NEW ZEALAND DATA SHEET

FLUTAMIN

1. Product Name
Flutamin, 250 mg, tablet.

2. Qualitative and Quantitative Composition

Each tablet contains 250 mg of flutamide.

Contains lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form
Yellow, 12.5 mm round, biconvex tablets debossed with FT above the score and 250 below the
score on one side of the tablet and G on the other side.

4. Clinical Particulars
4.1 Therapeutic indications
For the palliative treatment of advanced prostatic cancer in previously untreated patients or those
who have not responded or who have become refractory to hormonal manipulation.

As a component of the treatment used in the management of locally advanced prostatic carcinoma.

4.2 Dose and method of administration

The recommended dosage is one tablet three times a day at intervals of eight hours.

Flutamide tablets have been administered as monotherapy with or without surgical castration and
in combination with medical (luteinising hormone-releasing hormone [LHRH] agonist) hormonal
manipulation.

In combination with an LHRH agonist, flutamide tablets should be started 24 hours prior to initiation
of the LHRH agonist, to achieve the benefit of the adjunctive therapy.

In localised prostatic carcinoma, administration of flutamide and an LHRH agonist should begin
eight weeks prior to radiation therapy and continue through the course of radiation therapy. Prior to
radical prostatectomy, flutamide should be administered for 3 months.

4.3 Contraindications
Flutamide tablets are contraindicated in patients exhibiting sensitivity reactions to flutamide or any
components of this preparation.

Flutamide is also contraindicated in patients with severe hepatic impairment.

Page 1 of 7
4.4 Special warnings and precautions for use
Flutamide is indicated only for use in male patients.

When flutamide tablets are administered in combination with LHRH agonists, the possible adverse
effects of each product must be considered.

Since flutamide administration tends to elevate plasma testosterone and oestradiol levels, fluid
retention may occur.

Hepatic injury
There have been post-marketing reports of hospitalisation and rarely death due to liver failure in
patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels,
jaundice, hepatic necrosis, hepatic encephalopathy and death related to acute hepatic failure. The
hepatic injury was usually reversible after prompt discontinuation of therapy. Approximately half of
the reported cases of hepatic injury occurred within the initial 3 months of treatment with flutamide.

Treatment with flutamide should not be initiated in patients with serum transaminase levels
exceeding 2 to 3 times the upper limit of normal. Periodic liver function tests must be performed in
all patients. Appropriate laboratory testing should be done monthly for the first 4 months, and
periodically thereafter, and at the first symptom/sign of liver dysfunction (e.g. pruritus, dark urine,
persistent anorexia, jaundice, right upper quadrant tenderness or unexplained "flu-like” symptoms).
If the patient has laboratory evidence of liver injury or jaundice, in the absence of biopsy-confirmed
liver metastases, flutamide therapy should be discontinued if the patient develops jaundice or if the
serum transaminase levels rise to 2 to 3 times the upper limit of normal, even in clinically
asymptomatic patients. Liver function tests should be followed-up closely until resolution.

Precautions for patients

Patients should be informed prior to initiating flutamide, of the possibility of its causing hepatic
dysfunction. Instruct the patient to consult the doctor immediately if symptoms of hepatic
dysfunction appear. These include itching of the skin, dark urine (amber or yellow-green urine is
not a cause for concern – see section 4.8), nausea, vomiting, persistent lack of appetite, yellow
eyes or skin, tenderness in the right upper abdomen or “flu-like” symptoms.

Cardiovascular
Based on studies conducted in the literature, combined androgen blockade with an anti-androgen
plus LHRH analogue may increase risk of cardiovascular disease (heart attack, cardiac failure,
sudden cardiac death) and adversely affects independent cardiovascular risk factors (serum
lipoproteins, insulin sensitivity and obesity). Physicians should carefully consider whether the
benefits of combined androgen blockade outweigh the potential cardiovascular risk. Assessment of
cardiovascular risk factors, monitoring for signs and symptoms suggestive of development of
cardiovascular disease, and management according to local clinical practice and guidelines should
be considered.

