Symptoms
In animal studies with Flutamida Filaxis alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia and/or lacrimation, anorexia, tranquilisation, emesis and methaemoglobinaemia.
Clinical trials have been carried out with famotidine at doses of up to 1500 mg per day for periods of up to 36 weeks without reports of severe undesirable effects. The undesirable effects reported were gynaecomastia, breast sensitivity and some increases in SGOT.
The acute toxic dose of Flutamida Filaxis in man has not been established. One patient survived after ingesting more than 5 g as a single dose, with no apparent adverse effects. Since Flutamida Filaxis is an anilide compound, it has the theoretic potential of producing methaemoglobinaemia. Accordingly, a patient with acute intoxication may be cyanotic.
Management
If vomiting does not occur spontaneously it should be induced, provided that the patient is alert. Gastric lavage may be considered. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. General supportive measures are appropriate, including frequent monitoring of vital signs and close observation of the patient. Since Flutamida Filaxis is highly protein bound, dialysis may not be of any use as treatment for overdose.
Not applicable.
Monotherapy
The undesirable effects of Flutamida Filaxis most frequently reported are gynaecomastia and/or breast tenderness, sometimes accompanied by periods of galactorrhoea. These reactions often disappear with the suspension of the treatment or reduction of the dose.
It has been proven that famotidine has a low cardiovascular risk potential, significantly less than that of diethylstilboestrol.
Combined treatment
The undesirable effects most frequently reported during combined treatment of famotidine with an LHRH agonist were hot flushes, reduced libido, erectile dysfunction, diarrhoea, nausea and vomiting. With the exception of diarrhoea, these are known undesirable effects of LHRH agonists alone, with a similar frequency.
The high rate of occurrence of gynaecomastia observed with monotherapy with Famotidine decreased greatly in combined treatment. In clinical trials, no significant difference was observed in the rate of occurrence of gynaecomastia between the placebo group and the group treated with famotidine and LHRH agonists.
The following convention has been utilised for the frequency classification:
Very common - (>1 in 10)
Common - (>1 in 100 to <1 in 10)
Uncommon - (>1 in 1,000 to <1 in 100)
Rare - (>1 in 10,000 to <1 in 1,000)
Very rare - (<1 in 10,000)
Not known - (cannot be estimated from the available data)
| SOC | Monotherapy | Combination therapy with LHRH analog |
| Infections and infestations | ||
| Rare | Herpes zoster | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Very rare | Neoplasm of the male breast* | |
| Blood and lymphatic system disorders | ||
| Rare | Anaemia, leucopenia, thrombocytopenia | |
| Very rare | Haemolytic anaemia, megalocytic anaemia, methaemoglobinaemia, sulfhaemoglobinaemia, macrocytic anaemia | |
| Immune system disorders | ||
| Rare | Lupus-like syndrome | |
| Metabolism and nutrition disorders | ||
| Common | Increased appetite | |
| Rare | Anorexia | Anorexia |
| Very rare | Hyperglycaemia, aggravation of diabetes mellitus | |
| Psychiatric disorders | ||
| Common | Insomnia | |
| Rare | Anxiety, depression | Depression, anxiety |
| Nervous system disorders | ||
| Rare | Dizziness, headache | Numbness, confusion, nervousness, drowsiness |
| Eye disorders | ||
| Rare | Blurred vision | |
| Cardiac disorders | ||
| Rare | Cardiovascular disorders | |
| Not known | QT prolongation | |
| Vascular disorders | ||
| Very common | Hot flushes | |
| Rare | Hot flushes, hypertension, lymphoedema | Hypertension |
| Not known | Thromboembolism | |
| Respiratory, thoracic and mediastinal disorders | ||
| Rare | Interstitial pneumonitis, dyspnoea | |
| Very rare | Cough | Pulmonary symptoms (e.g. dyspnoea), interstitial lung disease |
| Gastrointestinal disorders | ||
| Very common | Diarrhoea, nausea, vomiting | |
| Common | Nausea, vomiting, diarrhoea | |
| Rare | Non-specific abdominal disorders, constipation, ulcer-like pain, dyspepsia, colitis, upset stomach, heartburn | Non-specific abdominal disorders, abdominal pain |
| Hepatobiliary disorders | ||
| Common | Hepatitis | |
