Фазлодекс

General characteristics. Structure:

Active agent: 250 mg of a fulvestrant;
Excipients: ethanol (96%) of 500 mg, benzyl alcohol of 500 mg, benzyl benzoate of 750 mg, castor oil to 5 ml.
Description
Transparent, from colourless till yellow color, viscous liquid.

Pharmacological properties:

Pharmacodynamics. The Fulvestrant is the competing antagonist of receptors of estrogen. On affinity level to receptors it is comparable to oestradiol. The Fulvestrant blocks trophic effect of estrogen, without showing own estrogenopodobny activity. The mechanism of action is connected with suppression of activity and degradation the estrogen receptors (ER).
Also the fulvestrant authentically reduces an expression of receptors of progesterone. The Fulvestrant does not render the stimulating effect on an endometria at women in a postmenopause. Effects of long therapy are not established by a fulvestrant on an endothelium in a postmenopause. Also there are no data on endometria morphology.
There are no data on influence of prolonged use of a fulvestrant on a bone tissue.

Pharmacokinetics. After an intramuscular injection the fulvestrant is slowly soaked up, reaching the maximum concentration in plasma approximately in 7 days. When using Fazlodeks's in a dose of 500 mg the equilibrium state is reached within the first month of therapy (AUC 546 нг · day/ml, Cmax of 25,1 ng/ml, Cmin of 16,3 ng/ml). At an equilibrium state the maintenance of a fulvestrant in plasma fluctuates in rather narrow borders – the maximum and minimum indicators differ approximately by 3 times.
After an intramuscular injection exposure is approximately proportional to the entered dose (in the range of doses from 50 to 500 mg).
The Fulvestrant is characterized by extensive and bystry distribution. The large seeming distribution volume (from 3 to 5 l/kg) at equilibrium concentration assumes preferential extravascular distribution. Communication with proteins of plasma – 99%. The main components of binding include fractions of lipoproteins of very low density (LPONP), lipoproteins of the low density (LPNP) and lipoproteins of the high density (LPVP). The role of the globulin connecting sex hormones is not established.
Metabolism of a fulvestrant includes combinations of a set of the potential ways of biotransformation similar to mechanisms of metabolism of endogenous steroids (17 ketone, sulphone, 3 sulfate, 3-and 17 glucuronide include metabolites). The identified metabolites are less active or equal on activity to a fulvestrant. CYP 3A4 is the only isoenzyme from the P450 family which participates in oxidation of a fulvestrant. However, it is represented that in vivo prevail biotransformations without participation of P450.
The Fulvestrant is generally removed with excrements, with urine less than 1% of substance are removed. The clearance of a fulvestrant makes 11±1,7 ml/min. that assumes the high level of hepatic extraction. The elimination half-life makes 50 days.
Special populations:
The pharmacokinetic profile of a fulvestrant does not depend on age (in the range of 33 - 89 years), body weights (40 – 127 kg) and race.
Renal failures
Easy and moderate renal failures do not exert clinically significant impact on pharmacokinetics of a fulvestrant.
Abnormal liver functions
At single introduction of a fulvestrant to patients with a weak or moderate abnormal liver function (classes A and B on classification of Chayld-Pyyu) increase in AUC by 2,5 times in comparison with healthy volunteers was noted. Researches of pharmacokinetics of a fulvestrant at patients with heavy abnormal liver functions (a class C on classification of Chayld-Pyyu) were not conducted.

Indications to use:

The locally-spread or disseminated breast cancer with positive receptors of estrogen at women in a postmenopause when progressing after or against the background of therapy by anti-estrogen.

Route of administration and doses:

Intramusculary, by slow (within 1-2 min.) injections. Contents of 2 syringes are consistently entered into the right and left rumps.
Female adult patients (including advanced age):
The recommended dose – 500 mg once a month. First month of therapy: 500 mg 2 times a month (the second introduction – in 2 weeks after the first dose of drug).
Children and teenagers:
Children and teenagers have no data on safety and efficiency.
Patients with renal failures:
In cases of an easy or moderate renal failure (clearance of  creatinine of 30 ml/min.) of dose adjustment it is not required. Safety and efficiency of drug at patients with heavy renal failures (clearance of creatinine <30 ml/min.) are not established.
Patients with abnormal liver functions:
Use of the drug Fazlodeks® for patients with an easy or moderate abnormal liver function does not demand dose adjustment. However, use of the drug Fazlodeks® for this group of patients demands care. Safety and efficiency of drug at patients with heavy abnormal liver functions are not established.

