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Agolutin Injection

SUMMARY OF PRODUCT CHARACTERISTICS 


1. NAME OF THE MEDICINAL PRODUCT

AGOLUTIN Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Progesteronum 30 mg in 1 mL of oil solution


3. PHARMACEUTICAL FORM
Solution for injection


4. CLINICAL PARTICULARS

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

4.2 Posology and method of administration
Agolutin is administered by intramuscular routes. 
In cases of secondary amenorrhoea the substitution of progesterone is effective only by proven sufficient production of ovarian estrogens only, i.e. if the progesterone test is positive. 
To avoid attacks of dysfunctional metrostaxis during premenopausal oligomenorrhoea is administered on every 42nd of cycle – if spontaneous menstruation does not occur – inject 60 mg of Agolutin inj. intramuscularly. If metrostaxis does not occur after repeating three such periodic applications of Agolutin, the reduced production of ovarian estrogens is considered to be stable and menopause is presumed. 
By threatened abortion (habitual abortion in anamnesis) the treatment by progesterone is justified only if the insufficient progesterone production has been proven. 25 – 100 mg of Agolutin 2-times weekly (or daily if necessary) is administered up to 8th – 16th week of pregnancy (or longer, respectively) depending on results of direct or indirect monitoring of progesterone level in the body. If a missed abort is suspected, gestagens should not be given. 
For the purpose of progesterone test 60 mg of Agolutin is administered; if the metrostaxis does not occur within 14 days - the test is negative – it means (by pregnancy exclusion) insufficient preparation of endometrium or organic disorder of the uterus. 
Preventive application of progesterone is justifiable only if the insufficient progesterone production is proven (during pregnancy, by luteal insufficiency, after therapy of anovulating sterility using clomiphene etc.). Also in this case it is suitable to monitor the progesterone level.

4.3 Contraindications
Absolute contraindication is metrostaxis before the exclusion of an organic defect; dysfunctional metrostaxis without concomitant administration of estrogens, thrombophlebitis, thromboembolic disease, pulmonary embolism also in the anamnesis, acute and chronic liver disease. Lactation. Allergy to any of the components.

4.4 Special warnings and precautions for use
Relative contraindication is the administration to patients with asthma, epilepsy, cardiopathy or renal dysfunction because of possible increased retention of liquids. It is necessary to be careful by administration to such patients. Progesterone impairs the liver functions and in acute or chronic liver disease it is contraindicated. In 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 which depends 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 by administration of progesterone, if a woman with endometriosis was taking the synthetic progestagens e.g. noretisterone. Progesterone induces false negativity or reduction of values for determination of iodine bound to albuminous and taking up 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 a “missed” abort is not suspected. 
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 increased number of ectopic pregnancies was reported.

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:     hormone, gestagen. 
ATC code:                              GO3DAO4
Agolutin is a mono-component drug containing progesterone – natural hormone with important physiological functions. It is determined especially for substitution of insufficient production of progesterone in the corpus luteum of ovary. By a higher concentration it is secreted in luteal phase of menstruation cycle, prepares endometrium for secretion phase and nidation of fertilized egg. During pregnancy it is produced in high quantities and is intended for pregnancy maintenance. It acts as an anti-estrogen. It reduces the motility of uterus and can cause birth delay. Progesterone, by feedback, inhibits production of gonadotropins. Together with estrogens it supports lobulo-alveolar development of breasts. By higher concentrations during the menstruation cycle it has a thermogenic effect. 
Clinical study of pharmaco-dynamic:
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 10-years lasting use of hormonal drug 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 30 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, distribution phase is 3 till 6 minutes and elimination phase ranges between 19 and 95 minutes. Distribution volume is ca 17 till 19 l; progesterone is taken up by fat from which it is released progressively. 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 drug is used in the clinical praxis more than 10 years. No unexpected adverse effects were registered which are not contained in the list of expected adverse effect. 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 quantitative difficulties. Long-time application in clinical conditions substitutes sufficiently the tests of chronic toxicity in experiment. 


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Alcoholum benzylicum, benzylis benzoas, oleum pro injectione.

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

6.3 Shelf life
3 years

6.4 Special precautions for storage
Store at 15 - 25 °C, protected from light and frost. 

6.5 Nature and contents of container, package size
1. 2 ml breaking ampoules with adhesive label, plastic moulding, package leaflet and paperboard folding box;
2. 2 ml non-breaking ampoules with adhesive label, file, plastic moulding, package leaflet and paperboard folding box.
Package size: 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, 56/462/69-S/C
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
1969
10. DATE OF REVISON OF THE TEXT
September 2013