| Uncommon | Hepatitis | |
| Rare | Liver function test abnormalities | Hepatic dysfunction, jaundice |
| Very rare | Cholestatic jaundice, hepatic encephalopathy, liver cell necrosis, hepatotoxicity with fatal outcome | |
| Skin and subcutaneous tissue disorders | ||
| Rare | Urticaria, pruritus, ecchymosis, alteration of the hair growth pattern and loss of hair (head) | Rash |
| Very rare | Photosensitivity reactions | Photosensitivity reactions, erythema, ulcers, bullous eruptions, epidermal necrolysis |
| Musculoskeletal and connective tissue disorders | ||
| Rare | Muscle cramps | Neuromuscular symptoms, reduced bone mineral density, osteoporotic disorders, arthralgia, myalgia |
| Renal and urinary disorders | ||
| Rare | Genitourinary tract symptoms, dysuria, changes in urinary frequency, change in urine colour to amber or yellow-green | |
| Reproductive system and breast disorders | ||
| Very common | Gynaecomastia and/or breast pain, breast tenderness, galactorrhoea | Decreased libido, impotence |
| Uncommon | Gynaecomastia | |
| Rare | Reversible increase of serum testosterone levels, reduced sperm counts, decreased libido | |
| General disorders and administration site conditions | ||
| Common | Somnolence, tiredness | |
| Rare | Oedema, asthenia, malaise, thirst, chest pain, hot flushes, weakness | Oedema, injection site irritation |
| Investigations | ||
| Common | Transient abnormal liver function | Changes in liver function |
| Rare | Elevated blood urea nitrogen (BUN) values, elevated serum creatinine values | |
* There have been a few cases reported of malignant breast neoplasms in male patients treated with famotidine. One of them consisted of the aggravation of a lump that had been detected previously, three or four months prior to commencing monotherapy with Flutamida Filaxis in a patient with benign prostatic hypertrophy. After the excision, a diagnosis was made of slightly differentiated ductal carcinoma. The other case consisted of gynaecomastia and a lump, observed, respectively, two to six months after the start of monotherapy with Flutamida Filaxis to treat an advanced prostate carcinoma. Nine months after the treatment began, the lump was removed and a moderately differentiated invasive ductal tumour was diagnosed in T4N0M0, G3 state.
The high incidence of gynaecomastia seen with Flutamida Filaxis monotherapy is generally reduced with combination therapy.
Micronodular alterations of the body of breast can uncommonly occur.
An increase in serum testosterone is initially possible during monotherapy with Flutamida Filaxis. In addition, hot flushes and changes in hair character can occur.
Following the marketing of Flutamida Filaxis, cases of acute renal failure, interstitial nephritis, and myocardial ischemia have been reported with frequency unknown.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.go.uk/yellowcard
The effects observed in oral repeat dose toxicology studies in the rat, dog and monkey were as expected for a potent anti-androgenic agent.
Studies have been performed in animals to determine the tolerance after repeated oral administration for a period of up to 6, 52 and 78 weeks in monkeys, rats and dogs, respectively. The oral doses administered daily reached 90 mg/kg in monkeys, 40 mg/kg in dogs and 180 mg/kg in rats, which corresponded to 1.5 to 18 times the dose used in humans. In addition to weight loss and anorexia, which occurred in all of the animal species, vomiting was observed in dogs and monkeys. The rest of the clinical observations did not reveal any anomalies.
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.
In addition, an increase in the weight of the liver in rats and dogs and elevated transaminase levels in dogs without the corresponding morphological changes were observed. In rats only, the emergence of adenomas of the interstitial testicular cells linked to the medicinal product were observed (although they were not dose-dependent). This effect is related to the mechanism of action of Flutamida Filaxis and is species-specific. In a long-term study in rats, increases were found in the rate of occurrence of adenomas or carcinomas of the mammary gland related to the dose.
Mutagenicity
No mutagenic potential was observed with Flutamida Filaxis in a variety of screening tests.
