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Agolutin Depot Injection

SUMMARY OF PRODUCT CHARACTERISTICS 


1. NAME OF THE MEDICINAL PRODUCT

AGOLUTIN DEPOT
Suspension for injection


2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Drug substance: Progesteronum 25 mg in 1 mL of micro-crystalline suspension

3. PHARMACEUTICAL FORM
Suspension for injection. Micro-crystalline aqueous suspension after mixing milky colour.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Insufficient production of progesterone in the corpus luteum of ovary (missing secretory transformation of endometrium). Main indications are hypofunctional menstrual disorders or dysfunctional metrostaxis. Induction of bleeding and rapid detachment of endometrium by insufficient production of progesterone by corpus luteum of ovary (by anovulation). It is applied in premenstrual syndrome and in prophylaxis of postnatal depression. It is also used for maintenance of pregnancy in case of habitual, or threatened abortion, in insufficient production of progesterone in pregnancy. 

4.2 Posology and method of administration
In secondary amenorrhoea the substitution of progesterone alone is effective only by proven sufficient production of ovarian estrogens, i.e. if the progesterone test is positive. The administration is the same as in oligomenorrhoea or in complete anovulatory cycle on 17th day of cycle 50 – 100 mg of Agolutin Depot.
To stop dysfunctional metrostaxis 100 mg of Agolutin Depot is applied always with 10 mg of Agofollin Depot.
To prevent regression of dysfunctional bleeding there is applied at least during three to six cycles always on 17th day of cycle firstly 100 mg and later 50 mg of Agolutin Depot.
In treatment of postmenopausal failure events, if woman reacts unsuitably on androgenic component of Folivirin, it is possible to combine 5 – 10 mg of Agofollin Depot with 50 – 100 mg of Agolutin Depot. 
Agolutin Depot is absolutely unsuitable for progesterone test, because there is a risk of false negative result.
In threatened abortion the treatment by progesterone is justified only if its reduced production was proven. 50 – 100 mg of Agolutin Depot 2 – 3 times weekly (or more frequently) is applied till 14th week of pregnancy (or longer), depending on the results of direct or indirect monitoring of progesterone level in the body. If a missed abort is suspected, the administration of gestagens is not suitable.
Preventive application of progesterone is justifiable only if insufficient progesterone production is proven (in pregnancy, by luteal insufficiency, after therapy of anovulatory sterility by clomiphene etc.); also in this case it is suitable to monitor the progesterone level. 
Agolutin Depot is applied intramuscularly. 

4.3 Contraindications
Absolute contraindication is metrostaxis before the exclusion of an organic defect; dysfunctional metrostaxis without concomitant administration of estrogens. Lactation. Allergy to any of the components. It is not administered in thrombophlebitis, thromboembolic disease, pulmonary embolism also in the anamnesis, acute and chronic liver disease.

4.4 Special warnings and precautions for use
Relative contraindication is the administration to female patients with asthma, epilepsy, cardiopathy or renal dysfunction because of possible increased retention of liquids. In application to these patients an increased attention must be paid. Progesterone impairs the liver functions and in acute or chronic liver disease it is contraindicated. 
Progesterone increases basal plasmatic level of insulin and by long-time application it can reduce the glucose tolerance. 
By very high doses the hypnotic effect can occur which depends on the dose.
By kidneys disease the absolute contraindications are not known, but it is necessary to be careful by its administration because of possible retention of liquids. 
Progesterone increases the basal plasmatic level of insulin and by long-term application it can reduce the glucose tolerance. By very high doses the hypnotic effect can occur depending on the dose. 

4.5 Interaction with other medicinal products and other forms of interaction
No clinically important interactions are known. Effect of progesterone is reduced by antihistamines, phenobarbital, phenytoin, riphampicin, primidon and carbamazepine. It increases the plasmatic level of cyclosporine by inhibition of its metabolism. 
Potentially useful interaction can occur at administration of progesterone, if before a woman with endometriosis was taking the synthetic progestagens e.g. norethisterone. Progesterone induces false negativity or reduction of values for determination of iodine bound to albumins and uptake of radioiodine by thyroid gland.  

