For the use of oncologists only

Enzalutamide Capsules 40 mg

XYLUTIDE Capsules

Qualitative and Quantitative Composition:

Each hard gelatin capsule contains:       

Enzalutamide…... 40 mg

Excipients…............ q.s.

Approved colours used in capsule shell.

Dosage Form and Strength:

Hard Gelatin Capsule and 40 mg

Clinical Particulars

Therapeutic Indication

For the treatment adults with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed on or after Docetaxel therapy.

Posology and Method of Administration

The recommended dose is 160 mg of Enzalutamide (four 40 mg capsules) as a single oral daily dose. Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated. If a patient misses taking Enzalutamide Capsule at the usual time, take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take a double dose to make up for the missed dose.

If more than one daily dose is missed, talk to your doctor.

If a patient has a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduced dose (3 capsules of 40 mg, 120 mg or 2 capsules of 40 mg, 80 mg) if warranted.

Concomitant Use with Strong CYP2C8 Inhibitors

If a patient requires administration of a strong CYP2C8 inhibitor with Enzalutamide, then the Enzalutamide dose should be reduced to 80 mg/day. If co-administration of the strong inhibitor is discontinued, the Enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor.

Concomitant Use with Strong CYP3A4 Inducers

The concomitant use of strong CYP3A4 inducers should be avoided if possible. If patients must be co-administered a strong CYP3A4 inducer, increase the Enzalutamide dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the Enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Method of Administration

Enzalutamide is for oral use. The capsules should be swallowed whole without opening and are not to be chewed or dissolved or opened. Patients receiving XYLUTIDE should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Contraindications

Individual hypersensitivity to the active substance or excipients of the product.

Enzalutamide is not indicated for use by women who are or may become pregnant.

Special Warnings and Precautions for Use

Seizures

Patients experiencing seizure were permanently discontinued from therapy, and all seizure events resolved.

Enzalutamide belongs to a class of antiandrogens that carry a risk of seizures. Caution should be used in administering Enzalutamide Capsule to patients with a history of seizures or other predisposing factors like brain metastases, brain atrophy associated with alcohol use, brain tumor, or patient on lidocaine therapy or any other drugs which can lower the seizure threshold. Advise patients of the risk of developing a seizure while receiving Enzalutamide and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue Enzalutamide in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by symptoms that can include seizure, headache, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension and can be confirmed by magnetic resonance imaging. If symptoms suggestive of PRES arise in patients receiving Enzalutamide, the drug should be discontinued immediately, and the diagnostic process should be initiated.

Hypersensitivity 

Hypersensitivity reactions manifested by symptoms including, but not limited to, oedema of face, tongue, lip and pharyngeal have been reported with Enzalutamide.

Permanently discontinue Enzalutamide for serious hypersensitivity reactions.

Ischemic Heart Disease

Ischemic heart disease has known to occur in patients with Enzalutamide. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue Enzalutamide for Grade 3-4 ischemic heart disease.

Falls and Fractures

Falls and fractures occurred in patients receiving Enzalutamide. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. The median time to onset of fracture was 336 days (range: 2 to 1914 days) for patients treated with Enzalutamide Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies.

Embryo-Fetal Toxicity

The safety and efficacy of Enzalutamide have not been established in females. Based on animal reproductive studies and mechanism of action, Enzalutamide can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enzalutamide and for 3 months after the last dose of Enzalutamide

Excipients

Enzalutamide contains a type of sugar called lactose. If you have an intolerance to some sugars, contact your doctor before taking this medicine.

Drug Interactions

In the drug interaction study with CYP2C8 and CYP3A4 inhibitors, coadministration of gemfibrozil (strong CYP2C8 inhibitor) increased the composite AUC∞ of Enzalutamide  plus N-desmethyl Enzalutamide  by 2.2-fold, and coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite AUC∞ by 1.3-fold. Based on these findings, it is recommended to avoid CYP2C8 inhibitor, however if a patient requires coadministration of a strong CYP2C8 inhibitor with Enzalutamide, then the Enzalutamide dose should be reduced to 80 mg once daily.

Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of Enzalutamide plus N-desmethyl Enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with Enzalutamide should be avoided if possible. St John's wort may decrease Enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with Enzalutamide cannot be avoided, increase the dose of Enzalutamide from 160 mg to 240 mg once daily, Enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, it reduces the plasma exposure to CYP3A4 substrate like midazolam, CYP2C9 substrate like warfarin, and CYP2C19 substrate like omeprazole. Concomitant use of Enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as Enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring.

P-gp Substrates

In in vitro experiments, Enzalutamide and N-desmethyl Enzalutamide were shown to be inhibitors of P-gp. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Enzalutamide Capsule and may require dose adjustment.

BCRP, MRP2, OAT3 and OCT1 Substrates

Enzalutamide is not a substrate of P-gp or the breast cancer resistance protein (BCRP). Inhibition of multidrug resistance-associated protein 2 (MRP2), BCRP and OATP1B1 could not be excluded based on in vitro data. Theoretically, induction of these transporters is also possible, and the net clinical effect is presently unidentified.

Medicinal Products which Prolong the QT Interval

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Enzalutamide Capsule with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA i.e. Fast sodium (Na) channel blockers like Quinidine, procainamide, disopyramide or class III i.e. Potassium (K) channel blockers like amiodarone, sotalol, dofetilide, ibutilide, other antiarrhythmic medicinal products, and methadone, moxifloxacin, antipsychotics, etc., should, therefore, be carefully evaluated.

Groups of medicinal products that can be affected include, but are not limited to:

• Analgesics (e.g., fentanyl, tramadol)
• Antibiotics (e.g., clarithromycin, doxycycline)
• Anticancer agents (e.g., cabazitaxel)
• Anticoagulants (e.g., acenocoumarol, warfarin)
• Antiepileptics (e.g., carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g., haloperidol)
• Betablockers (e.g., bisoprolol, propranolol)
• Calcium channel blockers (e.g., diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g., digoxin)
• Corticosteroids (e.g., dexamethasone, prednisolone)
• HIV antivirals (e.g., indinavir, ritonavir)
• Hypnotics (e.g., diazepam, midazolam, zolpidem)
• Statins metabolized by CYP3A4 (e.g., atorvastatin, simvastatin)
• Thyroid agents (e.g., levothyroxine)

Effect of Food on Enzalutamide Exposures

Food has no clinically significant effect on the extent of exposure to Enzalutamide. In clinical trials, Enzalutamide Capsule was administered without food.

Use in Special Populations

Patients with Renal Impairment

No significant   difference   in   Enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment compared to patients and volunteers with baseline normal renal function. No initial dosage adjustment is necessary for patients with mild to moderate renal impairment.  Patient with severe renal impairment and end-stage renal disease have not been assessed and caution is advised.

Patients with Hepatic Impairment

Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment.

Pregnant Women

It can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Enzalutamide is not indicated for use in women. Enzalutamide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

Lactating Women

Enzalutamide is not recommended to be used in women. Animal studies in rats suggest that enzalutamide and/or its metabolites are secreted in rat milk. However, there is no such evidence known in humans.

Paediatric Patients

Enzalutamide is not meant for use in the paediatric population.

Geriatric Patients

No overall difference in safety and effectiveness were observed between younger and older patients. No dose adjustment is necessary for older people, but greater sensitivity of some older individuals cannot be ruled out.

Females and Males of Childbearing Potential

Contraception

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Enzalutamide  

Infertility

Males

Based on animal studies, Enzalutamide may impair fertility in males of reproductive potential

Effects on Ability to Drive and Use Machines

No studies on the effects of Enzalutamide on the ability to drive or use machines have been performed. It is anticipated that Enzalutamide may have a moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported. Patients with a history of seizures or other predisposing factors should be advised of the risk of driving or operating machines.

