Taj Oncology Generics

What Flutamide is used for

• Flutamide is used together with another medicine (LHRH agonists) to treat cancer of the prostate gland. It is also used to prevent "flare" associated with LHRH agonists use.
• Flutamide contains the active ingredient flutamide, which is a non-steroidal antiandrogen. This medicine works by blocking the effects of androgens, male hormones, which prostate cancer cells need to grow.

Ask your doctor if you have any questions about why Flutamide has been prescribed for you. Your doctor may have prescribed Flutamide for another reason.

Flutamide is available only with a doctor's prescription.
There is no evidence that Flutamide is addictive.
As prostate cancer only occurs in men, this medicine therefore should not be used in women.

Before you take Flutamide

When you must not take it
Do not take Flutamide if you are allergic to medicines containing flutamide or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching or hives; swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing; wheezing or shortness of breath.

• Do not take Flutamide if you have serious liver problems.
• Do not take Flutamide if the expiry date (EXP) printed on the pack has passed.
• Do not take Flutamide if the packaging shows signs of tampering or the tablets do not look quite right.
• If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it
Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.
Tell your doctor if you have any medical conditions, especially the following:

• liver problems.

Your doctor may want to take special care if you have this condition.
Tell your doctor if you are pregnant or breastfeeding. Flutamide is only for use in men.

If you have not told your doctor about any of the above, tell him/her before you start taking Flutamide.

Taking other medicines
Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by Flutamide, or may affect how well it works. These include:

• warfarin, a medicine used to prevent blood clots
• theophylline, a medicine used in the treatment of asthma.

Your doctor can tell you what to do if you are taking this medicine.

If you are not sure whether you are taking the above medicine, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Flutamide.

How to take Flutamide

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist.

How much to take
The usual dose is one tablet three times a day.

When to take it
Take Flutamide every eight hours. Flutamide works best when the doses are spaced evenly throughout the day.

Take one tablet when you first get up, one in the afternoon and one at bedtime.
Flutamide can be taken with or without food.

Do not use meals as a reminder to take Flutamide because meals are not normally 8 hours apart.

How to take it
Swallow the tablets with a glass of water.

If you forget to take it
If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.
If you are not sure what to do, ask your doctor or pharmacist.

How long to take it for
To properly control your condition, Flutamide must be taken every day, even if you start to feel better.
Keep taking Flutamide for as long as your doctor recommends. How long to take Flutamide for depends on your response to treatment.

If you take too much (overdose)
Immediately telephone your doctor, or the Poisons Information Centre, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Flutamide.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Flutamide

Things you must do
Before starting any new medicine, tell your doctor or pharmacist that you are taking Flutamide.
Tell all the doctors, dentists and pharmacists who are treating you that you are taking Flutamide.

Visit your doctor regularly for check-ups. Your doctor may ask you to have blood tests to check your liver, especially during the first 4 months of treatment.
If you need to have any other blood tests, tell your doctor that you are taking Flutamide. Flutamide may affect the results of some tests.

Things you must not do

• Do not stop taking Flutamide, or change the dose, without checking with your doctor.
• Do not use Flutamide to treat any other conditions unless your doctor tells you to.
• Do not give Flutamide to anyone else, even if they have the same condition as you.

Things to be careful of
Be careful driving or operating machinery until you know how Flutamide affects you. Dizziness and tiredness have been reported in some people.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Flutamide. Flutamide helps most people with prostate cancer, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.
The side effects listed in this section have been reported in people receiving treatment with this medicine either alone and/or in combination with a LHRH agonist.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor immediately if you notice any of the following symptoms. These may indicate liver disorder, which has been reported very rarely with Flutamide.

• itching of the skin
• dark urine (amber or yellow-green urine is not a cause for concern)
• persistent lack of appetite
• yellow eyes or skin
• tenderness in the right upper stomach
• constant tiredness or "flu-like" symptoms.

