaction of apalutamide with many common drugs that are enzyme or transporter substrates is expected. The decrease in their plasma concentrations can be significant and lead to a loss or reduction of the clinical effect. There is also a risk of increased formation of active metabolites.

The effect of apalutamide on drug metabolizing enzymes

. In vitro studies have shown that apalutamide and N-desmethylapalutamide are moderate to potent inducers of CYP3A4 and CYP2B6 isoenzymes, moderate inhibitors of CYP2B6 and CYP2C8 isoenzymes and weak inhibitors of CYP2C9, CYP2C19 and CYP3A4 isoenzymes. Apalutamide and N-desmethylapalutamide do not affect CYP1A2 and CYP2D6 isoenzymes at therapeutically significant concentrations. The effects of apalutamide on CYP2B6 isoenzyme substrates have not been evaluated in vivo, and the final outcome is currently unknown. When CYP2B6 isoenzyme substrates (e.g., efavirenz) are used with Erleada, adverse reactions should be monitored and the loss of substrate efficacy evaluated, and adjustments in substrate dose may be necessary to maintain optimal plasma concentrations.

In humans, apalutamide is a potent inducer of the CYP3A4 and CYP2C19 isoenzymes and a weak inducer of the CYP2C9 isoenzyme. In a drug interaction study using a “cocktail” approach, co-administration of Erleada with a single oral administration of sensitive CYP substrates resulted in a 92% lower AUC of midazolam (CYP3A4 substrate), an 85% lower AUC of omeprazole (CYP2C19 substrate) and a 46% lower AUC of S-warfarin (CYP2C9 substrate). The drug Erleada did not cause clinically significant effects on the CYP2C8 substrate. Co-administration of Erleada with drugs that are metabolized mainly by CYP3A4 isoenzymes (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole) or CYP2C9 (e.g., warfarin, phenytoin) may lead to weakened action of these drugs. If possible, it is recommended to replace these drugs, or to monitor for a decrease in their effectiveness, if it is decided to continue therapy. International normalized ratio (INR) levels should be monitored when Erlead is coadministered with warfarin.

The induction of CYP3A4 isoenzyme by apalutamide suggests that UDF-glucuronosyltransferase (UDF-GT) may also be induced through activation of nuclear pregnan-X receptor (PXR). Co-administration of Erlead with drugs that are substrates of UDF-GT (e.g., levothyroxine, valproic acid) may lead to decreased systemic levels of these drugs. When Erlead is coadministered with UDF-GT substrates, the loss of substrate efficacy should be evaluated, and adjustments in substrate dose may be necessary to maintain optimal plasma concentrations.

The effects of apalutamide on drug transporters

Apalutamide has been shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and polypeptide transporting organic anion 1B1 (OATP1B1). A drug interaction study using a “cocktail” approach showed that co-administration of Erlead with single oral doses of sensitive transporter substrates resulted in a 30% reduction in AUC of fexofenadine (P-gp substrate) and a 41% reduction in AUC of rosuvastatin (BCRP / OATP1B1 substrate), but had no effect on Cmax. Co-administration of Erlead with drugs that are P-gp, BCRP or OATP1B1 substrates may result in attenuation of the effects of these drugs. If Erlead is coadministered with P-gp, BCRP or OATP1B1 substrates, the loss of substrate efficacy should be assessed, and adjustments in substrate dose may be necessary to maintain optimal plasma concentrations.

Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and drug and toxin extrusion proteins (MATE) by apalutamide and its N-desmethyl metabolite cannot be excluded. No inhibition of in vitro organic anion transporter 1 (OAT1) was observed.

The gonadotropin-releasing hormone (GnRH) analogue

In patients with metastatic hormone-sensitive breast cancer who received leuprorelin acetate (GnRH analogue), concurrent use with Erlead had no apparent effect on leuprorelin exposure in equilibrium.

Drugs that prolong the QT interval

Because anti-androgen therapy may contribute to prolongation of the QT interval, concomitant use of Erleada with other drugs for which they are known to prolong the QT interval or have the potential to cause pirouette tachycardia, such as antiarrhythmic drugs of class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, neuroleptics (e.g. haloperidol) and so on should be carefully evaluated (see Particular indications. Special Indications).

Children

Special Instructions

Convulsions

The drug Erleada is not recommended for patients with a history of seizures or other predisposing factors, particularly craniocerebral trauma, recent stroke (within one year), primary brain tumors or metastases in the brain. If convulsions develop during the use of Erlead, the drug should be permanently discontinued. The risk of seizures is higher in patients receiving additional drugs that lower the seizure threshold.

In two randomized trials (SPARTAN and TITAN), seizures occurred in 0.4% of patients receiving Erlead and 0.2% of patients receiving placebo. Patients with a history of seizures or predisposing factors to seizures were excluded in these studies.

There is no clinical experience with re-administration of Erleada in patients who have had seizures.