Undesirable Effects

The following is discussed in more detail under Warning and Precaution section:

• Seizure
• Posterior Reversible Encephalopathy Syndrome (PRES)
• Hypersensitivity
• Ischemic Heart Disease
• Falls and Fractures

Summary of the Safety Profile

In the placebo-controlled phase 3 clinical trial (AFFIRM) of patients with metastatic castration-resistant prostate cancer who had received docetaxel therapy, enzalutamide was administered at a dose of 160 mg daily (N = 800) versus placebo (N = 399). The median duration of treatment with treatment with enzalutamide was 8.3 months while with placebo it was 3 months. Patients were allowed, but not required, to take prednisone.

Seizures occurred in 0.8% of patients receiving enzalutamide. The most common adverse reactions were hot flush and headache.

Tabulated List of Adverse Reactions

Adverse reactions observed in AFFIRM are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse Reactions Identified in Phase 3 Clinical Trial

MedDRA System organ class	Very common	Common	Uncommon
Blood and lymphatic system disorders		Neutropenia	Leucopenia
Psychiatric disorders		Visual hallucinations, anxiety
Nervous system disorders	Headache	Cognitive disorder, memory impairment	Seizure, amnesia, disturbance in attention
Vascular disorders	Hot flush	Hypertension
Skin and subcutaneous tissue disorders		Dry skin, pruritus
Musculoskeletal and connective tissue disorders		Fractures *
Injury, poisoning and procedural Complications		Falls

*Indicates all fractures with the exception of pathological fractures

Description of Selected Adverse Reactions

Seizure

 

In AFFIRM, six patients (0.8%) experienced a seizure out of 800 patients treated with a daily dose of 160 mg enzalutamide whereas no seizures occurred in patients receiving placebo. Potentially contributing factors were present in several of these patients that may have independently increased their risk of seizure. The AFFIRM trial excluded patients with prior seizure or risk of seizure, as reflected by preclinical data and data from a dose-escalation study. The mechanism by which enzalutamide may lower the seizure threshold is not known, but could be related to data from in vitro studies showing that enzalutamide and its active metabolite bind to and can inhibit the activity of the GABA-gated chloride channel.

Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of Enzalutamide. 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.

Gastrointestinal Disorders: vomiting

Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES)

Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

There is no antidote for Enzalutamide. In the event of an overdose, treatment with Enzalutamide should be stopped and general supportive measures initiated taking into consideration the half-life of 5.8 days. Patients may be at increased risk of seizures following an overdose.

Pharmacological Properties:

Mechanism of Action

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.

Pharmacodynamic Properties

Cardio Electrophysiology

The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with Enzalutamide and that in patients treated with placebo, based on the Fridericia correction method.

However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design.

Pharmacodynamic Effects

In a phase 3 clinical trial (AFFIRM) of patients who failed prior chemotherapy with docetaxel, 54% of patients treated with enzalutamide, versus 1.5% of patients who received placebo, had at least a 50% decline from baseline in PSA levels.

Clinical Efficacy and Safety

The efficacy and safety of enzalutamide in patients with metastatic castration resistant prostate cancer who had received docetaxel and were using a gonadotropin-releasing hormone (GnRH) analog analogue or had undergone orchiectomy were assessed in a randomised, placebo-controlled, multicentre phase 3 clinical trial. A total of 1199 patients were randomised 2:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 800) or placebo once daily (N = 399). Patients were allowed but not required to take prednisone (maximum daily dose allowed was 10 mg prednisone or equivalent). Patients randomised to either arm were to continue treatment until disease progression (defined as confirmed radiographic progression or the occurrence of a skeletal-related event) and initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms:

The median age was 69 years (range 41 - 92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. The ECOG performance score was 0 - 1 in 91.5% of patients and 2 in 8.5% of patients; 28.4% had a mean Brief Pain Inventory score of ≥ 4 (mean of patient's reported worst pain over the previous 24 hours calculated for seven days prior to randomisation). Most (91.2%) patients had metastases in bone and 23.2% had visceral lung and/or liver involvement. At study entry, 41% of randomised patients had PSA progression only, whereas 59% of patients had radiographic progression. Fifty-one percent (51%) of patients were on bisphosphonates at baseline.

