Prostenongel

Oxytocic agent. Prostenongel Sterile Solution 10 mg/ml is indicated for the therapeutic termination of pregnancy, missed abortion and hydatidiform mole by the intravenous route.

Initiation of cervical ripening in patients, at term (from 37 completed weeks of gestation).

Prostenongel Gel is indicated for ripening an unfavorable cervix in pregnant women at or near term with a medical or obstetrical need for labor induction.

Posology

Adults

Directions for the Preparation of a Dilute Solution:

For use by IV drip (a drip set delivering 60 drops/ per ml must be used) or constant rate infusion pump. Withdraw 0.5 ml from the ampoule using an aseptic technique and add to 1,000 ml of sterile normal saline or 5% dextrose. Shake to ensure uniformity.

After dilution, attach the infusion bag label provided. Use dilute solution within 24 hours of preparation and store in a refrigerator at 2-8°C.

The following is a guide to dosage:

A solution of Prostenongel Sterile Solution in normal saline or 5% dextrose containing 5.0 micrograms per ml should be prepared in accordance with instructions given above. The initial rate of infusion (pump, or IV. drip delivering 60 drops per/ ml) will be 2.5 micrograms per minute, and this rate should be maintained for at least the first 30 minutes. If a satisfactory uterine contractility response is produced, this rate should be maintained; if not, the rate should be increased to 5 micrograms/ per minute. If satisfactory uterine activity is not produced after at least 4 hours at this rate of infusion, the rate may be increased up to 10 micrograms per minute, side-effects permitting, and maintained until abortion occurs or the treatment is considered a failure. If significant side-effects occur, the rate of infusion should be decreased by 50% or discontinued.

If a constant rate infusion pump is used, a different concentration of solution (e.g. 15 micrograms/ per ml) may be required, dependent on the type of pump, but the dose rates (micrograms/ per minute) should remain as above.

The appearance of uterine hypertonus requires cessation of therapy until the state returns to normal. The situation should be re-assessed and, if necessary, the infusion can be recommenced, but at lower dosage rates, 50% of the last dose level used.

In all cases the dosage should be adapted to the patient's response. Continuous administration of the drug for more than two days is not recommended.

Elderly

Not applicable.

Paediatric population

Not applicable.

Method of administration

For intravenous administration only.

Posology

One vaginal delivery system is administered high into the posterior vaginal fornix.

The vaginal delivery system should be removed after 24 hours irrespective of whether cervical ripening has been achieved.

A dosing interval of at least 30 minutes is recommended for the sequential use of oxytocin following the removal of the vaginal delivery system.

Paediatric population

The safety and efficacy of Prostenongel in pregnant women aged less than 18 years has not been established. No data are available.

Method of administration

Administration

Prostenongel should be removed from the freezer just prior to the insertion. No thawing is required prior to use.

There is a “tear mark” on the side of the foil sachet. Open the package along the tear mark across the top of the sachet. Do not use scissors or other sharp objects which may cut the retrieval system.

The vaginal delivery system should be inserted high into the posterior vaginal fornix using only small amounts of water soluble lubricants to aid insertion. After the vaginal delivery system has been inserted, the withdrawal tape may be cut with scissors always ensuring there is sufficient tape outside the vagina to allow removal. No attempt should be made to tuck the end of the tape into the vagina as this may make retrieval more difficult.

The patient should be recumbent for 20 minutes to 30 minutes after insertion. As dinoprostone will be released continuously over a period of 24 hours, it is important to monitor uterine contractions and fetal condition at frequent regular intervals.

Removal

The vaginal delivery system can be removed quickly and easily by gentle traction on the retrieval tape.

It is necessary to remove the vaginal delivery system to terminate drug administration when cervical ripening is judged to be complete or for any of the reasons listed below.

