New XTANDITM
(enzalutamide) 40 mg tablets

From 30th September 2019, XTANDI 40 mg tablets
are replacing 40 mg capsules


Medication not actual size

The same treatment regimen1

160 mg

Once a Day

40 mg X 4

Medication not actual size

XTANDI can
be taken

Due to the mechanism
of action of XTANDI,
concomitant use of
steriods is not required

Tablets not drawn to scale

XTANDI requires no
routine, product-
specific monitoring of
serum potassium, fluid
retention and serum
transaminases

The same efficacy and safety profile

XTANDI is generally well tolerated2–4*

XTANDI is efficacious in:1

  • The treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).
  • The treatment of adult men with metastatic castration-resistant prostate cancer (mCRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated.
  • The treatment of adult men with mCRPC whose disease has progressed on or after docetaxel therapy.
This webpage is intended for UK Healthcare Professionals only.

* A summary of the XTANDI safety profile and its special warnings and precautions for use can be found below.

mCRPC, metastatic castration-resistant prostate cancer;

nmCRPC, non-metastatic castration-resistant prostate cancer.

But smaller than existing XTANDI capsules

PIP code: 410-8338

XTANDI 40 mg tablets. It’s the little things
that can make a big difference to patients.

Summary of XTANDI safety profile1

Very common and common adverse reactions observed during clinical studies are listed by frequency category. These data are from clinical trials and post-marketing surveillance.1

For a complete list of the AEs observed with XTANDI, please refer to the Summary of Product Characteristics.1

Frequency categories are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10) 1

MedDRA System organ class Adverse reaction and frequency
Psychiatric disorders Common: Anxiety
Nervous System disorders Common: Headache, memory impairment, amnesia,
disturbance in attention, restless legs syndrome
Cardiac disorders Common: Ischaemic heart disease*
Vascular disorders Very Common: Hot flush, hypertension
Skin and subcutaneous tissue disorders Common: Dry skin, pruritus
Musculoskeletal and connective
tissue disorders
Very Common: Fractures †
Reproductive and breast disorder Common: Gynaecomastia
General disorders and administration
site condtions
Very Common: Asthenia, fatigue
Injury, poisoning
and procedural complications
Common: Falls

* As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomised placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery.

† Includes all preferred terms with the word ‘fracture’ in bones.

Use of enzalutamide has been associated with seizure. The decision to continue treatment in patients who develop seizure should be taken case by case. In the 9785-CL-0403 (UPWARD) single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months.1

Special warnings and precautions for use1

Risk of seizure: Use of enzalutamide has been associated with seizure. The decision to continue treatment in patients who develop seizure should be taken case by case.

Posterior reversible encephalopathy syndrome: There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of XTANDI in patients who develop PRES is recommended.

Concomitant use with other medicinal products: Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products. A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations. Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If XTANDI is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted.

Renal impairment: Caution is required in patients with severe renal impairment as enzalutamide has not been studied in this patient population.

Severe hepatic impairment: An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction may be increased.

Recent cardiovascular disease: The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if XTANDI is prescribed in these patients.

Androgen deprivation therapy may prolong the QT interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating XTANDI.

Use with chemotherapy: The safety and efficacy of concomitant use of XTANDI with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel; however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded.

Excipients: XTANDI capsules contain sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.5

Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide.

Effects on ability to drive and use machines: XTANDI has moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported. Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines. No studies to evaluate the effects of enzalutamide on the ability to drive and use machines have been conducted.

Prescribing Information

Prescribing Information: XTANDI™ (enzalutamide) 40 mg soft capsules
Prescribing Information: XTANDI™ (enzalutamide) 40 mg film-coated tablets

For full prescribing information, refer to the Summary of Product Characteristics (SPC)
Presentation: XTANDI 40 mg soft capsules and 40mg film-coated tablets each containing 40 mg of enzalutamide.
Indications: The treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC). The treatment of adult men with metastatic (CRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. The treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
Posology and method of administration: 160 mg enzalutamide (four 40 mg soft capsules or film-coated tablets) as a single oral daily dose. The soft capsules should not be chewed, dissolved or opened but should be swallowed whole with water, and can be taken with or without food. The film-coated tablets should not be cut, crushed or chewed but should be swallowed whole with water, and can be taken with or without food. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated. If a patient misses taking XTANDI at the usual time, the prescribed dose should be taken as close as possible to the usual time. If a patient misses a dose for a whole day, treatment should be resumed the following day with the usual daily dose. If a patient experiences 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 (120 mg or 80 mg) if warranted. Concomitant use with strong CYP2C8 inhibitors: The concomitant use of strong CYP2C8 inhibitors should be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor. Elderly: No dose adjustment is necessary for elderly patients. Hepatic impairment: No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C, respectively). Renal impairment: No dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is advised in patients with severe renal impairment or end-stage renal disease.
Contraindications: Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1 of the SPC. Women who are or may become pregnant (see sections 4.6 and 6.6 of the SPC).
Special warnings and precautions for use: Risk of seizure: Use of enzalutamide has been associated with seizure (see section 4.8 of the SPC). The decision to continue treatment in patients who develop seizure should be taken case by case. Posterior reversible encephalopathy syndrome: There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI (see section 4.8 of the SPC). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of XTANDI in patients who develop PRES is recommended. Concomitant use with other medicinal products: Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5 of the SPC). A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters (see section 4.5 of the SPC) should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations. Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If XTANDI is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted (see section 4.5 of the SPC). Renal impairment: Caution is required in patients with severe renal impairment as enzalutamide has not been studied in this patient population. Severe hepatic impairment: An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction (see section 4.5 of the SPC) may be increased. Recent cardiovascular disease: The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if XTANDI is prescribed in these patients. Androgen deprivation therapy may prolong the QT interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5 of the SPC) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating XTANDI. Use with chemotherapy: The safety and efficacy of concomitant use of XTANDI with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel (see section 4.5 of the SPC); however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded. Excipients: XTANDI soft capsules contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take XTANDI soft capsules. Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide (see section 4.8 of the SPC).
Effects on ability to drive and use machines: XTANDI has moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported. Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines. No studies to evaluate the effects of enzalutamide on the ability to drive and use machines have been conducted.
Interactions: CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80mg once daily (see section 4.5 of the SPC). Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5’-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers. The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed)