Effect on QT/QTc interval

The potential for QT/QTc prolongation has not been studied with flutamide tablets. Combined
androgen blockade studies with other anti-androgen plus LHRH analogue or surgical castration
have been associated with the potential to prolong QT/QTc interval on ECG. Physicians should
consider whether the benefits of androgen deprivation therapy outweigh the potential risk in
patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure
and in patients taking Class IA (e.g. quinidine, procainamide), Class III (e.g. amiodarone, sotalol,
dofetilide, ibutilide), or Class IC (e.g. flecainide, propafenone) antiarrhythmic medications.

Endocrine and metabolism

A reduction in glucose tolerance and/or glycated hemoglobin (HbAlc) has been observed in males
receiving combined androgen blockade. This may manifest as diabetes or loss of glycemic control
in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood

Page 2 of 7
glucose and/or glycated hemoglobin (HbAlc) in patients receiving flutamide tablets in combination
with LHRH analogues.

Hematologic
Anemia is a known physiologic consequence of testosterone suppression. Assessment of anemia
risk and management according to local clinical practice and guidelines should be considered.

Musculoskeletal / changes in bone density

Based on studies conducted in the literature, decreased bone mineral density can be anticipated
with long term combined androgen blockade with an anti-androgen plus LHRH analogue.
Combined androgen blockade is associated with increased risks of osteoporosis and skeletal bone
fractures. The risk of skeletal fracture increases with the duration of combined androgen blockade.
Assessment of osteoporosis risk and management according to clinical practice and guidelines
should be considered.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such
as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis or
chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids,
combined androgen blockade may pose an additional risk. In these patients, risk versus benefit
must be weighed carefully before therapy is instituted.

Carcinogenicity
Daily administration of flutamide to rats for 52 weeks at doses of 30, 90 or 180 mg/kg/day,
produced testicular interstitial adenomas at all doses.

In a 24-month carcinogenicity study conducted with male rats, daily administration of flutamide at
doses of 10, 30 and 50 mg/kg/day was associated with an increased number of testicular cell
adenomas at all doses tested and with dose-related increases in mammary gland adenomas and
carcinomas.

Two reports of malignant male mammary gland neoplasms have been reported in patients being
treated with flutamide (see section 4.8).

4.5 Interaction with other medicines and other forms of interaction

It should be remembered that flutamide is an antiandrogen and as such may interact
pharmacologically with androgens, oestrogens or other forms of hormonal therapy.

Clinical studies have suggested that flutamide when used with LHRH agonists, may suppress any
disease flare which may be caused by the LHRH agonist.

Increases in prothrombin time have been noted in patients receiving oral anticoagulant and
flutamide therapy concomitantly. Therefore, close monitoring of prothrombin time is recommended
and adjustment of the initiating or maintenance anticoagulant dose may be necessary.

Cases of increased theophylline plasma concentrations have been reported in patients receiving
concomitant theophylline and flutamide.

Flutamide inhibits steroid metabolism in rat testicular microsomes and alters their content of
cytochrome P-450. Although this may be organ specific, an effect on liver microsomes has not
been excluded, so the metabolism of some drugs by the liver may be affected by flutamide.
Although data are not available on potential interaction between flutamide and paracetamol, opioid
analgesics or non-steroidal anti-inflammatory agents, flutamide may affect the metabolism of these
drugs which are frequently administered to patients with prostate cancer.

The potential for QT/QTc prolongation has not been studied with flutamide tablets. Since combined
androgen blockade prolongs the QTc interval, the concomitant use of flutamide tablets or capsules
with medicinal products known to prolong the QTc interval or medicinal products able to induce
torsades de pointes should be carefully evaluated. Such medicinal products include but are not

Page 3 of 7
limited to the examples that follow: Class IA (e.g. quinidine, disopyramide), Class III (e.g.
amiodarone, sotalol, dofetilide, ibutilide, dronedarone), or Class IC (e.g. flecainide, propafenone)
antiarrhythmic medicinal products, antipsychotics (e.g. chlorpromazine), antidepressants (e.g.
amitriptyline, nortriptyline), opioids (e.g. methadone), macrolide antibiotics and analogues (e.g.
erythromycin, clarithromycin, azithromycin), quinolone antibiotics (e.g. moxifloxacin), antimalarials
(e.g. quinine), azole antifungals, 5-hydroxytryptamine (5-HT3) receptor antagonists (e.g.
ondansetron), and beta-2 adrenoceptor agonists (e.g. salbutamol).

