1479-Prostate metastatic flutamide SUPERSEDED

This protocol has been superseded as there are superior alternative treatments available, with fewer associated toxicities.

This protocol was published over 10 years ago and has been assessed by the reference committee as suitable to be reviewed as required. The review due date has been removed. If something in this protocol requires reference committee consideration, please click on the feedback button at the bottom of the page.

Read more about the as required review process in this factsheet.

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

Drug	Dose	Route
Flutamide	250 mg THREE times a day	PO

Continuous until disease progression or unacceptable toxicity (if used for preventing tumour flare, for 4 to 6 weeks)

Notes:: Treatment with LHRH agonist should be continued throughout treatment with flutamide

Drug status:: Flutamide is PBS authority opens in a new tab or window

Cost:: ~ $210 per month "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Flutamide	250 mg (PO)	THREE times a day (every 8 hours)

Continuous until disease progression or unacceptable toxicity (if used for preventing tumour flare, for 4 to 6 weeks)

Treatment schedule - Overview

Drug	Dose	Route
Flutamide	250 mg THREE times a day	PO

Continuous until disease progression or unacceptable toxicity (if used for preventing tumour flare, for 4 to 6 weeks)

Notes:: Treatment with LHRH agonist should be continued throughout treatment with flutamide

Drug status:: Flutamide is PBS authority opens in a new tab or window

Cost:: ~ $210 per month "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

Treatment schedule - Detail

Continuous treatment
Flutamide	250 mg (PO)	THREE times a day (every 8 hours)

Continuous until disease progression or unacceptable toxicity (if used for preventing tumour flare, for 4 to 6 weeks)

Indications and patient population

Locally advanced or metastatic castrate resistant prostate cancer in combination with LHRH agonist
Short term prevention of tumour flare associated with initiation of an LHRH agonist

Clinical information

Emetogenicity MINIMAL	No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.
Cardiovascular Risk	There may be a relation between androgen deprivation therapy (ADT) and cardiovascular events and death. The metabolic effects of ADT (increased body weight and abdominal girth, increased cholesterol and triglycerides, hyperinsulinaemia) may contribute to cardiovascular risk. Monitoring of blood pressure, lipid profile and blood glucose is recommended.
Prolongation of QT interval	Androgen deprivation therapy may prolong the QT interval and increase the risk of cardiac arrhythmia. Use with caution in patients with a congenital long QT syndrome, congestive heart failure, patients taking medications that may prolong the QT interval, and those with electrolyte disturbances. Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, and the concurrent use of drugs that may prolong the QT interval should be avoided. Baseline and periodic electrocardiogram (ECG) and electrolyte monitoring is recommended. Read more about drugs that may prolong QTc interval at crediblemeds.org opens in a new tab or window (registration required).
Hepatotoxicity	Severe hepatotoxicity (including fatal outcomes) has been observed with this treatment. Onset of hepatic dysfunction typically occurs within 3 to 6 months of starting treatment. Monitor for abnormal liver function tests (LFTs), jaundice and tiredness. Refer to blood tests and dose modification sections for specific recommendations.
Bone mineral density (BMD)	Baseline BMD and repeat as clinically indicated. Lifestyle modification including regular exercise, particularly weight bearing exercises should be encouraged.
Blood tests	LFTs, lipid studies, calcium, vitamin D and BSL at baseline and then repeat LFTs in the first 4 to 6 weeks and regularly throughout treatment. Regular INR and at treatment cessation (patients on warfarin).
Vaccinations	Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines. For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility and fathering a child	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and contraception timeframe should be discussed with all patients of reproductive potential. Read more about the impact of cancer treatment on fertility opens in a new tab or window

Dose modifications

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Kidney dosing recommendations

No dose modification necessary

Hepatic impairment
Hepatic dysfunction
Severe	Cease flutamide if jaundice develops or serum ALT or AST exceeds 2 to 3 x ULN

Interactions

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:

MIMS - interactions tab opens in a new tab or window (includes link to a CYP-450 table) (login required)
Australian Medicines Handbook (AMH) – interactions tab opens in a new tab or window, tables on drugs that may prolong the QT interval opens in a new tab or window, CYP enzymes opens in a new tab or window, P-glycoprotein interactions, opens in a new tab or window and seizure risk opens in a new tab or window (login required)
Micromedex Drug Interactions opens in a new tab or window (login required)
Cancer Drug Interactions opens in a new tab or window
Cytochrome P450 Drug Interactions opens in a new tab or window

For more information see References & Disclaimer.