The phase 3 study excluded patients with medical conditions that may predispose them to seizures and medicinal products known to decrease the seizure threshold, as well as clinically significant cardiovascular disease such as uncontrolled hypertension, recent history of myocardial infarction or unstable angina, New York Heart Association class III or IV heart failure (unless ejection fraction was ≥ 45%), clinically significant ventricular arrhythmias or AV block (without permanent pacemaker).

Of the 800 patients in the phase 3 trial who received enzalutamide, 568 patients (71%) were 65 years and over and 199 patients (25%) were 75 years and over. No overall differences in safety or effectiveness were observed between these older patients and younger patients.

The protocol pre-specified interim analysis after 520 deaths showed a statistically significant superiority in overall survival in patients treated with enzalutamide compared to placebo.

Overall survival of patients treated with either enzalutamide or placebo (intent-to-treat analysis)

	Enzalutamide (N=800)	Placebo (N=399)
Deaths (%)	308 (38.5%)	212 (53.1%)
Median survival (months)(95% CI)	18.4 (17.3, NR)	13.6 (11.3, 15.8)
p value 1	p < 0.0001
Hazard ratio (95% CI) 2	0.63 (0.53, 0.75)

NR = Not Reached.

1. P-value is derived from a log rank test stratified by ECOG performance status score (0-1 vs. 2) and mean pain score (< 4 vs. ≥ 4).
2. Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours enzalutamide.

Figure: Kaplan-Meir curves of overall survival (intent-to-treat analysis)

Subgroup survival analysis showed a consistent survival benefit for treatment with enzalutamide (see figure below).

Figure: Overall survival by subgroup– hazard ratio and 95% confidence interval

In addition to the observed improvement in overall survival, key secondary endpoints (PSA progression, radiographic progression-free survival, and time to first skeletal-related event) favoured enzalutamide and were statistically significant after adjusting for multiple testing.

Radiographic progression-free survival as assessed by the investigator using RECIST v 1.1 for soft tissue and appearance of 2 or more bone lesions in bone scan was 8.3 months for patients treated with enzalutamide and 2.9 months for patients who received placebo [HR = 0.404 (95% CI: 0.35, 0.466), p < 0.0001]. The analysis involved 216 events without documented progression and 645 documented progression events, of which 303 (47%) were due to soft tissue progression, 268 (42%) were due to bone lesion progression and 74 (11%) were due to both soft tissue and bone lesions.

Confirmed PSA decline of 50% or 90% were 54.0% and 24.8%, respectively, for patients treated with enzalutamide and 1.5% and 0.9%, respectively, for patients who received placebo (p < 0.0001). The median time to PSA progression was 8.3 months for patients treated with enzalutamide and 3.0 months for patients who received placebo [HR = 0.248 (95% CI: 0.204, 0.303), p < 0.0001].

The median time to first skeletal-related event was 16.7 months for patients treated with enzalutamide and 13.3 months for patients who received placebo [HR = 0.688 (95% CI: 0.566, 0.835), p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change of antineoplastic therapy to treat bone pain. The analysis involved 448 skeletal-related events, of which 277 events (62%) were radiation to bone, 95 events (21%) were spinal cord compression, 47 events (10%) were pathologic bone fracture, 36 events (8%) were change in antineoplastic therapy to treat bone pain, and 7 events (2%) were surgery to bone.

The efficacy of enzalutamide in patients who have previously received abiraterone acetate has not been studied.

Paediatric Population

The European Medicines Agency has waived the obligation to submit the results of studies with enzalutamide in all subsets of the paediatric population in prostate carcinoma.