Reproductive toxicity
The influence of Flutamida Filaxis on fertility and the development of the progeny has been studied in rats. Additional teratogenicity studies have been performed in rabbits. The effects were related to the anti-androgenic actions of Flutamida Filaxis. These effects are not relevant to the clinical use of Flutamida Filaxis in the treatment of prostate cancer.
Flutamida Filaxis is indicated for the treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated. Flutamida Filaxis may be used in combination with an LHRH agonist, both on commencement of treatment or as an adjunctive therapy in patients already receiving an LHRH agonist. Flutamida Filaxis may also be used in surgically castrated patients.
Pharmacotherapeutic group: Hormone anatagonists and related agents, Anti-androgens, ATC code: L02BB01
Mechanism of action
Flutamida Filaxis is a non-steroidal, highly specific, orally active anti-androgenic agent. It has been demonstrated to reduce prostate and seminal vesicle weights in intact immature rats and to prevent androgen-stimulated hypertrophy of these organs in castrated immature rats. Prostate weights in dogs and baboons were also reduced by Flutamida Filaxis treatment. The biological activity of oral Flutamida Filaxis is attributable to its pharmacologically active metabolite, hydroxyFlutamida Filaxis, which is believed to exert an anti-androgenic effect directly on the target tissues, either by inhibiting androgen uptake or by blocking cytoplasmic and nuclear binding of androgen.
Clinical efficacy and safety
In the clinical trial performed with Flutamida Filaxis linked to LHRH agonists as neoadjuvant therapy for locally confined prostate carcinomas, pre-radical surgery or radiotherapy, an increase in the survival rate has not been proven, although a decrease in the size of the tumour, a reduction in morbidity and surgical consequences and a delays in the disease progression have been witnessed.
Absorption
Flutamida Filaxis is rapidly and extensively absorbed and almost completely metabolised following oral administration.
Distribution
A high proportion of Flutamida Filaxis binds to plasma proteins (94-96%) as does its active metabolite (92-94%). The peak plasma concentration of hydroxyFlutamida Filaxis at steady state at the recommended therapeutic dose (250 mg t.i.d.) is approximately 1700 µg/L.
Biotransformation
The major metabolite is hydroxyFlutamida Filaxis, which has been demonstrated to possess potent anti-androgenic activity. Radiolabelled Flutamida Filaxis studies reveal a rapid and extensive conversion to its metabolites; at least 6 have been identified in the plasma up to 8 hours after administration.
Elimination
Approximately 45% of the administered dose is excreted in the urine and 2% in faeces during the first two days. The excretion and metabolism is essentially complete within two days. The elimination half-life in plasma is 5 to 6 hours in adults for Flutamida Filaxis and its main metabolite hydroxyFlutamida Filaxis and 8 hours in older people. The elimination half-life at steady-state is approximately 10 hours.
Hepatic injury
Flutamida Filaxis may be hepatotoxic and should be used with caution in patients with pre-existing hepatic dysfunction only after considering the benefits and potential risks.
There have been reports of elevated serum transaminase levels, cholestatic jaundice, hepatic necrosis and hepatic encephalopathy associated with Flutamida Filaxis treatment. The hepatic effects were usually reversible following discontinuation of Flutamida Filaxis, although cases have been reported of death after severe liver damage linked to the use of Flutamida Filaxis. Hepatotoxicity, which may be fatal, may occur after several weeks or months of therapy. Hepatic function should be monitored regularly before, during and after initiation of Flutamida Filaxis therapy. Treatment with Flutamida Filaxis should not be initiated in patients with serum transaminase levels exceeding 2-3 times the upper limit of normal.
Periodic liver function tests must be performed before initiation and during treatment, especially in patients receiving long term treatment with Flutamida Filaxis. Appropriate laboratory liver function tests should also be performed for every patient once a month for the first 4 months and then periodically or when the first sign or symptom of hepatic dysfunction occur (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu-like†symptoms).
Patients should be advised to discontinue Flutamida Filaxis therapy and seek medical advice immediately if any symptoms or signs suggestive of hepatotoxicity occur. If the patient presents liver function test results indicative of liver damage, clinical jaundice in the absence of hepatic metastasis confirmed by biopsy, or serum transaminase levels of 2 to 3 times above the normal limits in patients that do not present pathological signs, treatment with Flutamida Filaxis must be suspended.