Features of use:

Treatment by the drug Fazlodeks® has to be carried out only under observation of the doctor having experience of use of antineoplastic drugs.
It is recommended to be careful at drug Fazlodeks® use by patients with an easy or moderate abnormal liver function. It is recommended to be careful when using the drug Fazlodeks® at patients with a heavy renal failure (clearance of creatinine <30 ml/min.).
Considering a drug route of administration, it is recommended to be careful when using the drug Fazlodeks® at patients with tendency to bleedings, thrombocytopenia or at the patients accepting anticoagulants.
Thromboembolisms at women with a widespread breast cancer are observed often. Patients need to take it into account at purpose of the drug Fazlodeks® with risk of a thromboembolism.
Effects of prolonged use of a fulvestrant on a bone tissue are not established. Considering the mechanism of action of a fulvestrant, it is impossible to exclude potential risk of osteoporosis.
Фазлодекс® should not mix up with other medicines.
Influence on ability to drive the car and other mechanisms
Influence of the drug Fazlodeks® on ability to drive the car and other mechanisms slightly. Patients need to be careful with symptoms of an adynamy when driving or other mechanisms.
Instructions on the address and use
Attention: do not autoclave the needle which is included in the package with drug! It is impossible to touch a needle during its use.
1. To take the glass case of the syringe from a blister strip packaging and to be convinced of absence of damage. To break off external packaging of a safe needle (SafetyGlide). To break a crossing point of a white plastic cover of a tip of the syringe and to remove a cover with the attached rubber cap of a tip.
2. To fix by rotary motion a needle on a syringe tip. To remove a needle case strictly in its direction not to damage a needle tip. To visually estimate a solution condition for parenteral administration regarding lack of particles and discoloration before its use. To remove excess vials of gas from the syringe.
3. To slowly enter solution into a gluteus within 1-2 min. For convenience the plane of "bevel" of a tip of a needle corresponds to a lever arrangement on the safety control.
4. After extraction of a needle from a gluteus immediately to activate the protection device of a needle, pressing on the lever with transfer it in extreme antelocation until the tip of a needle is not completely closed. At activation of the protective mechanism the minimum splashes of liquid which can remain on a needle after an injection are possible. To be convinced visually that the lever is transferred to the extreme provision and a tip of a needle it is completely closed. If it is not possible to activate the protection device of a needle, immediately place a needle in a standard container for needles. Attention: For the maximum safety use one hand and carry out manipulations on a distance from yourself and people around.

Side effects:

The observed undesirable reactions are given below.
Determination of frequency of side reactions: very often (≥10%); often (≥1 - <10%); infrequently (≥0,1 - <1%).
From system of digestion:
Very often – nausea;
Often – vomiting, diarrhea, anorexia.
From cardiovascular system:
Often – feeling of heat ("inflows"), a thromboembolism.
From skin and skin appendages:
Often – rash.
Local reactions:
Very often – reactions in a drug injection site, including poorly expressed tranzitorny pain and an inflammation;
Infrequently – bleeding, a hematoma in an injection site.
From urinogenital system:
Often – infections of urinary tract;
Infrequently – vaginal candidiasis, bleach, vaginal bleedings.
From a liver and biliary tract:
Very often – increase in activity of "hepatic" enzymes (alaninaminotranspherase (ALT), aspartate aminotransferase (nuclear heating plant), an alkaline phosphatase);
Often – increase in concentration of bilirubin;
Infrequently – a liver failure, hepatitis, increase in activity gamma глютамилтрансферазы.
Others:
Very often – an adynamy;
Often – a headache, hypersensitivity reactions (hypostases, urticaria).

Interaction with other medicines:

By results of a research of clinical interaction with midazolam the fulvestrant does not suppress activity of CYP 3A4. These in vitro demonstrate that the fulvestrant does not influence activity of CYP 1A2, 2C9, 2C19 and 2D6. Possible suppression of activity of CYP 2A6, 2C8 and 2E1 was not estimated.
In a research of clinical interaction with rifampicin (inductor CYP 3A4) and ketokonazoly (CYP 3A4 inhibitor) clinically significant changes of clearance of a fulvestrant are not revealed. Therefore at purpose of a fulvestrant in a combination with inductors or CYP 3A4 inhibitors of dose adjustment it is not required.

Contraindications:

- Hypersensitivity to a fulvestrant or any other component of drug;
- heavy abnormal liver functions;
- pregnancy and period of feeding by a breast;
- children's age up to 18 years.

With care: at renal failures and a liver.

Overdose:

Overdose cases at the person are unknown. In researches on animals at introduction of high doses of a fulvestrant only effects, directly or indirectly connected with anti-oestrogenic activity were observed.
In cases of overdose symptomatic therapy is recommended.

Storage conditions:

At a temperature from 2 to 8 °C, in the place protected from light. To store in the places unavailable to children. Period of validity 4 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for intramuscular introduction of 250 mg / 5 ml. On 5 ml in the glass syringe with safe system of introduction. On one syringe together with the sealed safe sterile needle (SafetyGlide) in the blister strip packaging from polypropylene sealed by a polypropylene film. On one blister strip packaging together with the application instruction in a cardboard pack or on two blister strip packagings together with the application instruction in a cardboard pack with control of the first opening.