during the first month of enzalutamide treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment. In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter 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 XTANDI and may require dose adjustment to maintain optimal plasma concentrations.
Contraception in males and females: It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity (see section 5.3 of the SPC).
Undesirable effects: Summary of the safety profile: The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other important adverse reactions include fall, cognitive disorder, and neutropenia. Seizure occurred in 0.4% of enzalutamide-treated patients, 0.1% of placebo-treated patients and 0.3% in bicalutamide-treated patients. Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients (see section 4.4 of the SPC). Adverse reactions observed during clinical studies 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 and by MedDRA System organ class. Adverse reactions identified in controlled clinical trials and post-marketing: Blood and lymphatic system disorders: Uncommon: leucopenia, neutropenia; Not known*: thrombocytopenia. Immune system disorders: Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema. Psychiatric disorders: Common: anxiety; Uncommon: visual hallucination. Nervous system disorders: Common: headache, memory impairment, amnesia, disturbance in attention, restless legs syndrome; Uncommon: cognitive disorder, seizure¥; Not known*: posterior reversible encephalopathy syndrome. Cardiac disorders: Common: ischemic heart disease; Not known*: QT-prolongation (see sections 4.4 and 4.5 of the SPC). Vascular disorders: Very common: hot flush, hypertension. Gastrointestinal disorders: Not known*: nausea, vomiting, diarrhoea. Skin and subcutaneous tissue disorders: Common: dry skin, pruritus; Not known*: rash. Musculoskeletal and connective tissue disorders: Very common: fractures‡; Not known*: myalgia, muscle spasms, muscular weakness, back pain. Reproductive system and breast disorder: Common: gynaecomastia. General disorders and administration site conditions: Very common: asthenia, fatigue. Injury, poisoning and procedural complications: Common: fall. * Spontaneous reports from post-marketing experience. ¥ As evaluated by narrow Standardised MedDRA Queries (SMQs) of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures, partial seizures, and status epilepticus. This includes rare cases of seizure with complications leading to death. † As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery. ‡ Includes all preferred terms with the word ‘fracture’ in bones. Description of selected adverse reactions: Seizure: In controlled clinical studies, 13 patients (0.4%) experienced a seizure out of 3179 patients treated with a daily dose of 160 mg enzalutamide, whereas one patient (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide, experienced a seizure. Dose appears to be an important predictor of the risk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlled clinical studies, patients with prior seizure or risk factors for seizure were excluded. In the 9785-CL-0403 (UPWARD) single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months. 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. Ischemic Heart Disease: In randomized placebo-controlled clinical studies, ischemic heart disease occurred in 2.5% of patients treated with enzalutamide plus ADT compared to 1.3% patients treated with placebo plus ADT. Prescribers should consult the SPC in relation to other adverse reactions.
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.
Cost (excluding VAT): XTANDI 40mg soft-capsules/film-coated tablets x 112: £2,734.67.
Legal classification: POM.
Marketing Authorisation number: XTANDI 40mg soft-capsules EU/1/13/846/001, XTANDI 40mg film-coated tablets EU/1/13/846/002.
Marketing Authorisation Holder: Astellas Pharma Europe B.V. Sylviusweg 62. 2333 BE Leiden. The Netherlands.
Date of Preparation of Prescribing Information: May 2019.
Job Bag Number: XTD_2019_0009_UK.
Further information available from: Further information available from: Astellas Pharma Ltd, Medical Information 0800 783 5018. For full prescribing information, please see the Summary of Product Characteristics, which may be found at www.medicines.org.uk

Adverse events should be reported. Reporting forms and
information can be found at www.mhra.gov.uk/yellowcard.
Adverse events should also be reported to
Astellas Pharma Ltd. on 0800 783 5018.

References

1. XTANDI Tablet Summary of Product Characteristics.
2. Beer TM, et al. Eur Urol. 2017;71:151-4.
3. Hussain M, et al. New Engl J Med. 2018.378:2465–74.
4. Scher HI, et al. New Engl J Med. 2012;367(13):1187–1197.
5. XTANDI Capsule Summary of Product Characteristics.