SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Hemabate Sterile Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains carboprost tromethamine equivalent to carboprost 250 micrograms.

Excipient(s) with known effect

Hemabate sterile solution also contains 8.1-10.4 mg/ml benzyl alcohol For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

Colourless, sterile, aqueous solution for intramuscular injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of post-partum haemorrhage due to uterine atony and refractory to conventional methods of treatment with oxytocic agents and ergometrine used either alone or in combination.

Conventional therapy should usually consist of 0.5 - 1 mg ergometrine with up to 50 units of oxytocin infused intravenously over periods of time from 20 minutes to 12 hours. The dosage and duration of administration should reflect the seriousness of the clinical situation.

4.2 Posology and method of administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

An initial dose of 250 micrograms (1.0 ml) of Hemabate should be administered as a deep intramuscular injection.

If necessary, further doses of 250 micrograms may be administered at intervals of approximately 1.5 hours. In severe cases the interval between doses may be reduced at the discretion of the attending physician, but it should not be less than 15 minutes.

The total dose of Hemabate should not exceed 2 mg (8 doses).

Elderly:    Not applicable

Children:    Not applicable

4.3 Contraindications

1.    Hemabate should not be used where the patient is sensitive to carboprost tromethamine or any of the excipients.

2.    Acute pelvic inflammatory disease.

3.    Patients with known active cardiac, pulmonary, renal, or hepatic disease.

4.    Hemabate is contra-indicated in pregnancy.

4.4. Special warnings and precautions for use

Hemabate should be used by medically trained personnel and is available only to hospitals and clinics with specialised obstetric units where 24 hour resident medical cover is provided. Hemabate, as with other potent oxytocic agents, should be used only with strict adherence to recommended dosages.

This preparation should not be used for induction of labour.

Hemabate must not be given intravenously.

Special caution is necessary in patients with history of asthma, hypo- or hypertension, cardiovascular, renal, or hepatic disease, glaucoma or raised intraocular pressure, anaemia, jaundice, diabetes, or epilepsy.

Benefit/risk ratio should be assessed in patients with cardiovascular disease (risk of decreased blood pressure up to cardiovascular collapse, bradycardia), and in patients with a history of asthma (risk of bronchoconstriction) and pulmonary disease (possibility of decreased pulmonary blood flow and increased arterial pulmonary pressure).

Very rare cases of cardiovascular collapse have been reported following the use of prostaglandins. This should always be considered when using Hemabate.

Decreases in maternal arterial oxygen content have been observed in patients treated with carboprost tromethamine. A causal relationship to carboprost tromethamine has not been established, however, it is recommended that patients with pre-existing cardio-pulmonary problems receiving Hemabate are monitored during treatment and given additional oxygen if necessary.

As with any oxytocic agent, Hemabate should be used with caution in patients with previously compromised (scarred) uteri.

Prior treatment with, or concomitant administration of anti-emetics and antidiarrhoeal drugs significantly reduces the very high incidence of the gastrointestinal side effects common to all prostaglandins. Their use should be considered an integral part of the management of patients.

Transient pyrexia that may be due to hypothalamic thermoregulation has been observed after intramuscular Hemabate. Temperature elevations exceeding 1.1 °C were observed in approximately one-eighth of patients who received the recommended dosage regimen but if not complicated by endometritis, the temperature elevation will usually return to normal within several hours of the last injection.

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 have received prostaglandin E1 during prolonged treatment. There is no evidence that short-term administration of Hemabate can cause similar bone effects.

4.5 Interaction with other medicinal products and other forms of interaction

As Hemabate can potentiate the effect of other oxytocics, concomitant use is not recommended.

4.6 Fertility, pregnancy and lactation

Fertility

There are no clinical data on the effects of carboprost on fertility.

Pregnancy

Studies in animals have shown reproductive toxicity and any dose which produces increased uterine tone could put the embryo or foetus at risk.

Lactation

There are no data on the excretion into breast milk for carboprost tromethamine.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

There have been reports of undesirable effects such as syncope, dizziness and somnolence which could impair the ability to drive or use machines.

Therefore patients should refrain from driving until they know that Hemabate does not affect their ability to drive or use machines.

4.8 Undesirable effects

The table below lists the adverse effects identified through clinical trials and postmarketing surveillance by System Organ Class (SOC) and frequency. Within each frequency grouping, adverse events are presented in order of decreasing seriousness. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000), or not known (cannot be estimated from the available data).

The adverse effects of Hemabate are generally transient and reversible on discontinuation of therapy. The most frequent adverse reactions observed are related to its contractile effect on smooth muscles.

In patients studied, approximately two-thirds (66%) experienced vomiting and diarrhoea, approximately one-third (33%) had nausea, one-eighth (12%) had a temperature increase greater than 1.1° C, and one-fourteenth (7%) experienced flushing.