1. Onset of labour. For the purposes of induction of labour with Prostenongel, the onset of labour is defined as the presence of regular painful uterine contractions occurring every 3 minutes irrespective of any cervical change. There are two important points to note:

(i) Once regular, painful contractions have been established with Prostenongel they will not reduce in frequency or intensity as long as Prostenongel remains in situ because dinoprostone is still being administered.

(ii) Patients, particularly multigravidae, may develop regular painful contractions without any apparent cervical change. Effacement and dilatation of the cervix may not occur until uterine activity is established. Because of this, once regular painful uterine activity is established with Prostenongel in situ, the vaginal delivery system should be removed irrespective of cervical state to avoid the risk of uterine hyperstimulation.

2. Spontaneous rupture of the membranes or amniotomy.

3. Any suggestion of uterine hyperstimulation or hypertonic uterine contractions.

4. Evidence of fetal distress.

5. Evidence of maternal systemic adverse dinoprostone effects such as nausea, vomiting, hypotension or tachycardia.

6. At least 30 minutes prior to starting an intravenous infusion of oxytocin, as there is a much greater risk of hyperstimulation if the dinoprostone source is not removed before administration of oxytocin.

The opening on one side of the retrieval device is present only to allow the manufacturer to enclose the vaginal delivery system into the retrieval device during manufacture. The vaginal delivery system should NEVER be removed from the retrieval device.

Upon removal of the product from the vagina, the vaginal delivery system will have swollen to 2-3 times its original size and be pliable.

NOTE: USE CAUTION IN HANDLING THIS PRODUCT TO PREVENT CONTACT WITH SKIN. WASH HANDS THOROUGHLY WITH SOAP AND WATER AFTER ADMINISTRATION.

Prostenongel Gel should be brought to room temperature (59° to 86°F; 15° to 30°C) just prior to administration. Do not force the warming process by using a water bath or other source of external heat (eg, microwave oven).

To prepare the product for use remove the protective end cap (to serve as plunger extension) and insert the protective end cap into the plunger stopper assembly in the barrel of syringe. Choose the appropriate length shielded catheter (10 mm or 20 mm) and aseptically remove the sterile shielded catheter from the package. Careful vaginal examination will reveal the degree of effacement which will regulate the size of the shielded endocervical catheter to be used. That is, the 20 mm endocervical catheter should be used if no effacement is present, and the 10 mm catheter should be used if the cervix is 50% effaced. Firmly attach the catheter hub to the syringe tip as evidenced by a distinct click. Fill the catheter with sterile gel by pushing the plunger assembly to expel air from the catheter prior to administration to the patient. Proper assembly of the dosing apparatus is shown below.

To properly administer the product, the patient should be in a dorsal position with the cervix visualized using a speculum. Using sterile technique, introduce the gel with the catheter provided into the cervical canal just below the level of the internal os. Administer the contents of the syringe by gentle expulsion and then remove the catheter. The gel is easily extrudable from the syringe. Use the contents of one syringe for one patient only. No attempt should be made to administer the small amount of gel remaining in the catheter. The syringe, catheter, and any unused package contents should be discarded after use. Following administration of Prostenongel Gel, the patient should remain in the supine position for at least 15–30 minutes to minimize leakage from the cervical canal. If the desired response is obtained from Prostenongel Gel, the recommended interval before giving intravenous oxytocin is 6–12 hours. If there is no cervical/uterine response to the initial dose of Prostenongel Gel, repeat dosing may be given. The recommended repeat dose is 0.5 mg dinoprostone with a dosing interval of 6 hours. The need for additional dosing and the interval must be determined by the attending physician based on the course of clinical events. The maximum recommended cumulative dose for a 24-hour period is 1.5 mg of dinoprostone (7.5 mL Prostenongel Gel).

Prostenongel Sterile Solution should not be used where the patient is sensitive to prostaglandins.

Prostenongel Sterile Solution 10 mg/ml is not recommended in the following circumstances:

- For patients in whom oxytocic drugs are generally contra-indicated or where prolonged contractions of the uterus are considered inappropriate such as:

- Cases with a history of Caesarean section or major uterine surgery.