Patients receiving the combination of Flutamide plus medical castration may have:

• diarrhoea
• hot flushes (sudden sweating and feelings of warmth)
• increased breast size
• nausea (feeling sick)
• vomiting

Unwanted effects that may occur rarely include:

• bleeding or bruising more than normal
• loss of appetite
• injection site irritation or rash
• swelling of feet or lower legs
• shortness of breath
• muscle ache or twitching
• high blood pressure
• liver damage or brain coma from
• liver illness
• yellow discolouration of the skin or eyes due to failure to remove bile

Unwanted effects that may occur very rarely include:

• difficult or labored breathing
• feeling fatigued
• excessive thirst and urination
• unusual weight loss or weight gain
• nausea and vomiting
• slow healing cuts or infection
• blurred vision
• always feeling hungry
• headaches and feeling dizzy
• mood swings
• leg cramps, tingling/numbness in hands and/or feet

Tell your doctor or pharmacist if any of these occur. In general, patients will experience few additional effects when Flutamide therapy is added to medical castration.

The following tips may help if you are experiencing diarrhoea:

• drink plenty of fluids
• cut down on dairy products
• try eating smaller food portions
• eat more carbohydrates
• in consultation with your doctor, you may also try taking medication to manage diarrhoea.

Since a variety of medications can cause diarrhoea, it is important to tell your physician about all the medicines you take, including those that are non-prescription.

Any therapy that stops the production of male hormones, such as medical or surgical castration, will affect your sex drive. However, the addition of Flutamide to medical castration will not add to this effect. It is important to remember that the reduction of androgen levels may make erection more difficult. If you experience problems, please ask your doctor about available treatment options.

Check with your doctor as soon as possible if you have any problems while taking Flutamide even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Tell your doctor if you notice anything that is making you feel unwell. This is not a complete list of all possible side effects.

Other side effects not listed above may also occur in some people.

After using Flutamide

Storage

• Keep Flutamide where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.
• Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they will not keep well.
• Keep Flutamide in a cool dry place, away from direct light where the temperature stays below 30°C.
• Do not store Flutamide or any other medicine in the bathroom or near a sink.
• Do not leave Flutamide in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal
If your doctor tells you to stop taking Flutamide, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like
Flutamide is a round, yellow, scored tablet marked "TAJ" over "250" on one side and "T" on the other side.

Flutamide is available in packs of 100 tablets.

Ingredients
The active ingredient in Tablets is flutamide.
Each Flutamide tablet contains 250 mg of flutamide.
The tablets also contain the following inactive ingredients:

• lactose
• microcrystalline cellulose
• maize starch
• pregelatinised maize starch
• sodium lauryl sulfate
• colloidal anhydrous silica
• magnesium stearate.

Flutamide are gluten free.

Taj Oncology generics

Trade Name of the Medicinal Product
Flutamide250 mg tablet

Qualitative and Quantitative Composition
Flutamide 250 mg
For excipients, see 6.1.

Pharmaceutical Form
Tablet
Pale yellow round tablets

Clinical Particulars

Therapeutic indications

Treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated. Flutamide may be used as initial treatment in combination with LHRH agonists as adjunctive therapy in patients, already receiving LHRH agonist therapy. Flutamide may also be used in surgically castrated patients.

Posology and method of administration

Adults and Elderly: One tablet three times daily. The tablets should be taken preferably after meals.
When Flutamide tablets are used as initial treatment with an LHRH agonist, a reduction in severity of the flare reaction may be achieved if treatment with Flutamide is initiated before the LHRH agonist. Consequently, it is recommended that treatment with Flutamide should commence at least 3 days before the LHRH agonist.

In patients with impaired liver function, long-term treatment with flutamide should only be initiated after careful assessment of the individual benefits and risks.

Flutamide should be administered with caution in patients with impaired renal function.

Contraindications

Flutamide is contraindicated in patients who are hypersensitive to flutamide  or any component of the product.

For patients with severe liver impairment (Child Pugh C) the use of flutamide is also contraindicated.

Special warnings and special precautions for use

Hepatic Injury- In cases where impaired hepatic function exists, chronic flutamide therapy should only be used after a careful evaluation of the benefit-risk ratio. Liver function tests should be performed before treatment is started. Treatment with flutamide should not be started if the patient`s serum transaminase values are more than two- to threefold normal values.