MedDRA System Organ Class	Frequency	Undesirable Effects
Infections and Infestations	Uncommon	Septic shock, Urinary tract infection
	Common	Endometritis*
Immune system disorders	Not Known	Hypersensitivity reactions' (e.g. Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction, Angioedema)
Endocrine disorders	Not Known	Thyrotoxic crisis'
Psychiatric disorders	Uncommon	Sleep disorder
	Not Known	Anxiety', Nervousness'
Nervous system disorders	Common	Headache*
	Uncommon	Syncope vasovagal, Dizziness*, Dystonia, Paraesthesia, Somnolence, Dysgeusia, Lethargy
	Not Known	Syncope'
Eye disorders	Uncommon	Vision blurred, Eye pain
Ear and labyrinth disorders	Uncommon	Vertigo, Tinnitus
Cardiac disorders	Uncommon	Tachycardia
	Not Known	Palpitations'
Vascular disorders	Common	Flushing, Hot flush, Chills

	Uncommon	Hypertension
Respiratory, thoracic and mediastinal disorders	Common	Cough
	Uncommon	Asthma, Respiratory distress, Dyspnoea, Hyperventilation*,Wheezing, Hiccups
	Not Known	Bronchospasm, Pharyngeal oedema, Choking sensation1’, Epistaxis1, Dry throat1, Upper respiratory tract infection
Gastrointestinal disorders	Very common	Diarrhoea*, Nausea*, Vomiting*
	Uncommon	Haematemesis, Abdominal pain upper, Dry mouth
	Not Known	Retching1
Skin and subcutaneous tissue disorders	Uncommon	Hyperhidrosis
	Not Known	Rash1
Musculoskeletal and connective tissue disorders	Uncommon	Torticollis, Back pain, Myalgia,
	Not Known	Muscle spasms, Blepharospasm1
Reproductive system and breast disorders	Common	Uterine haemorrhage, Retained placenta or membranes
	Uncommon	Uterine rupture, Uterine cervical laceration, Pelvic pain*, Breast tenderness
	Not Known	Uterine disorder
General disorders and administration site conditions	Uncommon	Chest discomfort, Injection site pain
	Not Known	Chest pain1, Asthenia1, Excessive thirst1
Investigations	Very common	Body temperature increased

* Events reported for both intramuscular and intra-amniotic routes of administration are marked with an asterisk. All other events were reported only for the intramuscular route.

¹ Identified from post-marketing experience 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

Treatment of overdosage must be symptomatic and supportive as clinical studies with prostaglandin antagonists have not progressed to the point where recommendations may be made.

If evidence of excessive side-effects appears, the frequency of administration should be decreased or administration discontinued.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Carboprost is a synthetic 15-methyl analogue of dinoprost (prostaglandin F2 alpha). It is a uterine stimulant with a more prolonged action than dinoprost

and when used in post-partum haemorrhage, it stimulates the uterus to contract in a manner similar to that normally observed in the uterus following delivery. The resulting myometrial contractions provide haemostasis at the site of placentation and hence prevent further blood loss. Whether or not this action results from a direct effect on the myometrium has not been determined with certainty at this time. The fundamental actions of the prostaglandins include inhibition or stimulation of smooth muscle contraction and inhibition of the release of noradrenaline or modulation of its effects at neuroeffector sites. They affect the uterus, the cardiovascular system, the gastro-intestinal system, the nervous system, the urinary system and metabolic processes.

5.2 Pharmacokinetic properties

The presence of the methyl group delays inactivation by enzymic dehydrogenation.

Peak plasma levels vary depending on the route of administration. In the Rhesus monkey after a single i.m. injection of 20 - 30 micrograms of 15-methyl PGF2 alpha peak levels of 0.4 - 5 nanograms/mI resulted at 30 - 60 minutes, declining to baseline levels 6 - 8 hours after injection. In pregnant women, an i.m. injection of 100 - 400 micrograms resulted in peak plasma levels of 1 - 1.6 nanograms/ml 20 - 30 minutes after injection. Levels declined to 0.2 - 0.4 nanograms/ml after 3 hours. When i.m. doses of 250 micrograms were given every two hours, pre-injection plasma levels stabilised after four injections at 1.2 nanograms/ml.

After administration of 2.5 mg 15-methyl PGF2 alpha intra-amniotically to 5 subjects, plasma levels were from 100 - 580 picograms/ml during the first 15 hours after administration. In three subjects the levels were low and fairly constant, while the two other had higher, but more variable levels.

5.3 Preclinical safety data

None stated

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol Sodium chloride Tromethamine Sodium hydroxide Hydrochloric acid Water for injections

6.2 Incompatibilities

None known

6.3 Shelf life

Ampoules: 48 months Vial: 24 months

6.4 Special precautions for storage

The ampoules must be stored in a refrigerator at 2 - 8°C.

The vial must be stored in a refrigerator at 0 - 6°C

6.5    Nature and contents of container

Ampoule: Type 1 glass ampoule containing 1 ml solution, packed in cartons of two or ten ampoules.

Vial: Type 1 glass with butyl rubber closure, containing 10 ml solution, packed individually in a carton.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road