- Cases where there is evidence of a potential for obstructed labour.

- In patients with a past history of, or existing, pelvic inflammatory disease, unless adequate prior treatment has been instituted.

- Patients with active cardiac, pulmonary, renal or hepatic disease.

Prostenongel should not be used or left in place:

1. When labour has started.

2. When oxytocic drugs and/or other labour induction agents are being given.

3. When strong prolonged uterine contractions would be inappropriate such as in patients:

a. who have had previous major uterine surgery, e.g. caesarean section, myomectomy etc.

b. with cephalopelvic disproportion

c. with fetal malpresentation

d. with suspicion or evidence of fetal distress

e. who have had previous major surgery (e.g. other than biopsies and cervical abrasion) or rupture of the uterine cervix

4. When there is current pelvic inflammatory disease, unless adequate prior treatment has been instituted.

5.

6. When there is placenta previa or unexplained vaginal bleeding during the current pregnancy.

Endocervically administered Prostenongel Gel is not recommended for the following:

1. Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate, such as:
   • cases with a history of cesarean section or major uterine surgery
   • cases in which cephalopelvic disproportion is present
   • cases in which there is a history of difficult labor and/or traumatic delivery
   • grand multiparae with six or more previous term pregnancies cases with non-vertex presentation
   • cases with hyperactive or hypertonic uterine patterns
   • cases of fetal distress where delivery is not imminent
   • in obstetric emergencies where the benefit-to-risk ratio for either the fetus or the mother favors surgical intervention
2. Patients with hypersensitivity to prostaglandins or constituents of the gel (see WARNINGS and ADVERSE REACTIONS).
3. Patients with placenta previa or unexplained vaginal bleeding during this pregnancy.
4. Patients for whom vaginal delivery is not indicated, such as vasa previa or active herpes genitalia.

Use caution in handling this product to prevent contact with skin. Wash hands thoroughly with soap and water after administration.

It is advised that Prostenongel Sterile Solution should not be administered by the intramyometrial route since there have been reports of a possible association between this route of administration and cardiac arrest in severely ill patients.

Caution should be exercised in the administration of Prostenongel Sterile Solution in patients with:

- asthma or a history of asthma

- epilepsy or a history of epilepsy

- glaucoma or raised intra-ocular pressure

- compromised cardiovascular, hepatic, or renal function

- hypertension.

As with any oxytocic agent, Prostenongel Sterile Solution should be used with caution in patients with compromised (scarred) uteri.

Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone. Such effects have also been noted in newborn infants who received prostaglandin E₁ during prolonged treatment. There is no evidence that short-term administration of prostaglandin E₂ can cause similar bone effects.

Women aged 35 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of post-partum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labour induction. Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysis in the immediate post-partum phase.

Ethanol (alcohol)

Depending on the daily dose administered this medicinal product will deliver varying amounts of ethanol.

This product contains 84.16% v/v ethanol (alcohol).

Once diluted with appropriate diluent this medicinal product contains 0.04% v/v ethanol (alcohol) i.e. up to 996 mg per maximum daily dose (infusion rate of 10 microgram/min per 24 hrs), equivalent to 36 ml of a 3.5% vol beer, 9 ml of a 14% vol wine per maximum daily dose. Harmful for those suffering from alcoholism. It should also be taken into account when considering using this medicine in children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines.

The condition of the cervix should be assessed carefully before Prostenongel is used. After insertion, uterine activity and fetal condition must be monitored regularly. Prostenongel must only be used if facilities for continuous fetal and uterine monitoring are available. If there is any suggestion of maternal or fetal complications or if adverse effects occur, the vaginal delivery system should be removed from the vagina.

The experience of Prostenongel in patients with ruptured membranes is limited. Therefore, Prostenongel should be used with caution in those patients. Since the release of dinoprostone from the insert can be affected by the presence of amniotic fluid, special attention should be given to uterine activity and fetal condition.