Flutamide
	Interaction	Clinical management
CYP1A2 & CYP3A4 inhibitors (e.g. abiraterone, ciprofloxacin, amiodarone, fluvoxamine, azole antifungals, ritonavir, clarithromycin, erythromycin, grapefruit juice etc.)	Increased toxicity of flutamide possible due to decreased clearance	Avoid combination or monitor for flutamide toxicity
CYP1A2 & CYP3A4 inducers (e.g. omeprazole, tobacco, carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.)	Reduced efficacy of flutamide possible due to increased clearance	Avoid combination or monitor for decreased clinical response to flutamide
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.)	Additive effect with flutamide/LHRH agonist combination therapy; may lead to torsades de pointes and cardiac arrest	Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia
Warfarin	Increased anticoagulant effect/increased bleeding risk; mechanism unknown	Monitor INR regularly and adjust warfarin dosage as appropriate
Theophylline	Increased theophylline plasma levels; mechanism unknown	Monitor for theophylline toxicity
Paracetamol, opioid analgesics and NSAIDs	Flutamide may affect the metabolism of these drugs	Monitor for increased toxicity of the interacting drugs

Administration

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Administration

This is a continuous oral treatment

Safe handling and waste management (reproductive risk only)

Safe administration

Flutamide

administer orally THREE times a day, every 8 hours
to be swallowed whole with a glass of water; do not break, crush or chew
may be taken with food or without food
if nausea develops, flutamide may be taken with or after food.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Patient information

Ensure patient receives protocol patient information sheet.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting
Headache
Amber or yellow/green discolouration of urine	Amber/yellow/green coloured urine due to the presence of flutamide and/or its metabolites.

Early (onset days to weeks)
Dizziness	Feeling faint or lightheaded, weak or unsteady. Advise patients to stand up slowly from sitting down or lying down positions and increase fluid intake if dehydrated.
Photosensitivity	Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Diarrhoea	Read more about treatment induced diarrhoea
Hot flushes
Fatigue	Read more about fatigue
Fluid retention and oedema	An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Hepatotoxicity	Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation therapy may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Gynaecomastia	Enlargement of male breast tissue usually due to hormone imbalance or hormone therapy
Reduced libido and sexual dysfunction	Lowered sexual desire as well as any physical or psychological problem that interferes with the ability to have and/or enjoy sex.
Alopecia	Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out. Read more about alopecia and scalp cooling
Mood changes

Delayed (onset months to years)
Osteoporosis
Risk of coronary artery disease

Evidence

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

The evidence supporting this protocol is from a collaborative meta-analysis of 27 randomised trials conducted by the Prostate Cancer Trialists Collaborative Group. The trials were commenced between 1981 and 1989 and data gathered from 8275 men with locally advanced or metastatic prostate cancer. The data was reanalysed to compare the effects of maximum androgen blockade (MAB) and androgen suppression (AS) alone on the duration of survival. MAB involved AS (orchiectomy or long term use of a luteinising-hormone releasing hormone (LHRH) agonist) plus an antiandrogen (nilutamide 300 mg/day, flutamide 750 mg/day or cyproterone 100-300 mg/day).¹

A more recent systemic review conducted by Lukka et al. examined the evidence from meta-analytic reports which were published between 1980 and 2004 to determine whether MAB using flutamide, nilutamide and cyproterone acetate is associated with a survival advantage.²

Efficacy

Patients who received nilutamide and flutamide had a 27.6% 5-year survival for MAB vs 24.7%, p=0.005 in AS alone. However the results for cyproterone appeared slightly unfavourable to MAB where 5-year survival was 15.4% vs 18.1%, p=0.04 in AS alone. Overall, the 5-year survival was 25.4% with MAB and 23.6%, p=0.11 with AS alone resulting in an absolute survival difference of about 2%.¹

The Lukka et al. meta-analysis concluded that the small survival benefit conferred by MAB with flutamide and nilutamide is of questionable clinical significance, given the added toxicity and decline in quality of life observed in patients treated with MAB.²

Toxicity²

References References

1: 2000. "Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group." Lancet 355(9214):1491-1498.

Read abstract

Background In advanced prostate cancer, androgen suppression (AS) by surgery or drugs controls testicular hormone secretion, and the further addition of an antiandrogen such as nilutamide, flutamide, or cyproterone acetate is referred to as maximum androgen blockade (MAB). The aim of this overview was to compare the effects on the duration of survival of MAB and of AS alone. Methods The collaborative meta-analysis of 27 randomised trials involved central reanalysis of the data on each of 8275 men (98% of those ever randomised in trials of MAB vs AS) with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow-up was typically for about 5 years. Findings 5932 (72%) men have died; of the deaths for which causes were provided, about 80% were attributed to prostate cancer. 5-year survival was 25·4% with MAB versus 23·6% with AS alone, a non-significant gain of 1·8% (SE 1·3; logrank 2p=0·11). There was no significant heterogeneity in the treatment effect (MAB vs AS) with respect to age or disease stage. The results for cyproterone acetate, which accounted for only a fifth of the evidence, appeared slightly unfavourable to MAB (5-year survival 15·4% MAB vs 18·1% AS alone; difference –2·8% [SE 2·4]; logrank 2p=0·04 adverse), whereas those for nilutamide and flutamide appeared slightly favourable (5-year survival 27·6% MAB vs 24·7% AS alone; difference 2·9% [SE 1·3]; logrank 2p=0·005). Non-prostate-cancer deaths (although not clearly significantly affected by treatment) accounted for some of the apparently adverse effects of cyproterone acetate. Interpretation In advanced prostate cancer, addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%.
2: Lukka, H., T. Waldron, L. Klotz, et al. 2006. "Maximal androgen blockade for the treatment of metastatic prostate cancer--a systematic review." Curr Oncol 13(3):81-93.