Since transaminase abnormalities, cholestatic jaundice, hepatic necrosis, and hepatic encephalopathy have been reported with the use of flutamide Tablets or Capsules, periodic liver function tests should be considered. The hepatic conditions were usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide Tablets or Capsules.

Appropriate laboratory liver function tests should be done for every patient once monthly for the first 4 month and then periodically or when first sign/symptoms of liver dysfunction (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained flu-like symptoms) occur. Flutamide Tablet or Capsule therapy should be discontinued if the patient has laboratory evidence of liver injury or clinical jaundice in the absence of biopsy-confirmed liver metastases, or if the serum transaminase values exceed two-to threefold normal values in patients without pathological findings.

Flutamide is indicated only for use in male patients.
Contraceptive measures should be taken during treatment.

Flutamide should be used with caution in patients with impaired renal function.

Flutamide may lead to elevated testosterone and estradiol plasma levels, resulting in fluid retention.  In severe cases this can lead to an increased risk of angina and heart failure.  Therefore, flutamide should be used with caution in the presence of cardiovascular disease. Flutamide can exacerbate edema or ankle swelling in patients prone to these conditions.

An increase in estradiol levels may predispose to thromboembolic events.

Men who receive long-term flutamide treatment in the absence of pharmaceutical or surgical castration, should have sperm counts checked at regular intervals.

Patients with rare hereditary galactose-intolerance, lactose-deficiency or glucose-galactose malabsorption should not take flutamide.

In patients developing a flutamide refractory stage of prostate cancer, flutamide withdrawal may provide short-term (months) therapeutic benefit in about 30% of the patients. Cessation of flutamide for at least 4 weeks is needed to assess flutamide withdrawal response in terms of reduced PSA levels.

Interaction with other medicinal products and other forms of interaction

Interactions between flutamide and leuprolide have not occurred, however, in combination therapy of flutamide Tablets or Capsules administered with an LHRH agonist, the possible adverse effects of each product must be considered.

Increases in prothrombin time have been noted in patients receiving oral anticoagulants therapy after flutamide Tablets or Capsules was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide Tablet or Capsule is administered concomitantly with oral anticoagulants.

Cases of increased theophylline plasma concentrations have been reported.

Concurrent administration of other potentially hepatotoxic drugs should be undertaken only after careful assessment of benefits and risks.

Given the known potential liver and renal toxicities of the product, excessive consumption of alcohol should be avoided.

Pregnancy and lactation

Flutamide is intended only for use in male patients. Contraceptive measures should be taken during treatment.

Flutamide Tablets or Capsules may cause fetal harm when administered to a pregnant woman. In animal studies, the reproductive toxicity of flutamide was associated with the anti-androgenic activity of this agent. There was decreased 24-hour survival in the offspring of rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose) during pregnancy. A slight increase in minor variations in the development of the sternebra and vertebra was seen in fetuses of rats at the two higher doses. Feminization of the males also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day; equal to 1.4 times the human dose).

No studies have been conducted in pregnant or lactating women. Therefore, the possibility that flutamide Tablets or Capsules may cause fetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women, must be considered.

Effects on ability to drive and use machines

No studies on effects on the ability to drive and use machines have been performed with flutamide. However, possible adverse reactions such as fatigue, dizziness and confusion have been reported and may impair the ability to drive and use machines.

Undesirable effects

Monotherapy
The most frequently reported adverse reactions to flutamide Tablets or Capsules are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhea. Mild gynecomastia was observed in 57%, moderate gynecomastia in 36% and massive gynecomastia in 8% of patients.These reactions usually disappear upon discontinuation of treatment or reduction in dosage.

Flutamide Tablets or Capsules demonstrates a low potential for cardiovascular liability, and when compared to diethylstilbestrol this liability has been shown to be significantly lower.

Combination Therapy
The most frequently reported adverse effect experienced during combination therapy of flutamide Tablets or Capsules with an LHRH agonist were hot flushes (61%), decreased libido (36%), impotence (33%), diarrhea (13,6%), nausea and vomiting (14%). With the exception of diarrhea, these adverse experiences are known to occur with LHRH agonists alone, and at comparable frequency.