4.6 Fertility, pregnancy and lactation

Flutamide is indicated only for use in male patients. No studies have been conducted in pregnant
or lactating women. Therefore, the possibility that flutamide may cause foetal harm if administered
to a pregnant woman, or may be present in the breast milk of lactating women, must be
considered.

Fertility
No data available.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Cholestatic jaundice, hepatic encephalopathy and hepatic necrosis have been reported. The
hepatic conditions were usually reversible after discontinuing therapy; however, there have been
reports of death following severe hepatic injury associated with the use of flutamide.

In combination therapy of flutamide with LHRH agonists, the most frequently reported adverse
effects experienced were hot flushes, decreased libido, impotence, diarrhoea, nausea and
vomiting. With the exception of diarrhoea, these adverse effects are known to occur with LHRH
agonists alone, and at comparable frequency.

The most frequently reported adverse reactions to flutamide monotherapy are gynecomastia
and/or breast tenderness, sometimes accompanied by galactorrhea. These are greatly reduced
when flutamide tablets are administered concomitantly with an LHRH agonist.

Central nervous system reactions including drowsiness, confusion, depression, anxiety and
nervousness have also been reported.

Two cases of pulmonary embolism have been reported in patients receiving flutamide but a
relationship to flutamide has not been established. Very rarely, interstitial lung disease has
occurred.

Other adverse reactions

Other less frequent adverse reactions reported with flutamide monotherapy and/or combination
therapy include:

Gastrointestinal:
Constipation, increased appetite, anorexia

Central nervous system:

Insomnia, tiredness, headache, dizziness, malaise, drowsiness, confusion, depression, anxiety,
nervousness

Skin and subcutaneous tissue disorders:

Ecchymoses, herpes zoster, pruritus

Page 4 of 7
Haematological:
Anemia, leucopenia, thrombocytopenia, haemolytic anemia, macrocytic anemia,
methaemoglobinemia, sulfhaemoglobinemia

Others:
Peripheral oedema, genitourinary, neuromuscular symptoms, photosensitivity reactions (including
erythema, ulcerations, bullous eruptions and epidermal necrolysis), injection site irritation and rash
associated with the administration of the LHRH agonist. Change in urine colour to an amber or
yellow-green appearance which can be attributed to flutamide and/or its metabolites. Usually these
other reactions have not been of sufficient severity to require dosage reduction or discontinuation
of treatment. If adverse reactions are severe, a reduction in dosage, without loss of efficacy, may
be beneficial.

Hyperglycaemia and aggravated diabetes mellitus have been reported very rarely.

Reduced sperm counts have been reported rarely in long-term treatment. Flutamide tablets
demonstrate a low potential for cardiovascular liability, and when compared to diethylstilboestrol,
this liability has been shown to be significantly lower. Although there have been reports of
cardiovascular adverse events in patients on flutamide therapy, the relation of these to flutamide
has not yet been elucidated.

Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been
reported. One involved aggravation of a pre-existing nodule which was first detected three to four
months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy.
After one month of treatment, the nodule was excised and was diagnosed as a poorly differentiated
ductal carcinoma. The other report involved a patient who developed gynaecomastia and a breast
nodule noted two and six months respectively after initiation of flutamide monotherapy for
treatment of advanced prostatic carcinoma. Nine months after the initiation of therapy the nodule
was excised and diagnosed as a moderately differentiated invasive ductal tumour staged T4N0M0,
G3.

Laboratory tests
Abnormal laboratory test values reported include changes in liver function tests (e.g. elevated
transaminases), elevated blood urea nitrogen (BUN) levels and rarely elevated serum creatinine
levels. Changes in liver function tests have been observed in 3 to 31% of patients treated with
flutamide monotherapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are
asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose
The single flutamide dose ordinarily associated with symptoms of overdosage or considered to be
life-threatening has not been established. One patient survived after ingesting more than 5 grams
of flutamide as a single dose. No adverse effects were observed.

