Hemabate Sterile Solution

Solution for injection. Colourless, sterile, aqueous solution for intramuscular injection.

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 *Paediatric population:*: Not applicable4.3 Contraindications

1. Hemabate should not be used where the patient is sensitive to carboprost tromethamine or to any of the excipients listed in section 6.1.
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 intra-ocular 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. Benzyl alcohol: This medicine contains 9.45 mg benzyl alcohol in each ampoule which is equivalent to 9.45 mg/ml. Benzyl alcohol may cause allergic reactions. The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping syndrome”, and death in paediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys' capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis). Sodium: This medicine contains less than 1 mmol sodium (23 mg) per ml of solution, that is to say essentially 'sodium-free'.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. Benzyl alcohol can cross the placenta **Breast-feeding** There are no data on the excretion into breast milk for carboprost tromethamine4.7 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 post-marketing 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 (frequency 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 sensation†, Epistaxis†, Dry throat†, Upper respiratory tract infection | | ***Gastrointestinal disorders*** | Very common | Diarrhoea\, Nausea\, Vomiting\* | | Uncommon | Haematemesis, Abdominal pain upper, Dry mouth | | Not Known | Retching† | | ***Skin and subcutaneous tissue disorders*** | Uncommon | Hyperhidrosis | | Not Known | Rash† | | ***Musculoskeletal and connective tissue disorders*** | Uncommon | Torticollis, Back pain, Myalgia, | | Not Known | Muscle spasms, Blepharospasm† | | ***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 pain†, Asthenia†, Excessive thirst† | | ***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. † 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.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.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Prostaglandins, ATC code: G02AD04. 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/ml 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 Data not available

6.1 List of excipients Benzyl alcohol Sodium chloride Tromethamine Sodium hydroxide Hydrochloric acid Water for injections6.2 Incompatibilities None known6.3 Shelf life 4 years6.4 Special precautions for storage Store in a refrigerator at 2 - 8°C.6.5 Nature and contents of container Type 1 glass ampoule containing 1 ml solution, packed in cartons of two or ten ampoules. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling 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.