Falls and fractures in patients with non-metastatic castration-resistant BCP

In a randomized clinical trial in patients with non-metastatic castration-resistant BCP who received Erleada (SPARTAN), falls and fractures were reported (see Side Effects). The risk of falls and fractures should be assessed before starting Erleada, patients should be monitored during treatment, and the use of specialized bone products should be considered.

Ischemic cardiovascular events in patients with metastatic hormone-sensitive RA

In a randomized trial in patients with metastatic hormone-sensitive RA (TITAN), cardiovascular ischemic events were noted in 4% of patients treated with Erlead and 2% of patients treated with placebo. Two patients in each group died due to a cardiovascular ischemic event. Most patients in the TITAN study had cardiovascular risk factors.

In patients with metastatic hormone-sensitive PCa, coronary heart disease should be monitored and managed for cardiovascular risk factors, particularly the presence of hypertension, diabetes mellitus, or dyslipidemia, according to the standard of care.

Simultaneous use with other medicinal products

Apalutamide is a potent enzyme inducer and may be the cause of reduced effectiveness of many commonly used medicinal products (see Interaction with other medicinal products). Therefore, the use of concomitant drugs should be analyzed before treatment with apalutamide. Concomitant use of Erlead with drugs that are sensitive substrates of many metabolizing enzymes or transporters should be avoided if their therapeutic effect is important for the patient and if dose adjustment cannot be easily performed on the basis of efficacy or plasma concentration monitoring.

The co-administration of Erleada with warfarin and coumarin-like anticoagulants should be avoided. If Erleada is coadministered with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol), additional monitoring of the international normalized ratio (INR) should be performed (see Interaction with other medicinal products).

Latest cardiovascular events

. Patients with clinically significant cardiovascular disease within the past 6 months, including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular events including transient ischemic attacks), or clinically significant ventricular arrhythmias were excluded from clinical trials. Therefore, the safety of Erleada administration in these patients has not been established. When prescribing Erleada, patients should be screened for cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, or other cardio-metabolic disorders (see Side Effects). These pathological conditions should be treated as necessary, after initiation of the drug Erleada, according to the established treatment protocol.

The anti-androgen therapy may prolong the QT interval

In patients with a history of prolonged QT interval or associated risk factors, as well as in patients receiving concomitant medications that may prolong the QT interval (see “Interaction with Other Medications” on page 25). Interactions with other medications), the benefit-risk ratio, including the likelihood of pirouette tachycardia, should be evaluated before initiating therapy with Erleada.

The effect of Erleada on driving and other machinery

There have been no studies of the effect of Erleada on the ability to drive or operate machinery. There is no information that the drug Erleada affects the ability to drive vehicles and operate mechanisms. Taking into account the side effect profile, including the occurrence of seizures, caution should be exercised when driving motor transport and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Synopsis

Olong, slightly biconvex, slightly yellowish-green to greenish-gray tablets with “AR 60” engraved on one side.

Contraindications

– Women of childbearing age, pregnant women

– Hypersensitivity to the active ingredient or any excipient of the drug

– Children under 18 years of age./p>

– Severe impairment of renal and hepatic function

With caution

In patients at risk of or with a history of seizures, with risk of falls and fractures; Co-administration with CYP3A4 (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole), CYP2C9 (e.g, warfarin, phenytoin), UDF-glucuronosyltransferase (UGT) (e.g., levothyroxine, valproic acid), with P-glycoprotein transporter (P-gp) substrate drugs (e.g, colchicine, dabigatran etexilate, digoxin), breast cancer resistance protein (BCRP), or organic anion transport polypeptide 1B1 (OAPTP1B1) (eg, lapatinib, methotrexate, rosuvastatin, repaglinide), with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol) in patients with clinically significant cardiovascular disease within the last 6 months; in patients with a history of prolonged QT interval or relevant risk factors; and in patients receiving concomitant medications that may prolong the QT interval (see “Administration of the drug”). Special Indications).

Side effects

The most common adverse reactions are fatigue (26%), skin rash (26% any degree and 6% 3rd or 4th degree), hypertension (22%), hot flashes (18%), arthralgia (17%), diarrhea (16%), falls (13%) and weight loss (13%). Other important adverse reactions are fractures (11%) and hypothyroidism (8%).

The adverse reactions observed during clinical trials are listed in the table below and divided into groups according to frequency. By frequency, reactions are classified as follows: very frequent (≥1/10); frequent (≥1/100 to < 1/10); infrequent (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (< 1/10,000) and of unknown frequency (frequency cannot be estimated from available data).

In each frequency group, adverse reactions are presented in decreasing order of severity.

