1. Name Of The Medicinal Product
Farlutal 500 suspension for injection
2. Qualitative And Quantitative Composition
Medroxyprogesterone Acetate, 20.0 % W/V
Farlutal 500 for injection contains 500 mg medroxyprogesterone acetate in 2.5 ml.
For excipients see section 6.1.
3. Pharmaceutical Form
Suspension for injection.
White sterile suspension for injection which settles on standing but readily disperses on shaking.
4. Clinical Particulars
4.1 Therapeutic Indications
Palliative treatment of hormone-sensitive malignancies. Farlutal has been successfully used to produce regressions in breast, endometrial, prostatic and renal cell carcinoma. High dose Farlutal therapy has proved especially useful in breast carcinoma and in achieving subjective improvements in terminally ill patients, notably pain relief and improved performance status.
4.2 Posology And Method Of Administration
Route of administration: Intramuscular injection
The suspension should be well shaken before use and injected deeply into healthy gluteal muscle.
Suggested dosage schemes are as follows:
Recurrent and/or Metastatic Breast Cancer:
Initial dose: 500 - 1000 mg/day i.m. for 4 weeks
Maintenance: 500 mg i.m. twice a week
Recurrent and/or Metastatic Endometrial or Renal Cancer:
The recommended initial dose is 400-1000 mg per week. If improvement is noted within a few weeks or months and the disease appears to be stabilised, it may be possible to maintain improvement with as little as 400 mg per month.
Metastatic Prostate Cancer:
Initial dose: 500 mg i.m. twice weekly for 3 months
Maintenance: 500 mg i.m. weekly
Children and Elderly:
None stated.
4.3 Contraindications
Medroxyprogesterone acetate is contraindicated in the following conditions:
• thrombophlebitis, thrombo-embolic disorders, and where there is a high risk of developing such manifestations [presence or history of atrial fibrillation, valvular disorders, endocarditis, heart failure, pulmonary embolism; transitory ischaemic attack (TIA), cerebral infarction; atherosclerosis; immediate post surgery period]
• previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism)
• active or recent arterial thrombo-embolic disease (e.g., angina, myocardial infarction)
• severe hepatic insufficiency
• hypercalcaemia in patients with osseous metastases
• suspected or early breast carcinoma,
• missed abortion, metrorrhagia, known or suspected pregnancy
• undiagnosed vaginal bleeding
• known hypersensitivity to medroxyprogesterone acetate or any other component of Farlutal Injection.
Progestogens are known to be porphyrogenic. Patients with a history of attacks or aged under 30 are at greatest risk of an acute attack while on progesterone treatment. A careful assessment of potential benefit should be made where this risk is present.
4.4 Special Warnings And Precautions For Use
Farlutal should be used under the direction of those experienced in cancer chemotherapy.
Warnings
Although medroxyprogesterone acetate has not been causally associated with thrombotic or thrombo-embolic disorders, patients with a relevant history or who develop this kind of event while undergoing therapy with medroxyprogesterone acetate should have their status and need for treatment carefully assessed before continuing therapy.
In the event of a sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia or migraine, administration of medroxyprogesterone acetate should be halted. If examination reveals papilloedema or retinal vascular lesions, medication should not be re-instated.
Treatment with medroxyprogesterone acetate should be discontinued in the event of:
• jaundice or deterioration in liver function
• significant increase in blood pressure
• new onset of migraine-type headache
In the event of vaginal bleeding occurring, an accurate diagnosis should be made. If endometrial or endocervical tissue is submitted for histological examination, the pathologist (laboratory) should be informed that the patient has been receiving a progestogen.
The pathologist or laboratory should be advised that the patient is receiving medroxyprogesterone acetate as this can decrease the levels of the following endocrine biomarkers:
• Plasma/urinary steroids (e.g., cortisol, oestrogen, pregnanediol, progesterone, testosterone)
• Plasma/urinary gonadotrophins (e.g., LH and FSH)
• Sex-hormone-binding-globulin
Precautions
Animal studies have shown that medroxyprogesterone acetate possesses adrenocorticoid activity and this effect has also been observed in humans.
Some patients receiving medroxyprogesterone acetate may exhibit suppressed adrenal function. Medroxyprogesterone acetate may also decrease ACTH and hydrocortisone blood levels.
When used in oncology indications, medroxyprogesterone acetate may cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing. Thus the ability of the adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered. The pathologist/laboratory should be made aware that the patient is being treated with medroxyprogesterone acetate.
Medroxyprogesterone acetate may produce Cushingoid symptoms.
Patients with the following conditions should be carefully monitored while taking progestogens:
• Conditions which may be influenced by potential fluid retention
o Epilepsy
o Migraine
o Asthma
o Cardiac dysfunction
o Renal dysfunction
• Hyperlipidaemia
• History of mental depression
• Diabetes (a decrease in glucose tolerance has been observed in some patients)
Farlutal may raise plasma calcium levels; some cases of hypercalcaemia have been reported in the treatment of breast carcinoma.
