To reduce the risk of preterm birth (delivery <37 weeks gestation) in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth

Proluton must always be administered by deep intramuscular injection, preferably intragluteally or in the upper arm. Injection must always be extremely slow (see section 4.8). The use of a plaster on the injection site is recommended to prevent Proluton from oozing out.

 

Dosage:

      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 may only be used if the patient urgently wants to have a baby and has a history of singleton pre-term birth.          To achieve this goal and to maintain pregnancy, Proluton Depot must be injected in sufficiently high doses for a protracted period.

 

   

      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 or in individual cases for longer.

 

Additional notes for special groups of patients

 

Children and adolescents up to the age of 18:

There is no indication for Proluton Depot use in children and adolescents

Proluton Depot must not be used if any of the conditions listed below apply; this information also derives from other progestogen-only preparations. If any of these conditions arises during the use of Proluton Depot, the administration of the preparation must be discontinued at once. • Present venous thromboembolic events • Present or past arterial and cardiovascular conditions (e.g. myocardial infarction, cerebrovascular events, coronary cardiac condition) • Diabetes mellitus with impaired vessels • Present or past serious hepatic disease as long as the hepatic function readings have not returned to normal • Present or past hepatic tumors (benign or malignant) • Present or suspected malignant diseases dependent on sexual hormones • Hypersensitivity to the active ingredient or any other constituents listed in section 6.1

If any of the conditions/risk factors listed below applies or deteriorates, an individualized risk-benefit assessment should be conducted before starting or continuing the administration of Proluton Depot.

 

Circulatory disturbances

It is known that the use of oral ovulation inhibitors that contain estrogens/progestogens occasions an enhanced risk for the occurrence of thromboembolic conditions. It is for this reason that an enhanced thromboembolic risk must not be ignored when treating with Proluton Depot, especially when there is a history of thromboembolic conditions.

 

The generally recognized risk factors for venous thrombotic events (VTEs) include a personal or family history (hereditary or acquired predisposition for VTE, VTE in a sibling or parent at a relatively young age), increasing age, obesity, protracted immobilization, major surgery or serious injuries.

 

The enhanced thromboembolic risk attendant on the puerperium must be taken into account.

 

If symptoms of an arterial or venous thromboembotic event occur or are suspected, treatment must be discontinued immediately.

 

Tumors

In rare cases benign, or in even rarer cases malignant, hepatic tumors have been reported in users of hormonal substances, one of which is contained in Proluton Depot. In isolated cases these tumors have led to life-threatening intra-abdominal hemorrhages. If severe upper abdominal pain, liver engorgement or signs of intra-abdominal hemorrhage occurs when Proluton Depot is being used, differential diagnosis should also include the possibility of an hepatic tumor.

 

Other conditions

 

Strict medical supervision is necessary if the patient suffers from diabetes.

On occasions, chloasma may occur, particularly in women with a history of chloasma gravidarum. Women with a propensity for chloasma should avoid sunlight or ultraviolet radiation during treatment with Proluton Depot.

 

Patients with a history of psychic depression should be closely monitored, and the drug should be discontinued, if severe depression returns.

 

Examination

A thorough history-taking must be conducted before treatment with Proluton Depot begins or restarts, with special attention being given to the Contraindications (section 4.3) and Warnings (section 4.4); and a general medical and gynecological examination should be repeated during the use of Proluton Depot.

 

The frequency and depth of these examinations should be adapted to the individual woman and should cover especially blood pressure, examination of the breasts, abdomen and pelvic organs, including cervical cytology.

 

During the course of protracted therapy it is necessary to ensure that pregnancy is continuing by conducting 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.

 

Intravascular injection must be avoided at all costs.

Drug interactions resulting from an enhanced clearance of sex hormones may result in a reduced therapeutic effect. This applies to many drugs that induce hepatic enzymes (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, oxcarbazepine, products containing St. John’s wort and rifabutin), and is suspected in the case of griseofulvin.

 

Sexual steroids may also impair the metabolism of other drugs. Consequently, plasma and tissue levels may be altered (e.g. cyclosporine).

 

The need for oral antidiabetic agents or insulin may change.

 

Note: The professional datasheet for any co-medication should be consulted in order to rule out any potential interactions.

·      Laboratory tests

The use of progestogens may influence the results of certain laboratory tests. This includes the biochemical parameters of the hepatic, thyroid, adrenal and renal functions as well as plasma levels of (vector) proteins, e.g. of corticoid binding globulin and of the lipid/lipoprotein fractions, likewise the carbohydrate metabolism parameters, blood coagulation and fibrinolysis. As a rule, however, these changes remain within the normal range

 

Pregnancy

Hydroxyprogesterone caproate should only be used if the patient urgently wants to have a baby and has a history of singleton pre-term birth.

 

Epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used sex steroids prior to pregnancy, nor a teratogenic effect when sex steroids were used inadvertently during early pregnancy.

However, it must be clearly understood, that no drug ‑ including sex hormones ‑ can be claimed with absolute certainty to be free from teratogenic effects.