Prostenongel should be used with caution in patients with a previous history of uterine hypertonus, glaucoma or asthma.

Medication with non-steroidal anti-inflammatory drugs, including acetylsalicylic acid, should be stopped before administration of dinoprostone.

If uterine contractions are prolonged or excessive, there is possibility of uterine hypertonus or rupture and the vaginal delivery system should be removed immediately.

Uterine rupture has been reported in association with the use of Prostenongel, mainly in patients with contra-indicated conditions. Therefore, Prostenongel should not be administered to patients with a history of previous caesarean section or uterine surgery given the potential risk for uterine rupture and associated obstetrical complications.

Prostenongel should be used with caution when there is a multiple pregnancy. No studies in multiple pregnancy have been performed.

Prostenongel should be used with caution when the woman has had more than three full term deliveries. No studies in woman with more than three full term deliveries have been performed.

A second dose of Prostenongel is not recommended, as the effects of a second dose have not been studied.

The use of the product in patients with diseases which could affect the metabolism or excretion of dinoprostone, e.g. lung, liver or renal disease, has not been specifically studied. The use of the product in such patients is not recommended.

Women aged 35 and over, women with complications during pregnancy, such as gestational diabetes, arterial hypertension and hypothyroidism, and women at gestational age above 40 weeks have a higher post-partum risk for developing disseminated intravascular coagulation (DIC). These factors may additionally enhance the risk of disseminated intravascular coagulation in women with pharmacologically induced labour. Therefore, dinoprostone and oxytocin should be used with caution in these women. In the immediate post-partum phase the physician should look out carefully for early signs of a developing DIC (e.g. fibrinolysis).

The Clinician should be alert that, as with other labour induction methods, use of dinoprostone may result in inadvertent abruption of placenta and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).

WARNINGS

For Hospital Use Only

Dinoprostone, as with other potent oxytocic agents, should be used only with strict adherence to recommended dosages. Dinoprostone should be administered by physicians in a hospital that can provide immediate intensive care and acute surgical facilities.

Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of post-partum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labor induction (see ADVERSE REACTIONS). Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysis in the immediate post-partum phase.

The Clinician should be alert that the intracervical placement of dinoprostone gel may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).

There have been post-marketing reports of serious and life-threatening hypersensitivity reactions including anaphylaxis and angioedema with Prostenongel Gel (dinoprostone). Onset of these reported reactions occurred within minutes to hours after initiation with Prostenongel Gel (dinoprostone). If a hypersensitivity reaction is suspected, if possible remove Prostenongel Gel (dinoprostone). Assess for other potential causes of the event, and institute symptomatic and supportive therapy, as needed.

PRECAUTIONS

General Precautions

During use, uterine activity, fetal status, and character of the cervix (dilation and effacement) should be carefully monitored either by auscultation or electronic fetal monitoring to detect possible evidence of undesired responses, e.g., hypertonus, sustained uterine contractility, or fetal distress. In cases where there is a history of hypertonic uterine contractility or tetanic uterine contractions, it is recommended that uterine activity and the state of the fetus should be continuously monitored. The possibility of uterine rupture should be borne in mind when high-tone myometrial contractions are sustained. Fetopelvic relationships should be carefully evaluated before use of Prostenongel Gel (see CONTRAINDICATIONS).

Caution should be exercised in administration of Prostenongel Gel in patients with:

• asthma or history of asthma
• glaucoma or raised intraocular pressure

Caution should be taken so as not to administer Prostenongel Gel above the level of the internal os. Careful vaginal examination will reveal the degree of effacement which will regulate the size of the shielded endocervical catheter to be used. That is, the 20 mm endocervical catheter should be used if no effacement is present, and the 10 mm catheter should be used if the cervix is 50% effaced. Placement of Prostenongel Gel into the extra-amniotic space has been associated with uterine hyperstimulation.