Risk of venous thromboembolism (VTE)
The risk of VTE has not been assessed for progesterone alone. However, VTE is a known risk factor of oestrogen-only and combined hormone replacement therapy. When prescribing medroxyprogesterone acetate for oncology indications the following precautions and risk factors should be considered in the light of the patient's condition, the dose of medroxyprogesterone acetate and the duration of therapy:
• Generally recognised risk factors for VTE include a personal or family history of VTE or known thrombo-embolic states, severe obesity (BMI> 30 kg/m2) and systemic lupus erythematosus
• The risk of VTE may be temporarily increased with prolonged immobilisation, trauma or surgery or acute illnesses.
If VTE develops after initiating therapy, medroxyprogesterone acetate should be discontinued. Patients should be told to contact their doctor immediately if they become aware of a symptom suggestive of potential thromboembolism (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction with other medicaments
The metabolism of progestogens may be increased by concomitant administration of compounds known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes. These compounds include anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz,).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of progestogens. Progestogen levels may therefore be reduced.
Aminoglutethimide administered cocurrently may decrease medroxyprogesterone acetate availability.
Medroxyprogesterone acetate may be used in combination with cytotoxic drugs. In these circumstances it has been reported that the haematological toxicity of chemotherapy might be reduced.
Special care should be taken in the concomitant use of medroxyprogesterone acetate (particularly at higher doses) and drugs which also cause oedema, such as NSAIDs and vasodilators.
Concurrent administration of ciclosporin and MPA has been reported to lead to increased plasma ciclosporin levels and/or decreased plasma MPA levels.
Interactions with oral anti-coagulants have been reported rarely, but causality has not been established.
Other forms of interaction
Medroxyprogesterone acetate can influence certain laboratory tests (e.g., hepatic function tests, coagulation tests and thyroid function tests).
4.6 Pregnancy And Lactation
Pregnancy
Farlutal is contra-indicated during pregnancy.
Administration of progesterone during the first months of pregnancy may possibly be associated with the occurrence of congenital cardiac malformations in the neonate. In addition, instances of masculinisation of female foetuses have been reported following high dose therapy during pregnancy.
It should be noted that long term administration of medroxyprogesterone acetate to beagle dogs has resulted in the development of mammary nodules which were occasionally found to be malignant. The relevance of these findings to humans has, however, not been established.
Lactation
Medroxyprogesterone acetate and its metabolites are excreted in breast milk. Therefore, the use of Farlutal in breast-feeding is not recommended.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
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4.9 Overdose
No positive action is required.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Progestogens. ATC Code: L02AB02.
MPA has an antigonadotrophic effect, it blocks the pre-ovulatory intermenstrual oestrogen peak by direct action on the ovary. Its effects at low doses include contraceptive action, secretion by the endometrium, delay in the menstrual flow, a decrease in the viscosity of cervical mucus and a reduction in the vaginal karyopycnotic index.
At higher doses, oncological actions are evident. There is a direct cytotoxic action on tumour cells manifested by a decrease in DNA and RNA synthesis.
5.2 Pharmacokinetic Properties
The absorption and metabolism of the MPA are affected by both the administration route used and the type of pharmaceutical preparation.
After i.m. administration of MPA in an aqueous solution, absorption is slow. The highest blood levels are found during the first 2 days, measurable amounts being found up to 100 days after treatment. Variations in plasma concentrations are interpreted as being due to irregular release from the injection site.
Only 3-6% of the administered dose is recovered in urine after 24 hours. After 6 days approximately 11% is found in the urine and 3% in the faeces, hence elimination is slow after i.m. administration. Traces of metabolites have been found in the urine up to 6 months after high doses of MPA. Only a slight increase in porter-silber steroids is found in the urine of patients treated by the i.m. route.
5.3 Preclinical Safety Data
No further preclinical safety data available.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Polysorbate 80
Sodium Chloride
Carbowax 400
Methyl Hydroxybenzoate
Propyl Hydroxybenzoate
Water for Injections
6.2 Incompatibilities
Farlutal injection should not be mixed with other agents.
6.3 Shelf Life
48 months
6.4 Special Precautions For Storage
The vials should be stored between 15° - 30°C and should not be frozen.
6.5 Nature And Contents Of Container
Colourless siliconised glass vial (Type I) with grey chlorobutyl rubber stopper and aluminium seal containing 2.5 ml of suspension.
6.6 Special Precautions For Disposal And Other Handling
Farlutal should be well shaken before use and should not be mixed with other agents. It should be administered using a long wide-bore needle. Narrow-bore or short needles must not be used.
The vials are for single dose administration only. Discard any remaining solution.
7. Marketing Authorisation Holder
Farmitalia Carlo Erba Limited
Davy Avenue
Milton Keynes
MK5 8PH
UK
8. Marketing Authorisation Number(S)
PL 03433/0045
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of First Authorisation: 14 August 1981
10. Date Of Revision Of The Text
December 2004
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