PROLUTON® DEPOT 250 MG
Hydroxyprogesterone caproate ampoules
1. NAME OF THE MEDICINAL PRODUCT
Proluton Depot 250 mg ampoules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One 1-ml ampoule contains 250 mg hydroxyproges- terone caproate.
Other constituents: 517.7 mg benzyl benzoate,
297.3 mg castor oil for injection See section entitled “List of other constituents“ for a full list of the other constituents.
3. DOSAGE FORM
Oily, pale yellow solution for injection, free of parti- cles
4. CLINICAL PARTICULARS
Habitual and threatened abortion due to corpus lute- um deficiency
4.2 Dosage, mode and duration of employment Like all oily solutions Proluton Depot 250 mg must be injected via the intramuscular route. Experience has shown that the transient patient reactions that occur in rare cases during or immediately after the injection of oily solutions (urge to cough, coughing bouts, shortness of breath) can be prevented by injecting particularly slowly.
In line with the latest scientific knowledge any medicinal therapy in early pregnancy requires an unequivocal indication. This applies similarly to the use of hormonal preparations like Proluton Depot to maintain pregnancy. Consequently, Proluton Depot must only be used if the patient urgently wants to have a baby, especially if there is corpus luteum insufficiency or a history of miscarriage.
To achieve this goal and to maintain pregnancy Proluton Depot must be injected in sufficiently high doses for a protracted period.
• Habitual abortion
As soon as pregnancy has been diagnostically confirmed, one to two ampoules of Proluton Depot 250 mg are to be injected at weekly intervals during the first months of pregnancy, in isolated cases even longer.
• Threatened abortion
Therapy is initiated by injecting 2 ampoules of Proluton Depot 250 mg i.m. twice to three times per week until bleeding ceases.
Bed rest is strongly recommended during this time. After this one ampoule of Proluton Depot 250 mg is to be injected i.m. twice a week for several weeks, until such time as the patient demonstrates neither bleed- ing nor other complaints despite being mobile again. Whether Proluton Depot should be given prophylac- tically for an even longer period depends on the indi- vidual case.
Hypersensitivity to the active ingredient or any other constituents; a history of herpes gestationis; past or present liver tumors.
4.4 Special warnings and precautions for use
A thorough general medical examination (including measurement of blood pressure, testing the urine for sugar, possibly also conducting special liver diag- nostic tests) must be conducted before treatment begins in order to be able to detect any diseases needing treatment as well as any risk factors.
Special caution and monitoring are required in the case of diabetes mellitus.
Although there is no conclusive evidence that proges- togens are effective in maintaining pregnancy after previous abortions, tentative treatment may be indi- cated, depending on the individual circumstances.
During the course of protracted therapy it is neces- sary to ensure that pregnancy is continuing by con- ducting appropriate checkups (e.g. sonography) and immunological tests, because a dead embryo may be retained owing to the relaxing effect that Proluton-Depot has on the uterus.
8 to 14 days after unsuccessful treatment of threat- ened abortion and the subsequent necessary curet- tage, withdrawal bleeding may sometimes occur owing to the continuing effect of Proluton-Depot which subsides only gradually. No further measures are necessary, however.
Intravascular injection must be avoided at all costs.
4.5 Interactions with other medications and other interactions
The need for oral antidiabetics or insulin may change.
4.6 Pregnancy and lactation
Hydroxyprogesterone caproate must only be used if the patient urgently wants to have a baby, if there is corpus luteum insufficiency or a history of miscarriage. There is no tangible evidence from clinical studies or postmarketing experience that the administration of Proluton during pregnancy is deleterious.
Because minute amounts of the hormone dose pass into the mother‘s milk the risk-benefit ratio should be weighed up very carefully before using during lacta- tion.
4.7 Effects on ability to drive and use machines
4.8 Side effects
Most of the serious adverse effects - in connection with the use of medicinal products containing pro- gestogens only - are listed in section 4.4 “Warnings and special precautions for use“. Moreover, the fol- lowing undesired effects have been reported in users of Proluton Depot, although a causal link could not always be ascertained.
Body system (MedDRA v.8.0)
Immune system diseases
Allergic skin reactions e.g. allergic rash, allergic urticaria, allergic edema
Anaphy- lactoid reactions
General disorders and complaints at the admministrattion site
Complaints at the administra- tion site, red- dening, swelling, pain
Respiratory, thoracic and mediastinal disorders Experience has shown that the transient patient reactions that occur in rare cases during or imme- diately after the injection of oily solutions (urge to cough, coughing bouts, shortness of breath) can be prevented by injecting particularly slowly.