Table 1. Adverse reactions identified in clinical trials

Organ system class

/td>

Undesired response and frequency

Endocrine system disorders

Frequent: Hypothyroidism*

Metabolic and nutritional disorders

Frequent: hypercholesterolemia, hypertriglyceridemia

Nervous system disorders

Frequent: dysgeusia

Infrequent: seizures (see. Special Indications)

Cardiac disorders

Frequent: coronary artery disease§

Unknown: QT interval prolongation (see Special Indications, Interactions with other drugs)

Vascular disorders

Very frequent: hot flashes, hypertension

Gastrointestinal disorders

Very frequent: Diarrhea

Skin and subcutaneous tissue disorders

Very frequent: skin rash**

Frequent: Itching

Musculoskeletal and connective tissue disorders

Very frequent: fracture+, arthralgia

Frequent: muscle spasm

General disorders and disorders at the site of administration

Very frequent: Fatigue

Laboratory and instrumental findings

Very frequent: Weight loss

Injuries, intoxications, and complications of manipulation

Very frequent: Cases of falls

* Includes hypothyroidism, increased thyroid hormone in the blood, decreased thyroxine, autoimmune thyroiditis, decreased free thyroxine levels, decreased triiodothyronine levels.

** See “Skin rash” under “Description of individual adverse reactions”.

+ Observed in patients with non-metastatic castration-resistant PCP. Includes rib fracture, lumbar spine fracture, spinal compression fracture, spine fracture, foot fracture, hip fracture, humerus fracture, thoracic spine fracture, upper extremity fracture, sacrum fracture, arm fracture, pubic bone fracture, acetabular fracture, ankle fracture, compression fracture, cartilaginous rib fracture, skull facial bone fracture, lower extremity fracture, osteoporotic fracture, wrist bone fracture, breakaway fracture, fibula fracture, coccygeal bone fracture, pelvic bone fracture, radial bone fracture, sternal fracture, stress fracture, traumatic fracture, cervical spine fracture, femoral neck fracture, tibia fracture. See Falls and fractures below.

§ Were seen in patients with metastatic hormone-sensitive PCP. Includes angina, myocardial infarction, acute myocardial infarction, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, coronary atherosclerosis, abnormal ECG findings with exercise, myocardial ischemia.

Description of individual adverse reactions

Skin rash

The skin rash associated with Erleada use has most commonly been described as macular or maculopapular rash. Skin rash includes rash, maculopapular rash, generalized rash, urticaria, pruritic rash, macular rash, conjunctivitis, erythema multiforme, papular rash, skin flaking, genital rash, erythematous rash, stomatitis, drug rash, ulcerative stomatitis, pustular rash, blisters, papules, pemphigoid, skin erosion, dermatitis, and vesicular rash. Adverse reactions in the form of skin rash were reported in 26% of patients treated with Erleada. A grade 3 rash (defined as covering > 30% of the entire body surface area) was noted in 6% of patients.

The median days to onset of the skin rash was 83 days. In 78% of patients, the rash resolved in an average of 78 days. Medications to correct the rash included topical forms of corticosteroids, oral antihistamines, and 19% of patients received systemic corticosteroids. Among patients with a skin rash, 28% temporarily discontinued the medication and 14% reduced the medication doses (see Administration and Doses – Dose Adjustment). Skin rash recurred in 59% of patients in whom the drug was reapplied after temporary discontinuation of therapy. Erlead was discontinued because of a skin rash in 7% of patients.

Falls and fractures

In the ARN-509-003 clinical trial, fractures were reported in 11.7% of patients treated with Erlead and 6.5% of patients treated with placebo. Half of the patients had cases of falls within 7 days prior to fracture in both treatment groups. Falls occurred in 15.6% of patients treated with Erlead and 9.0% of patients treated with placebo (see Special Instructions).

Hypothyroidism

Hypothyroidism, as measured by thyrotropic hormone (TSH) testing every 4 months, was reported in 8% of patients receiving Erlead and 2% of patients receiving placebo. There were no adverse events of grade 3 or 4 severity. Development of hypothyroidism was observed in 30% of patients already receiving thyroid hormone replacement therapy in the Erlead group and in 3% of patients in the placebo group. In patients without hormone replacement therapy hypothyroidism developed in 7% of patients receiving Erleda and 2% of patients receiving placebo. Thyroid hormone replacement therapy or adjustment of the drug dose should be started in case of clinical indications (see Interaction with other medicinal products).

Overdose

There is no specific antidote for apalutamide. At a dose equal to 480 mg once daily (2 times the recommended daily dose), no dose-limiting toxicity was noted.

Therapy

If an overdose develops, Erlead should be discontinued and general supportive treatment initiated until clinical toxicity decreases or resolves.

Pregnancy use

Pregnancy

The drug Erleada should not be used during pregnancy and if there is a possibility of its occurrence. Information on the mechanism of action suggests that taking Erleada during pregnancy may have adverse effects on the fetus. There are insufficient data on the use of Erleada during pregnancy. Studies of the effect of Erleda on reproductive function and fetal development in animals have not been conducted.

Contraception

The Erleda drug may have a damaging effect on the developing fetus. Patients who have sexual intercourse with fertile partners should use highly effective contraception throughout treatment and for 3 months after the last dose of the drug.

Breastfeeding

It is not known whether apalutamide or its metabolites penetrate into breast milk or have any effect on the health of breastfed children or on the mother’s milk production.

Fertility

In an animal study, it has been shown that the drug Erlead can reduce fertility in men with active fertility.