Read abstract

Introduction Maximal androgen blockade (MAB) versus castration alone in patients with metastatic prostate cancer has been extensively evaluated in randomized trials. The inconsistent results have led to the publication of multiple meta-analyses. The present review examines the evidence from meta-analytic reports to determine whether MAB using agents such as flutamide, nilutamide, and cyproterone acetate (CPA) is associated with a survival advantage. Methods We conducted a systematic review of the literature (MEDLINE, EMBASE, and the Cochrane Library through July 2004; CANCERLIT through October 2002) for metaanalyses that compared MAB with castration alone in previously untreated men with metastatic prostate cancer (D1 or D2, N+/M0 or M1). Two reviewers selected papers for eligibility; disagreement was resolved by all the authors through consensus. Results The literature search identified six meta-analyses that met the eligibility criteria of the review. Two of those reports were based on individual patient data (IPD), and four were based on data from the published literature. All six meta-analyses pooled data on overall survival. The best evidence came from the largest metaanalysis, conducted by the Prostate Cancer Trialists Collaborative Group and based on IPD (8725 patients) from 27 trials. That analysis detected no difference in overall survival between MAB and castration alone at 2 or 5 years. However, a subgroup analysis showed that MAB with nonsteroidal anti-androgens (NSAAs) was associated with a statistically significant improvement in 5-year survival over castration alone (27.6% vs. 24.7%; p = 0.005). The combination of MAB with CPA, a steroidal anti-androgen, was associated with a statistically significant increased risk of death (15.4% vs. 18.1%; p = 0.04). Compared with castration alone, MAB was associated with more side effects (that is, gastrointestinal, endocrine function) and reduced quality of life in domains related to treatment symptoms and emotional functioning. Conclusions The small survival benefit conferred by MAB with NSAA is of questionable clinical significance given the added toxicity and concomitant decline in quality of life observed in patients treated with MAB. Therefore, combined treatment with flutamide or nilutamide should not be routinely offered to patients with metastatic prostate cancer beyond the purpose of blocking testosterone flare. Monotherapy, consisting of orchiectomy or the administration of a luteinizing hormone–releasing hormone agonist is recommended as standard treatment.
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Read abstract

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History

Version 5

Date	Summary of changes
12/03/2024	Protocol assessed by eviQ medical oncology reference committee and deemed suitable to be reviewed as required. Flag added, review date removed and version number increased to V.5. Read more about as required review protocol status in this factsheet.

Version 4

Date	Summary of changes
27/07/2023	Protocol updated with ADDIKD guideline recommendations. PDF of previous protocol. Version number changed to V.4.

Date

Summary of changes

27/07/2023

Protocol updated with ADDIKD guideline recommendations.

PDF of previous protocol.

Version number changed to V.4.

Version 3

Date	Summary of changes
30/09/2022	Protocol reviewed electronically by Medical Oncology Reference Committee. Decision made to supersede protocol as there are superior alternatives with less associated toxicities available. Version number increased to Version 3. Next review in 4 years.
21/11/2022	Pneumonitis clinical information removed.

Date

Summary of changes

30/09/2022

Protocol reviewed electronically by Medical Oncology Reference Committee. Decision made to supersede protocol as there are superior alternatives with less associated toxicities available.

Version number increased to Version 3. Next review in 4 years.

21/11/2022

Pneumonitis clinical information removed.

Version 2

Date	Summary of changes
09/05/2014	New protocol taken to Medical Oncology Reference Committee meeting.
20/07/2014	Approved and published on eviQ.
27/03/2015	Reviewed electronically by Medical Oncology Reference Committee. No change. Review 2 years.
15/05/2015	Skin rash (Dryness, Erythema and Pruritus) side effect removed.
31/03/2017	Protocol discussed and decided to have a 5 year review period. Next due for review in 2020.
31/05/2017	Transferred to new eviQ website. Protocol version number changed to V.2.
30/11/2017	Link to Androgen Deprivation Therapy (ADT) patient information sheet added to protocol and patient information.
30/06/2020	Protocol reviewed electronically by Medical Oncology Reference Committee. No changes. Review 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 20 July 2014
Last reviewed:: 12 March 2024
Review due:: As required
Superseded:: 30 September 2022

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1479

01 Jul 2025

Prostate metastatic flutamide SUPERSEDED

Treatment schedule Treatment schedule

Administration

Flutamide

Discharge information

Patient information

Efficacy

Toxicity2

References References

Version 5

Version 4

Version 3

Version 2

Toxicity²