Impaired renal function
Flutamida Filaxis should be administered with caution in patients with impaired renal function.
Cardiovascular
Periodic sperm counts should be considered in patients receiving chronic treatment with Flutamida Filaxis who have not received medical or surgical castration. Flutamida Filaxis administration may lead to elevated plasma testosterone and oestradiol levels in such patients, resulting in fluid retention. In severe cases this can lead to an increased risk of angina and heart failure. Therefore caution should be exercised in the use of Flutamida Filaxis if cardiac disease is present. It can exacerbate oedema or ankle swelling in patients prone to these conditions.
An increase in oestradiol levels may predispose to thromboembolic events.
It has been reported in the literature that increased cardiovascular risk (myocardial infarction, cardiac insufficiency, sudden cardiac death) and the adverse effects on independent cardiovascular risk factors (serum lipoproteins, insulin sensitivity and obesity) may be linked to androgen deprivation with LHRH analogues in patients with prostate cancer. It must be evaluated whether the benefits of the combined androgen blockade compensate the potential cardiovascular risk in patients with risk factors. Patients treated whose signs or symptoms suggest the development of a cardiovascular disease must be monitored.
Effect on the QT/QTc interval
The potential QT/QTc prolongation with Flutamida Filaxis has not been studied. 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 Flutamida Filaxis.
Endocrinology and metabolism
A decreased tolerance to glucose has been observed in males in treatment with combined androgen blockade. This may manifest as diabetes or a loss of glycaemic control in patients with pre-existing diabetes. Monitoring of the blood glucose and/or glycosylated haemoglobin (HbA1c) levels must be considered in patients who are in treatment with Flutamida Filaxis in combination with LHRH agonists.
Musculoskeletal/changes in bone density
Androgen depletion therapy is known to reduce bone mineral density and increase the risk of osteoporotic fractures. In recent studies this has been seen in patients treated with LHRH analogues plus Flutamida Filaxis. The risk of bone fractures increases with the duration of combined androgen blockade. These complications may be potentiated when patients are already osteoporotic due to their advanced age at diagnosis of prostate cancer.
Bone mineral density (BMD) should be measured regularly to identify patients at higher risk for fractures. BMD should be measured at baseline, and then a year later as a minimum. Further measurements can be considered at yearly intervals in men with BMD approaching osteoporosis or those with decreased bone mineral density in whom life expectancy warrants it.
In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic consumers of alcohol and/or tobacco, a presumed or marked family history of osteoporosis or chronic use of medicinal products that can reduce bone mass such as anticonvulsants or corticosteroids, the combined androgen blockade can represent an additional risk. In these patients the risk and benefit must be weighed up carefully before starting the treatment.
There have been cases of interstitial pneumonitis reported in patients undergoing treatment with Flutamida Filaxis. Patients should be monitored for the development of respiratory symptoms such as dyspnoea during the first few weeks of therapy.
Flutamida Filaxis is indicated only for use in male patients.
Contraceptive measures must be taken during treatment.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No studies on effects on the ability to drive and use machines have been performed with Flutamida Filaxis. Possible undesirable effects such as fatigue, dizziness and confusion have been reported and may interfere with the ability to drive and use machines.
Posology
Adults and older people: One tablet three times daily at 8 hour intervals. When Flutamida Filaxis is used as initial treatment with an LHRH agonist, a reduction in severity of the flare reaction may be achieved if treatment with Flutamida Filaxis is initiated before the LHRH agonist. Consequently, it is recommended that treatment with Flutamida Filaxis should commence simultaneously or at least 24 or more hours before the LHRH agonist.
The administration of Flutamida Filaxis should begin 8 weeks prior to radiotherapy and continue for its duration, or for 12 weeks pre-prostatectomy.
In patients with impaired liver function, long-term treatment with Flutamida Filaxis should only be initiated after careful assessment of the individual benefits and risks.
Flutamida Filaxis should be administered with caution in patients with impaired renal function.
Method of administration
For oral use.
The tablets are to be taken preferably after food.
No special requirements.
