1 Name of Medicine
Carboprost (as trometamol).
2 Qualitative and Quantitative Composition
Each vial contains carboprost trometamol equivalent to 250 microgram carboprost.
Excipients with known effect.
Contains benzyl alcohol (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Solution for injection for single use only.
Carboprost Dr.Reddy's injection is a colourless, sterile aqueous solution for intramuscular administration.
4.1 Therapeutic Indications
Carboprost Dr.Reddy's is indicated for the treatment of postpartum haemorrhage due to uterine atony which has not responded to conventional methods of management.
4.2 Dose and Method of Administration
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
An initial dose of 250 microgram (1.0 mL) should be administered by deep intramuscular injection. If necessary, further doses of 250 microgram 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 should not exceed 2 mg (8 doses).
Product is for single use in one patient only. Discard any residue.
4.3 Contraindications
1. Hypersensitivity to carboprost trometamol or to any of the excipients (see Section 6.1 List of Excipients).
2. Acute pelvic inflammatory disease.
3. Patients with active cardiac, pulmonary, renal or hepatic disease.
4. Carboprost Dr.Reddy's is contraindicated in pregnancy.
4.4 Special Warnings and Precautions for Use
Identified precautions.
Carboprost should be used by appropriately trained personnel in hospitals and clinics with specialised obstetric units. Carboprost, as with other potent oxytocic agents, should be used only with strict adherence to recommended dosages.
This preparation should not be used for the induction of labour.
Carboprost must not be given intravenously.
Very rare cases of cardiovascular collapse have been reported following the use of prostaglandins. This should always be considered when using carboprost.
Carboprost Dr.Reddy's contains benzyl alcohol which has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
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).
Carboprost should be used with caution in patients with a history of glaucoma or raised intra-ocular pressure, asthma, hypotension or hypertension, cardiovascular, renal or hepatic disease, anaemia, jaundice, diabetes or epilepsy.
During the clinical trials with carboprost, 5/115 (4%) patients had an increase in blood pressure reported as a side effect. The degree of hypertension was moderate. The cases reported did not require specific therapy for the elevated blood pressure.
Since prostaglandins may potentiate the effect of oxytocin, it is recommended that the use of these drugs simultaneously or in sequence should be carefully monitored.
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 carboprost can cause similar bone effects.
As with any oxytocic agent, carboprost should be used with caution in patients with previously compromised (scarred) uteri.
Use in patients with chorioamnionitis.
During the clinical trials with carboprost, chorioamnionitis was identified as a complication contributing to postpartum uterine atony and haemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to carboprost. This complication during labour may have an inhibitory effect on the uterine response to carboprost similar to what has been reported for other oxytocic agents.
Use in patients with pre-existing cardio-pulmonary problems.
Decreases in maternal arterial oxygen content have been observed in patients treated with carboprost trometamol. A causal relationship to carboprost trometamol has not been established, however, it is recommended that patients with pre-existing cardio-pulmonary problems receiving carboprost are monitored during treatment and given additional oxygen if necessary.
Use in hepatic impairment.
Carboprost should be used with caution in patients with a history of impaired liver function and is contra-indicated in patients with active liver disease.
Use in renal impairment.
Carboprost should be used with caution in patients with a history of impaired renal function and is contra-indicated in patients with active renal disease.
Use in the elderly.
No data available.
Paediatric use.
Safety and efficacy in paediatrics patients have not been established.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
As Carboprost Dr.Reddy's can potentiate the effect of other oxytocics, concomitant use is not recommended.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
There are no clinical data on the effects of carboprost trometamol on human fertility.
Administration of carboprost at doses up to 3 times the expected maximum human dose (based on surface area) for 3 or 6 days prior to mating had no effect on male or female fertility in rats, although other carboprost-like drugs are known to disrupt fertility.
(Category D)
Administration of prostaglandins such as carboprost during pregnancy stimulates the uterus and may cause inability to sustain pregnancy and irreversible fetal damage or death. Carboprost is indicated in the postpartum period. It is not indicated for use during pregnancy.
Carboprost has been found to cross the placenta and distribute to the fetus in pregnant women. Any dose of carboprost that produces increased uterine tone could put the fetus at risk.
In animal studies, administration of carboprost for 3 or more days during gestation caused a high incidence of resorptions in rats and rabbits and embryotoxic effects in rats. The lowest dose of carboprost which caused these effects was approximately 6 and 36 times lower, in rats and rabbits respectively, than the recommended maximum dose in humans (based on surface area comparisons).
Administration of carboprost to rats for 7-8 days prior to delivery was associated with shortened gestation length, dystocia, increased incidence of still births and decreased offspring body weight. The lowest dose of carboprost which caused these effects was approximately 100 times lower than the recommended maximum dose in humans (based on surface area comparisons).
Carboprost Dr.Reddy's contains benzyl alcohol which can cross the placenta (see Section 4.4 Special Warnings and Precautions for Use).
It is not known if carboprost is secreted into breast milk, however, this possibility cannot be ruled out.
Administration of carboprost to rats during the pre- and post-natal period resulted in failure of dams to lactate. The lowest dose of carboprost which caused these effects was approximately 100 times lower than the recommended maximum dose in humans (based on surface area comparisons). The effect was reversible.
The relevance of these findings to lactation in humans treated with carboprost is unclear. However, based on plasma clearance rates it is recommended that breast feeding does not occur for at least 6 hours after administration.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
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 Carboprost Dr.Reddy's does not affect their ability to drive or use machines.
4.8 Adverse Effects (Undesirable Effects)
The adverse effects of carboprost are generally transient and reversible on cessation of therapy.
Clinical trials.
