This information is intended for use by health professionals

1. Name of the medicinal product

Prostin E2 Sterile Solution 10 mg/ml.

2. Qualitative and quantitative composition

Each ml contains 10 mg dinoprostone (5 mg per ampoule).

Following dilution in accordance with instructions, each ml of the resultant solution for infusion contains 100 micrograms dinoprostone.

Excipient(s) with known effect

Each 0.5 ml ampoule contains 332 mg dehydrated alcohol (ethanol).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a clear, colourless, alcoholic solution free from particulate matter, for extra-amniotic administration after appropriate dilution.

4. Clinical particulars
4.1 Therapeutic indications

Oxytocic agent. Prostin E2 Sterile Solution 10 mg/ml is indicated for the therapeutic termination of pregnancy, by the extra-amniotic route.

4.2 Posology and method of administration

Posology

Adults

Directions for the Preparation of a Dilute Solution:

Withdraw 0.5 ml from the ampoule, using an aseptic technique and add to contents of the vial of diluent (50 ml) provided. Shake to ensure uniformity.

After dilution, attach the infusion bag label provided. Use dilute solution within 48 hours of preparation. Store in a refrigerator at 2-8°C.

The following is a guide to dosage:

A solution containing 100 micrograms/ per ml dinoprostone should be prepared using the diluent provided. This should be installed into the extra-ovular space via a 12-14 French gauge Foley catheter with self-retaining balloon (a fine polyethene catheter may also be used). After filling the catheter system dead space with a predetermined quantity of dilute drug solution, the initial installation should be 1 ml. Subsequent installations will vary between 1 and 2 ml (usually 2 ml) in accordance with uterine response. Two hours should usually elapse between each installation and never less than 1 hour.

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 extra-amniotic administration only.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Prostin E2 Sterile Solution should not be used where the patient is sensitive to prostaglandins.

Prostin E2 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.

• In patients with cervicitis or vaginal infections.

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

4.4 Special warnings and precautions for use

This product is only available to hospitals and clinics with specialised obstetric units and should only be used where 24-hour resident medical cover is provided.

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

It is advised that Prostin E2 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 Prostin E2 Sterile Solution to 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, Prostin E2 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 (see section 4.8). 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 the appropriate diluent this medicinal product contains 0.84% v/v ethanol (alcohol) i.e. up to 332 mg per maximum daily dose (instillation rate of 2 ml/hour per 24 hrs), equivalent to 12 ml of a 3.5% vol beer, 3 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.

4.5 Interaction with other medicinal products and other forms of interaction

Since it has been found that prostaglandins potentiate the effect of oxytocin, it is not recommended that these drugs are used together. If used in sequence, the patient's uterine activity should be carefully monitored.

4.6 Fertility, pregnancy and lactation

Pregnancy

Prostin E2 Sterile Solution 10 mg/ml is only used during pregnancy for therapeutic termination of pregnancy. There has been some evidence in animals of a low order of teratogenic activity, therefore, if abortion does not occur or is suspected to be incomplete as a result of prostaglandin therapy, (as in spontaneous abortion, where the process is sometimes incomplete), the appropriate treatment for complete evacuation of the pregnant uterus should be instituted in all instances.

Breast-feeding

Prostaglandins are excreted in breast milk. This is not expected to be a hazard given the circumstances in which the product is used.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 (see section 4.4). 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.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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.

6. Pharmaceutical particulars
6.1 List of excipients

Dehydrated alcohol (ethanol).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in a refrigerator at 2-8°C.

Once diluted, the diluted solution should be stored in a refrigerator at 2-8°C and used within 48 hours.

6.5 Nature and contents of container

Ph. Eur. Type I glass ampoule, containing 0.5 ml sterile solution, packed in a carton, together with a vial containing diluent.

6.6 Special precautions for disposal and other handling

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.

7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

UK

CT13 9NJ

8. Marketing authorisation number(s)

PL 00057/1030

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 1 July 1991

Date of latest renewal: 15 October 2002

10. Date of revision of the text

01/2018

Ref: PR 4_4