4.6 Pregnancy and lactation
Lactation is a contraindication. Pregnancy is not a contraindication for natural and so called “clear” synthetic gestagens (without any androgenic and estrogenic side effects), if it does not concern a missed abort. 
Administration in pregnancy is justifiable only in case of proven insufficient progesterone secretion, in habitual abortion prophylactically, in abortus iminens therapeutically. But the virilization of fetus threatens and the increased number of ectopic pregnancies was reported.
Administration to newborns and in paediatrics is excluded.

4.7 Effects on ability to drive and use machines
No special tests were performed in order to prove the reduction of concentration; it is not probable that within the scope of therapeutic doses the vigilitis could be influenced. Theoretically, after very high doses a hypnotic effect is described, depending on a dose. 

4.8 Undesirable effects
Acute life-endangering adverse effects after administration of therapeutic doses are not known. 
In consequence of long-time application the most frequent are the disorders in the area of GIT: nausea, vomiting eventually hyperpyrexia, changes in body weight, edema; in the area of CNS: nervousness, spasms, changes in libido, somnipathy, tendency to depression, rarely headache. Further melasma or chloasma can occur, only rarely tension in breasts, urticaria, pruritus vulvae, candidosis and local irritation are reported. 

4.9 Overdose 
No data on acute toxicity are known; by application of the doses of ca 100 mg only 1/10 of the concentration usual during pregnancy is reached. By extremely high doses somnolence or uterine spasms can occur. 


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties 
Pharmacotherapeutic group:         hormones, gestagens. 
ATC code:                                  G03DA04

Agolutin is a mono-component preparation containing progesterone – natural hormone with important physiological functions. 
It is determined especially for substitution of insufficient production of progesterone in corpus luteum of ovary. 
Clinical studies of pharmaco-dynamics:
In clinical praxis it is used as the natural progesterone for substitution of insufficient progesterone. 
Most evidence for indication of progesterone application has an empiric character from more than several years lasting use of hormonal preparation in various pharmaceutical forms. The results of open clinic studies are at the disposal and for the indication of premenstrual tension the significantly better results are known after progesterone compared to placebo, gained in randomized controlled study under the double-blind conditions.

5.2 Pharmacokinetic properties
Intramuscular injection 25 mg of progesterone creates the plasmatic level of 20 to 40 nmol/l-1 what responds to plasmatic level in luteal phase. The doses higher than 50 mg create the levels close to the levels during pregnancy. Plasmatic half-life is too short, only several minutes. 
Distribution volume is ca 17 till 19 l; progesterone is taken up by fat from which it is released progressively. After intramuscular application of aqueous suspension (Agolutin Depot) the effect is prolonged. Circulating progesterone is bound to plasmatic albumin eventually to corticosteroids binding globulin between 95 till 96 %. Concentration in CSF reaches 10 % of plasmatic level. It is metabolised especially in liver – ca 65 %, also in kidneys, brain and uterus and skin. It is biotransformed to pregnandiol which is secreted by urine as glucuronate. About 10 % is excreted in stool and significant is also enterohepatal circulation. The active ingredient passes through placental barrier and into breast milk. 

5.3 Preclinical safety data
The data on acute toxicity are not available, because after the intramuscular application it is not possible to reach the toxic levels in regard to limitations of application. Long-time application in clinical conditions substitutes sufficiently the tests of chronic toxicity in experiment. 


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Carmellosum natricum, sorbitolum, polysorbatum 80, phenolum, aqua ad iniectabilia.

6.2 Incompatibilities
Oxidizing substances, alkali and light induce the decomposition of progesterone. Progesterone induces a false negativity or reduction of values for determination of iodine bound to albumins and uptake of radioiodine by thyroid gland.  

6.3 Shelf life
3 years

6.4 Special precautions for storage
Store at 10 - 25 °C, protect from light and frost. 
Keep the ampoules in vertical position.

6.5 Nature and contents of container, package size
1)  2 mL non-breaking ampoules with adhesive label, file, plastic moulding, package leaflet: information for the user, paperboard folding box;
2)  2 mL breaking ampoules with adhesive label, plastic moulding, package leaflet: information for the user, paperboard folding box.
Package size: 1 ampoule of 2 mL 
  5 ampoules of 2 mL

6.6 Instructions for use and other handling
Injections are administered intramuscularly.

7. MARKETING AUTHORISATION HOLDER
BB Pharma a.s., Pod Višňovkou 1662/21, Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER(S)
56/0462/69-S, 56/463/69-S/C
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
1969
10. DATE OF REVISON OF THE TEXT
September 2013