As Prostenongel Gel is extensively metabolized in the lung, liver, and kidney, and the major route of elimination is the kidney, Prostenongel Gel should be used with caution in patients with renal and hepatic dysfunction.

Patients With Ruptured Membranes

Caution should be exercised in the administration of Prostenongel Gel in patients with ruptured membranes. The safety of use of Prostenongel Gel in these patients has not been determined.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenic bioassay studies have not been conducted in animals with Prostenongel Gel due to the limited indications for use and short duration of administration. No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay.

Pregnancy

Teratogenic Effects

Prostaglandin E2 produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since Prostenongel Gel is administered after the period of organogenesis. Prostenongel Gel has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine tone could put the embryo or fetus at risk. See statements under General Precautions.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

The amount of ethanol (alcohol) in this medicinal product may impair the patient's ability to drive or use machines.

Not relevant.

Cardiac disorders: Cardiac arrest

Vascular disorders: Hypertension

Gastrointestinal disorders: Diarrhoea, nausea, vomiting

General disorders and administration site conditions: Fever, local tissue irritation / erythema (injection site), temporary pyrexia, local infections

Immune system disorders: Hypersensitivity reactions such as anaphylactoid reactions and anaphylactic reactions including anaphylactic shock

Investigations: Elevated WBC

Musculoskeletal and connective tissue disorders: Back pain

Nervous system disorders: Transient vasovagal symptoms (flushing, shivering, headache, dizziness)

Pregnancy and puerperium conditions:

Maternal-related conditions: Uterine hypertonus, uterine rupture, abruptio placenta, pulmonary amniotic fluid embolism, rapid cervical dilatation

Respiratory, thoracic and mediastinal disorders: Asthma, bronchospasm

Blood and lymphatic system disorders: An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labour was induced by pharmacological means, either with dinoprostone or oxytocin. The frequency of this adverse event, however, appears to be rare (<1 per 1,000 labours).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of safety profile:

The most commonly reported adverse drug reactions in placebo-controlled and active comparator efficacy clinical trials (N=1116) were “fetal heart rate disorder” (6.9%), “uterine contractions abnormal” (6.2%) and “abnormal labour affecting foetus” (2.6 %).

The table below displays the main ADRs distributed by system organ classes (SOC) and frequency. Further, the ADRs seen during post-marketing experience are mentioned with unknown frequency.

Adverse reactions observed in clinical studies are presented according to their incidence, post authorisation reported adverse reactions are presented in the column frequency unknown.

1* “Fetal heart rate disorder” was in clinical studies reported as “fetal heart rate abnormalities”, “fetal bradycardia”, “fetal tachycardia”, “unexplained absence of normal variability”, “fetal heart rate decreased”, “fetal heart rate deceleration”, “early or late decelerations”, “variable decelerations”, “prolonged decelerations”.

2* “Abnormal labour affecting foetus” as expression for hyperstimulation syndrome was in clinical studies reported as “uterine tachysystole” combined with “late decelerations”, “fetal bradycardia”, or “prolonged decelerations ”

3* “Fetal distress syndrome” was also reported as “fetal acidosis” , “pathological CTG”, “fetal heart rate abnormalities”, “intrauterine hypoxia” or “threatening asphyxia”. The term itself is unspecific, has a low positive predictive value and is often associated with an infant who is in good condition at birth.

4* “Uterine contractions abnormal” were reported as “uterine hyperstimulation” and “uterine hypertonus”.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Prostenongel Gel is generally well-tolerated. In controlled trials, in which 1731 women were entered, the following events were reported at an occurrence of ≥ 1%:

In addition, in other trials amnionitis and intrauterine fetal sepsis have been associated with extraamniotic intrauterine administration of PGE₂. Uterine rupture has been reported in association with the use of Prostenongel Gel intracervically. Additional events reported in the literature, associated by the authors with the use of Prostenongel Gel, included premature rupture of membranes, fetal depression (1 min Apgar < 7), and fetal acidosis (umbilical artery pH < 7.15).