The high incidence of gynecomastia observed with flutamide Tablets or Capsules monotherapy was markedly lower in combination therapy. In clinical trials, no significant difference in gynecomastia incidence was observed between the placebo- and the flutamide Tablets or Capsules- LHRH agonist treatment groups.

The following convention has been utilised for the classification of frequency: 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) and Very rare (<1/10.000), and not known (cannot be estimated from the available data).

*Few reports of malignant male breast neoplasms in patients being dosed with flutamide tablets have been reported. One involved aggravation of a preexisting nodule which was first detected three to four months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma. The other report involved gynecomastia and a 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 tumor, stage T4N0M0, G3.

Micronodular alterations of the body of breast can uncommonly occur.

An increase in serum testosterone is initially possible during monotherapy with flutamide; in addition, hot flushes and changes in hair character can occur.

Following the marketing of flutamide, cases of acute renal failure, interstitial nephritis, and myocardial ischemia have been reported with frequency unknown.

Overdose

1. In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis and methemoglobinemia.
2. Clinical trials have been conducted with flutamide Tablets or Capsules in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness and some increases in SGOT.
3. The single dose of flutamide Tablets or Capsules ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established. Since flutamide Tablets or Capsules is highly protein bound, dialysis may not be of any use for overdose treatment. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Gastric lavage may be considered.

If vomiting does not occur spontaneously it should be induced, provided that the patient is alert.Pharmacological Properties

Pharmacodynamic properties

Pharmacotherapeutic group: Anti-androgens

Flutamide is a nonsteroidal substance (derivative of anilide) with antiandrogen properties. Flutamide acts on the cellular level. It exerts its antiandrogenic action by inhibiting androgen (mainly testosterone) uptake and/or by inhibiting nuclear binding in target tissues. By combined treatment with an antiandrogen such as flutamide and an LHRH-agonist so-called total androgen block, less androgen effect in the tumour is obtained compared with the LHRH-agonist used as monotherapy. This is caused by flutamide blocking the peripheral androgen receptor and thereby preventing androgens which are produced both in the adrenal gland and testis to affect the target tissues. Patients in an advanced stage with small tumour burden will benefit most of the treatment. Concomitant treatment with an LHRH-agonist also prevents a flare-up reaction of the disease which occurs during the first month of treatment with the LHRH-agonist caused by an initial elevation of the testosterone levels with a significant increase of prostate specific antigen (PSA).

Pharmacokinetic properties

The pharmacokinetic characteristics of flutamide used as monotherapy are incompletely studied. Peak serum concentration is obtained after about 1-2 hours. The plasma protein binding is about 95%. Flutamide is extensively metabolised. One hour after dosing only 2.5% of given dose consists of unchanged flutamide. The major metabolite in plasma is alphahydroxy flutamide which is pharmacologically active and contributes to the pharmaco­logical effect to a higher degree than the main substance. About 30 times higher plasma concentration of the active metabolite is achieved. The terminal plasma half-lifes of the flutamide and the active metabolite are about 8 hours and 9 hours respectively. After repeated dose the steady-state concentration of flutamide is obtained within about 4 days. Flutamide is mainly eliminated by metabolism and the metabolites are excreted via urine. Only about 5% is excreted via the faeces.

Preclinical safety data

The effects observed in oral repeat dose toxicology studies in the rat, dog and monkey were as expected for a potent anti-androgenic agent. Reductions in prostate gland and seminal vesicle weights were observed in all species and reduced testicular weights were observed in the rat and monkey. Histological changes characteristic of anti-androgenic activity were observed in all species and there was evidence of suppression of spermatogenesis.

Pharmaceutical Particulars

List of excipients

Microcrystalline cellulose, maize starch, sodium lauryl sulphate, lactose monohydrate, colloidal anhydrous silica, magnesium stearate.

Incompatibilities

Not applicable

Shelf life

5 years.

Special precautions for storage

No special precautions for storage

Nature and contents of container

PVC/Aluminium foil blister strips with 21, 50, 84, 90, 100, 105, or 200 tablets in each box.
Not all pack sizes may be marked.

Instructions for use and handling

No special requirements.