 

Breastfeeding:

As Proluton Depot is indicated for use in preventing pre-term birth there is no therapeutic need to use the product during breast feeding.

 

None known.

The most serious undesirable effects associated with the use of progestogen only preparations are listed in Section “Special warnings and special precautions for use“. In addition the following undesirable effects have been reported in users of Proluton Depot although a causal relationship could not always be confirmed.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on reporting rates from postmarketing experience and literature.

 

System organ class	Common (³1/100)	Uncommon (³1/1,000 to <1/100)	Rare (³1/10,000 to <1/1,000)	Very Rare (<1/10,000)
Immune system disorders	Allergic skin reaction, e.g. Allergic rash, Allergic urticaria, Allergic edema			Anaphylactoid reaction
General disorders and administration site conditions	Injection site reaction, e.g. Injection site redness, Injection site swelling, Injection site pain

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

 

Respiratory, thoracic and mediastinal disorders

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.

 

Serious undesired effects, in connection with the use of progestogen-only drugs, are listed in section 4.4 “Special warnings and precautions for use”.

 

Reporting suspected side effects

Reporting suspected side effects after marketing authorisation has been given is very important. This facilitates an ongoing monitoring of the risk-benefit ratio of the drug. Healthcare professionals are asked to report any suspected case of a side effect to the national reporting system.

To report any side effect(s):

National Pharmacovigilance and Drug Safety Center (NPC).

Fax: + 966 - 11 - 205 - 7662.

Call NPC at +966 - 11 - 2038222,

Ext.: 2317 - 2356 - 2353 - 2354 - 2334 - 2340.

Toll - free: 8002490000.

E - mail: npc.drug@sfda.gov.sa. Website: www.sfda.gov.sa/npc

For other countries, please refer to the health authorities in your country.

 

On the basis of studies into the acute toxicity in experimental animals, the risk of adverse effects due to overdose appears low.

Pharmacotherapeutic group: Pregnene-4 derivatives

ATC code: G03DA03

 

Proluton Depot contains the progestogen hydroxyprogesterone caproate in an oily solution. Hydroxyprogesterone caproate is an ester of the naturally occurring hydroxyprogesterone and possesses typical progesterone-like progestogenic effects in women, such as antigonadotrophic effects, the secretory transformation of the endometrium and thickening of the cervical mucus. Unlike the short-lived effect of progesterone, hydroxyprogesterone caproate possesses a progestogenic depot effect. Peak plasma levels are reached within two to five days of intramuscular administration. The thermogenic effect of the substance is small.

 

Administration of 250 mg hydroxyprogesterone caproate leads to a secretory transformation of the endometrium; the effect persists for approx. 10 days when an estrogen is administered concomitantly.

 

Proluton Depot does not inhibit progesterone production in the corpus luteum phase and does not possess estrogenic, corticoid or antiandrogenic properties. Moreover it does not have any inhibitory effect on the placental production of hormones

Absorption

After intramuscular injection, hydroxyprogesterone caproate is gradually and completely released from the depot within about 30 days. Hydroxyprogesterone caproate is completely bioavailable. The original substance reaches its serum peak

 

level within two to five days of administration. The serum levels of hydroxyprogesterone caproate then slowly decline and this substance is no longer detectable in the serum after about 23 to 28 days.

 

Distribution

The depot effect of hydroxyprogesterone caproate is based on the delayed release from the established depot and not on the formation of a secondary depot (e.g. fatty tissue) in the body.

 

Metabolism

The bulk of the hydroxyprogesterone caproate is metabolized as a complete steroid ester. Only small amounts of estradiol and its metabolites can be found. The original substance is practically undetectable in the urine and feces, which points to an almost complete metabolism of hydroxyprogesterone caproate in humans.

 

Elimination

Hydroxyprogesterone caproate and its metabolites are eliminated in the feces and urine in the ratio 8 : 2. A half-life of approx. 6 days was ascertained; the elimination speed is determined by the rate of release of the drug from the depot. If administered weekly or more often, it must be expected that hydroxyprogesterone caproate and its metabolites will accumulate in the body

Conventional animal studies into repeated dose toxicity, carcinogenicity or mutagenicity have not been conducted with Proluton Depot or its active substance hydroxyprogesterone caproate. Nor are they considered necessary for risk estimation in humans.

 

Hydroxyprogesterone caproate is an ester of the hydroxyprogesterone occurring naturally in intermediary 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.

 

However, it should be kept in mind that sex steroids might stimulate the growth of hormone-dependent tissues 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 generation.

 

Studies into local tolerance of Proluton Depot provided no evidence that hydroxyprogesterone caproate leads to an increased irritative effect above and beyond that caused by the solvent mix itself.

 

benzyl benzoate

castor oil for injection

 

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

2 years

Light protection needed

Do not store above 30°C.

One amber glass ampoule containing 1 ml, hydrolytic class I

Unused medicinal products or waste is to be disposed of as required by national regulations