Gastrointestinal tract disorders
In rare cases after the use of hormonal active ingre- dients such as those that are contained in Proluton Depot, benign liver tumors, and even more rarely malignant liver tumors have been observed, which in isolated cases led to life-threatening hemorrhages in the abdominal cavity.
If severe upper abdominal complaints, liver enlarge- ment or signs of intraabdominal hemorrhage occur, differential diagnostic considerations should also include the possibility of hepatic tumor, and the drug must be discontinued as the case may be.
On the strength of animal experimental studies into acute toxicity the risk of side effects from an over- dose appears to be small.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties Pharmacotherapeutic category: Pregnene-4 derivatives ATC code: G03DA03
Hydroxyprogesterone caproate is a long-acting pro- gestogen which causes secretory transformation of the endometrium at a dose of 250 mg. The effect of hydroxyprogesterone caproate on the endometrium persists for about 10 days if an estrogen is adminis- tered at the same time.
Hydroxyprogesterone caproate is an ester of the naturally occurring hydroxyprogesterone and pos- sesses progesterone-like progestogenic effects such as antigonadotropic effects, the secretory transformation of the endometrium and thickening of the cervical mucus. The transformation of the endo- metrium facilitates the implantation of a fertilized ovum and creates favorable conditions for the main- tenance of any pregnancy.
In the case of parenteral administration the trans- formation dose of hydroxyprogesterone caproate is 250 mg. The progestogen possesses only a minor inhibitory effect on LH secretion and no effect on the placental production of hormones like progesterone. Hydroxyprogesterone caproate has no estrogenic, androgenic, antiandrogenic or corticoid effects.
Unlike the short-lived effect of progesterone, hydroxyprogesterone caproate possesses a distinct depot effect. For this reason, if a single intramuscu- lar injection is performed when an estrogen is being administered at the same time, an effect on the endometrium lasting 10 days can be observed. The thermogenic effect of hydroxyprogesterone caproate is small.
The retardant effect that all sexual hormones have on the anterior pituitary-hypothalamus system is relatively weak in the case of hydroxyprogesterone caproate: It inhibits neither the progesterone produc- tion in the corpus luteum phase nor hormone pro- duction in the placenta.
The thermogenic effect is small. Only doses of 500 mg and more increase basal temperature.
5.2 Pharmacokinetic properties Hydroxyprogesterone caproate is not cleaved into the free steroid alcohol and the fatty acid residue.
The active ingredient hydroxyprogesterone capro- ate is thus bioavailable to 100%. In vitro, 95% of the active ingredient is bound to plasma proteins (human plasma).
On the second day after intramuscular injection the level of active ingredient plus metabolites in the entire blood pool amounted to approx. 1% of the dose.
Elimination is exclusively in the form of conjugates, with approx. 80% being excreted via the bile and approx. 20% via the kidneys.
The speed of release can be deduced from the elim- ination half-life of 6 days. The depot is exhausted after 3 - 4 weeks.
5.3 Preclinical safety data
Conventional animal studies into repeated dose tox- icity, carcinogenicity or mutagenicity have not been conducted with Proluton Depot or its active sub- stance hydroxyprogesterone caproate because this was not considered necessary for determining risk in humans.
Hydroxyprogesterone caproate is an ester of the hydroxyprogesterone occurring naturally in inter- mediary metabolism. For this reason - provided it is used in humans as prescribed - no symptoms of systemic intolerance or tumorigenic effects are to be expected. No mutagenic potential can be expected on account of its structure.
On the other hand it must be remembered that sex steroids can trigger the growth of hormone-depen- dent tissue and tumors. Reproduction toxicology studies gave no indication that Proluton Depot has any teratogenic potential or any deleterious effects on reproductive capacity in the subsequent F1 gen- eration.
6. PHARMACEUTICAL PARTICULARS
6.1 List of other constituents
Benzyl benzoate Castor oil for injection
1.1 Special precautions for storage
Light protection needed Store below 30°C.
1.2 Nature and contents of container
One 1-ml amber glass ampoule
1.3 Special precautions for disposal and other notes on handling
No special requirements
2. MANUFACTURER Bayer Schering Pharma AG Berlin, Germany.