Pharmacokinetic Properties

Enzalutamide is poorly water soluble. The pharmacokinetics of Enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. In a reported dose-escalation study, Enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30–360 mg/day, and inter-subject variability was ≤30 %. In the multiple-dose period, Enzalutamide was absorbed rapidly on day 84, with the median tmax ranging from 0.00 to 2.07 h, which was similar to the median tmax in the single-dose period. The mean CL/F was 0.61 L/h, also similar to the CL/F during the single-dose period. In general, dosing for 1 month was required to reach steady state, and the daily fluctuations in plasma concentrations were low (mean peak-to-trough ratio, 1.25). Clearance of Enzalutamide is primarily via hepatic metabolism, producing an active metabolite, N-desmethyl Enzalutamide that is equally as active as Enzalutamide and circulates at approximately the same plasma concentration as Enzalutamide.

Absorption

Absorption after single and multiple-dose oral administration, the tmax generally occurred around 1 h post dose, showing that Enzalutamide is rapidly absorbed. Based on excretion of metabolites in urine and feces in the mass balance and biotransformation study, the extent of absorption of Enzalutamide after oral administration is at least 84.2 %. Maximum plasma concentrations (Cmax) of Enzalutamide in patients are observed 1 to 2 hours after administration. Based on a mass balance study in humans, oral absorption of Enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. At steady state, the mean Cmax values for Enzalutamide and its active metabolite are 16.6 μg/mL (23% coefficient of variation [CV]) and 12.7 μg/mL (30 %CV), respectively. Food has no clinically significant effect on the extent of absorption. In clinical trials, Enzalutamide was administered without regard to food.

Distribution

The mean apparent volume of distribution (V/F) of Enzalutamide in patients after a single oral dose is 110 L (29% CV).

Enzalutamide is highly bound (97 to 98%) to plasma proteins, primarily albumin. The active metabolite is about 95% plasma proteins bound. There was no protein binding displacement between Enzalutamide and other highly bound drugs (warfarin, ibuprofen and salicylic acid) in vitro.

Metabolism

In a study following single oral administration of ¹⁴C-enzalutamide 160 mg, plasma samples were analyzed for Enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl Enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the ¹⁴C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total ¹⁴C-AUC0-inf.

In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of Enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

Elimination

Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of ¹⁴C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).

The mean terminal half-life (t1/2) for Enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of Enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl Enzalutamide is approximately 7.8 to 8.6 days.

Renal Impairment

Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. Patient with severe renal impairment and end-stage renal disease have not been assessed and hence caution is advised.

Hepatic Impairment

Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment.

Body Weight and Age

Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to Enzalutamide.

Gender

The effect of gender on the pharmacokinetics of Enzalutamide has not been evaluated.

Race

Most patients in the reported clinical trials (>84%) were Caucasian. Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of Enzalutamide in other races.

Non-Clinical Properties

Animal Toxicology or Pharmacology

A two-year carcinogenicity study was conducted in male and female rats at oral Enzalutamide doses of 10, 30, and 100 mg/kg/day. Enzalutamide increased the incidence of benign Leydig cell tumors in the testes at all dose levels tested (≥ 0.3 times the human exposure based on AUC) and combined incidence of urothelial papilloma and carcinoma in the urinary bladder in male rats at 100 mg/kg/day (1.4 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of Enzalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Administration of Enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of Enzalutamide, male fertility may be impaired by treatment with Enzalutamide. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Description

Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3- (trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. Its structural formula is:

Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.

Chemical formula:C₂₁H₁₆F₄N₄O₂S 

Molecular weight:  464.44 g/mol

ATC code: L02BB04

Pharmacotherapeutic group: Anti Neoplastic

Pharmaceutical Particulars

List of Excipients

Lactose Monohydrate,Labrasol ALF (Caprylocaproyl Polyoxyl-8 glycerides), Colloidal Silicon Dioxide, Lactose  Anhydrous.

Incompatibilities

Not Applicable

Shelf-life

Packaging Information

28 Capsules packed in Aluminium PVC Blister such 4 blisters packed in carton along with pack insert.

Storage and Handling Instructions

Store below 30°C, Protect from light & moisture.

Keep out of reach & sight of children.

Patients Counselling Information

What is XYLUTIDE?

XYLUTIDE is a prescription medicine that is used to treat adult men with prostate cancer that has spread away from the prostate, no longer responds to a medical or surgical treatment that lowers testosterone and has progressed while on or after chemotherapy with docetaxel.