Treatment
As in the management of overdosage with any drug, the possibility that multiple agents may have
been taken should be considered. If vomiting does not occur spontaneously, it should be induced if
the patient is alert. General supportive care, including frequent monitoring of the vital signs and
close observation of the patient, is indicated. Since flutamide is highly protein bound, dialysis may
not be of any use as treatment for an overdose.

For further advice on management of overdose please contact the National Poisons Information
Centre (0800 POISON or 0800 764 766).

Page 5 of 7
5. Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-androgens, ATC code: L02BB01

Mechanism of action
FLUTAMIN (flutamide) demonstrates potent antiandrogenic effects by inhibiting androgen uptake
and/or by inhibiting nuclear binding of androgen in target tissues.

Pharmacodynamic effects
Flutamide exhibits specific antiandrogenic effects, largely directed to the prostate as target organ.
Flutamide, administered orally to intact immature male rats at doses ranging from 1 to 25 mg/kg,
significantly reduced prostate and seminal vesicle weights. Other endocrine structures were not
altered. In studies of dogs with benign prostatic hypertrophy, daily oral administration of flutamide
(5 to 50 mg/kg) for six weeks reduced the size of the prostate gland and reversed the associated
histologic and histochemical changes.

Studies of the mechanism of flutamide's antiandrogenic action on the ventral prostate gland of the
rat indicate that it either inhibits androgen uptake or blocks nuclear binding of androgens in target
tissues. While flutamide exerts antiandrogenic action on the accessory sex structures, it did not
decrease sexual activity or spermatogenesis in male rats at pharmacologically active doses.

Flutamide exhibits specific activity towards androgen-dependent receptors with little effect on other
hormonal receptors. It lacks estrogenic, antiestrogenic, progestational and antiprogestational
activities.

5.2 Pharmacokinetic properties

Analysis of plasma, urine and feces of three male volunteers following a single oral 200 mg dose of
tritium-labelled flutamide revealed that the drug is rapidly and completely absorbed and excreted
mainly in the urine. At least six metabolites have been identified in plasma. The distribution and
elimination half-lives for flutamide are 0.8 and 7.8 hours respectively, and the corresponding half-
lives for its active metabolite, 2-hydroxyflutamide, are 1.7 and 8.1 hours respectively. The major
urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.

Tissue distribution of flutamide was examined in male rats given an oral dose of 14C-flutamide at
5 mg/kg. Total drug levels were highest 6 hours after drug administration in all tissues. Levels
declined at roughly similar rates to low levels at 18 hours. The major metabolite, hydroxyflutamide,
was present at higher concentrations than flutamide in all tissues studied.

Hydroxyflutamide was relatively concentrated in the rat ventral prostate gland and seminal vesicles,
previously demonstrated to be the target organs of pharmacological activity. It was similarly concentrated in
the rat pituitary gland.

The very rapid and almost complete conversion of flutamide to metabolites strongly suggests that
the biological activity shown by this substance is due to an active metabolite. Hydroxyflutamide is
the major metabolite in man and laboratory animals, and has been shown to possess potent
antiandrogenic activity.

5.3 Preclinical safety data

No data available.

Page 6 of 7
6. Pharmaceutical Particulars
6.1 List of excipients
Lactose monohydrate, maize starch, pre-gelatinised maize starch, cellulose, sodium lauryl sulfate,
silica, magnesium stearate

Flutamin is gluten free.

6.2 Incompatibilities
Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store at or below 30°C. Protect from light.

6.5 Nature and contents of container

Al/PVC blister pack of 100 tablets.

6.6 Special precautions for disposal

Not applicable.

7. Medicines Schedule
Prescription Medicine

8. Sponsor Details
Mylan New Zealand Ltd
PO Box 11183
Ellerslie
AUCKLAND
Telephone 09-579-2792

9. Date of First Approval

11 March 1999

10. Date of Revision of the Text

15 May 2018 Revise to SmPC format

Page 7 of 7