Post-Marketing Surveillance

Blood And Iymphatic System Disorders

An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labor was induced by pharmacological means, either with dinoprostone or oxytocin (see WARNINGS). The frequency of this adverse event, however, appears to be rare (<1 per 1,000 labors).

Immune System Disorders

Hypersensitivity reactions (e.g., Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction).

Overdosage may be expressed by uterine hypercontractility and uterine hypertonus. During use, uterine activity and the progression of cervical dilation should be carefully monitored to detect possible evidence of undesired responses, e.g. hypertonus or sustained uterine contractions. Because of the transient nature of prostaglandin E₂ (PGE₂)-induced myometrial hyperstimulation, non-specific, conservative management should be used (rate of infusion should be decreased or discontinued, maternal position change and administration of oxygen). If conservative management is not effective, a tocolytic agent may be used in appropriate patients as a treatment of hyperstimulation following administration of PGE₂ or appropriate measures should be considered.

Overdosage or hypersensitivity may lead to hyperstimulation of the uterine muscle with or without fetal distress. If fetal distress occurs, remove Prostenongel immediately and manage in accordance with local protocol.

Overdosage with Prostenongel Gel may be expressed by uterine hypercontractility and uterine hypertonus. Because of the transient nature of PGE₂ -induced myometrial hyperstimulation, nonspecific, conservative management was found to be effective in the vast majority of the cases; i.e., maternal position change and administration of oxygen to the mother. β-adrenergic drugs may be used as a treatment of hyperstimulation following the administration of PGE₂ for cervical ripening.

Pharmacotherapeutic group: Prostaglandins, ATC-code: G02AD02

Dinoprostone is a prostaglandin of the E series with actions on smooth muscle. It induces contraction of uterine muscle at any stage of pregnancy.

Pharmacotherapeutic group: oxytocics, ATC-code: G02AD02

Prostaglandin E2 (PGE2) is a naturally occurring compound found in low concentrations in most tissues of the body. It functions as a local hormone.

Prostaglandin E2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a transformation of the uterine cervix which must be transformed from a rigid structure to a soft, dilated configuration to allow passage of the fetus through the birth canal. This process involves activation of the enzyme collagenase which is responsible for the breakdown of the collagen.

Local administration of dinoprostone to the cervix results in cervical ripening which then induces the subsequent events which complete labour.

Dinoprostone is rapidly metabolised in the body. Intravenous administration results in very rapid distribution and metabolism, with only 3% of unchanged drug remaining in the blood after 15 minutes. At least nine PGE₂ metabolites have been identified in human blood and urine.

PGE2 is rapidly metabolised primarily in the tissue of synthesis. Any which escapes local inactivation is rapidly cleared from the circulation with a half-life generally estimated as 1-3 minutes.

No correlation could be established between PGE2 release and plasma concentrations of its metabolite, PGEm. The relative contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm could not be determined.

The reservoir of 10mg dinoprostone serves to maintain a controlled and constant release. The release rate is approximately 0.3mg per hour over 24 hours in women with intact membranes whereas release is higher and more variable in women with premature rupture of membranes. Prostenongel releases dinoprostone to the cervical tissue continuously at a rate which allows cervical ripening to progress until complete, and with the facility to remove the dinoprostone source when the clinician decides that cervical ripening is complete or labour has started, at which point no further dinoprostone is required.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

Preclinical studies have demonstrated that dinoprostone is a locally acting substance which is rapidly inactivated and thus it has no significant systemic toxicity.

The hydrogel and polyester polymers are inert compounds with good local tolerability.

Reproduction toxicity, genotoxic or carcinogenic effects of the polymers have not been investigated but systemic exposure is negligible.

Not applicable.

Not applicable

Use caution in handling this product to prevent contact with skin. Wash hands thoroughly with soap and water after administration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Prostenongel should be removed from the freezer just prior to the insertion.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.