Before taking XYLUTIDE, tell your healthcare provider about all your medical conditions, including if you:

• have a history of seizures, brain injury, stroke, or brain tumors.
• have a history of heart disease.
• have high blood pressure.
• have abnormal amounts of fat or cholesterol in your blood (dyslipidemia).
• are pregnant or plan to become pregnant. XYLUTIDE can cause harm to your unborn baby and loss of pregnancy (miscarriage).
• have a partner who is pregnant or may become pregnant.
• Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XYLUTIDE and for 3 months after the last dose of XYLUTIDE
• Males must use a condom during sex with a pregnant female.
• are breastfeeding or plan to breastfeed. It is not known if XYLUTIDE passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XYLUTIDE may affect the way other medicines work, and other medicines may affect how XYLUTIDE works. You should not start or stop any medicine before you talk with the healthcare provider that prescribed XYLUTIDE. Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I take XYLUTIDE?

• Take XYLUTIDE exactly as your healthcare provider tells you.
• Your healthcare provider may change your dose if needed.
• Do not change or stop taking your prescribed dose of XYLUTIDE without talking with your healthcare provider first.
• XYLUTIDE can be taken with or without food.
• Swallow XYLUTIDE capsule or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets.
• If you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment during your treatment with XYLUTIDE unless you have had a surgery to lower the amount of testosterone in your body (surgical castration).
• If you miss a dose of XYLUTIDE, take your prescribed dose as soon as you remember that day. If you miss your daily dose, take your prescribed dose at your regular time the next day. Do not take more than your prescribed dose of XYLUTIDE each day. If you take too much XYLUTIDE, call your healthcare provider or go to the nearest emergency room right away. You may have an increased risk of seizure if you take too much XYLUTIDE.

What are the possible side effects of XYLUTIDE?

XYLUTIDE may cause serious side effects including:

• Seizure. If you take XYLUTIDE you may be at 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 loss of consciousness or seizure.
• Posterior Reversible Encephalopathy Syndrome (PRES). If you take XYLUTIDE you may be at risk of developing a condition involving the brain called PRES. Tell your healthcare provider right away if you have a seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision, or other visual problems. Your healthcare provider will do a test to check for PRES.
• Allergic Reactions. Allergic reactions have happened in people who take XYLUTIDE. Stop taking XYLUTIDE and get medical help right away if you develop swelling of the face, tongue, lip or throat.
• Heart disease. Blockage of the arteries in the heart (ischemic heart disease) that can lead to death has happened in some people during treatment with XYLUTIDE. Your healthcare provider will monitor you for signs and symptoms of heart problems during your treatment with XYLUTIDE. Call your healthcare provider or go to the nearest emergency room right away if you get chest pain or discomfort at rest or with activity or shortness of breath during your treatment with XYLUTIDE.
• Falls and fractures. XYLUTIDE treatment may increase your risk for falls and fractures. 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 XYLUTIDE.

Your healthcare provider will stop treatment with XYLUTIDE if you have serious side effects.

The most common side effects of XYLUTIDE include:

• weakness or feeling more tired than usual
• back pain
• hot flashes
• constipation
• joint pain
• decreased appetite
• diarrhea
• high blood pressure XYLUTIDE may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of XYLUTIDE. Call your doctor for medical advice about side effects.

How should I store XYLUTIDE?

Store below 30°C, Protect from light & moisture.

Keep out of reach & sight of children.

General information about the safe and effective use of XYLUTIDE.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XYLUTIDE for a condition for which it was not prescribed.

Do not give XYLUTIDE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider for information about XYLUTIDE that is written for health professionals.

Details of Manufacturer

BDR Pharmaceuticals Int’l Pvt. Ltd.

1. S. No. 578, Near Effluent Channel Road,

Vill. Luna, Tal. Padra, Dist. Vadodara-391 440. Gujarat.

Marketed By:

Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400 013 INDIA

Details of Permission or Licence Number with Date:

G/25/2071 issued on JULY 2017

Date of Revision:

March, 2021