The most frequent adverse effects observed with the use of carboprost in clinical trials (n = 448 patients) are related to its contractile effect on smooth muscle. In Study # 7055 (n = 115 patients) events occurring at an incidence > 1% were vomiting, diarrhoea and/or nausea (19%), temperature elevation (7%) and increased blood pressure (4%). In the post-marketing study (n = 333 patients) adverse events did not appear to be dose related and included diarrhoea (8.1%), vomiting (4.8%) and increased blood pressure (5.1%).
Other adverse effects reported rarely in clinical use include pulmonary oedema, diaphoresis, dizziness, asthma and wheezing.
Adverse effects are listed in Table 1 by body system:
Hyperthermia and flushing have been observed after intramuscular carboprost but, if not complicated by endometritis, temperature will usually return to normal within several hours of the last injection.
Post-marketing experience.
The following adverse events were identified from post-marketing experience:
Immune system disorders.
Hypersensitivity reactions (e.g. anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, angioedema).
Endocrine disorders.
Thyrotoxic crisis.
Psychiatric disorders.
Anxiety, nervousness.
Nervous system disorders.
Syncope.
Cardiac disorders.
Palpitations.
Respiratory, thoracic and mediastinal disorders.
Choking sensation, epistaxis, dry throat.
Gastrointestinal disorders.
Retching.
Skin and subcutaneous tissue disorders.
Rash.
Musculoskeletal and connective tissue disorders.
Blepharospasm.
General disorders and administration site conditions.
Chest pain, asthenia, excessive thirst.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
Treatment of overdosage must be symptomatic at this time, as clinical studies with prostaglandin antagonists have not progressed to the point where recommendations may be made. If evidence of adverse effects appears, the frequency of administration of carboprost should be decreased or administration discontinued.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Carboprost is a synthetic 15-methyl analogue of dinoprost (prostaglandin F2α). It is a uterine stimulant with a more prolonged action than dinoprost. When used in postpartum 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 prostaglandins include inhibition or stimulation of smooth muscle contraction and inhibition of the release of noradrenaline or modulation of its effects at neuroeffector sites. In addition to effects on the uterus, carboprost stimulates the smooth muscle of the gastrointestinal tract, which commonly results in vomiting or diarrhoea or both when used at recommended doses. It may cause a transient elevation of body temperature and transient bronchoconstriction.
At higher doses in both animals and humans, carboprost can increase blood pressure, possibly through the contraction of vascular smooth muscle.
Clinical trials.
Two open label clinical trials have been conducted to support the efficacy and safety of carboprost in the treatment of postpartum haemorrhage due to uterine atony and refractory to conventional therapeutic measures. The first was an uncontrolled, multicentre study in 115 patients with refractory postpartum haemorrhage conducted in the USA (Study # 7055). Carboprost was reported to achieve haemostasis, thus avoiding further intervention, such as surgery, in 87.8% of patients, with the majority of patients (73.3%) requiring only a single dose. Adverse events reported were dose related and not serious.
The second report relates to a post-marketing study conducted over 12 months at 14 centres in the USA. In this uncontrolled epidemiological study, a total of 333 patients were evaluated and carboprost was found to control the postpartum haemorrhage, thus avoiding surgical intervention in 83.8% of cases. 81.4% of patients required only a single dose of carboprost. Adverse events did not appear to be dose-related.
5.2 Pharmacokinetic Properties
Absorption.
Five women who had spontaneous vaginal deliveries (at term) were treated immediately post partum with a single intramuscular injection of 250 microgram carboprost. Peripheral blood samples were collected at several times during the four hours following treatment. The highest concentration was observed at 15 minutes in two patients (3009 and 2916 picogram/mL), at 30 minutes in two patients (3097 and 2792 picogram/mL) and at 60 minutes in one patient (2718 picogram/mL).
5.3 Preclinical Safety Data
Genotoxicity.
Carboprost showed no evidence for mutagenic activity in the AMES test or for clastogenic activity in a rat micronucleus test. However, the genotoxic potential of the human metabolites of carboprost was not assessed in these studies.
Carcinogenicity.
Long term studies have not been conducted to evaluate the carcinogenic potential of carboprost, nor has comprehensive battery of genotoxicity assays.
Teratogenicity.
Carboprost has been found to cross the placenta and distribute to the fetus in pregnant women. Any dose of carboprost that produces increased uterine tone could put the fetus at risk.
In animal studies, administration of carboprost for 3 or more days during gestation caused a high incidence of resorptions in rats and rabbits and embryotoxic effects in rats. The lowest dose of carboprost which caused these effects was approximately 6 and 36 times lower, in rats and rabbits respectively, than the recommended maximum dose in humans (based on surface area comparisons).6 Pharmaceutical Particulars
6.1 List of Excipients
Trometamol, sodium chloride, benzyl alcohol (as preservative), sodium hydroxide and/or hydrochloric acid (for pH adjustment), water for injections.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store at 2 to 8°C (Refrigerate. Do not freeze).
6.5 Nature and Contents of Container
Carboprost Dr.Reddy's injection is available as 250 micrograms/1 mL packed in a 2 mL Type I clear glass vial, closed with a Teflon coated rubber stopper and an aluminium polypropylene flip-off seal.
Pack size: 10 vials.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Carboprost trometamol is the trometamol salt of the (15S)-15 methyl analogue of naturally occurring prostaglandin F2α. The chemical name is (15S)-9α, 11α, 15-trihydroxy-15-methylprosta-cis-5, trans-13-dienoic acid trometamol salt.
Chemical structure.
CAS number.
58551-69-2.7 Medicine Schedule (Poisons Standard)
Prescription Only Medicine (S4).
Summary Table of Changes
