1 Proposal for Inclusion of Carbetocin in the Who List

Home , Carbetocin, Oxytocin (medication)

PROPOSAL FOR INCLUSION OF CARBETOCIN IN THE WHO LIST OF ESSENTIAL MEDICINES

General items

1. Summary statement of the proposal for inclusion, change or deletion.

This proposal is to request the inclusion of heat stable Carbetocin in the World Health Organization (WHO) Model Lists of Essential Medicines (EML) for prevention of postpartum haemorrhage (PPH) in the section covering maternal health medicines.

Carbetocin (1-deamino-1-monocarba-(2-0-methyltyrosine)-oxytocin) is a long-acting synthetic agonist analogue of the human oxytocin. When injected to a woman, it induces uterine contractions. This medicine is stable at 30°C for 3 years, at 40°C for 6 months, at 50°C for 3 months and at 60°C for 1 month.1

In June 2018, a WHO randomized controlled trial (CHAMPION trial) showed that carbetocin is non-inferior to oxytocin in preventing blood loss of at least 500 ml or the use of additional uterotonics agents. Non- inferiority was not shown for the outcome blood loss of at least 1000 ml; however, the trial was underpowered for this outcome.

Following the publication of the results of the WHO CHAMPION trial, RHR/WHO updated the WHO recommendations on uterotonics for the prevention of PPH, and recommended the use of carbetocin (100 µg, IM/IV) for the prevention of PPH for all births in contexts where its cost is comparable to other effective uterotonics.2 This recommendation was based on a large Cochrane systematic review with a network meta- analysis of seven uterotonic options (NMA).3

Indication: prevention of postpartum haemorrhage due to uterine atony

Population: women following delivery of an infant

Role in therapy: uterotonic for prevention of PPH

2. Relevant WHO technical department and focal point (if applicable).

Department of Reproductive Health and Research (RHR)

3. Name of organization(s) consulted and/or supporting the application.

Not applicable

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine.

INN: Carbetocin (NB: In heat stable formulation)

ATC: H01BB03

5. Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths (if appropriate).

Dose form: Solution for injection IM or IV

Strength: 100 micrograms/ml (µg/ml)

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class.

Individual medicine

Treatment details, public health relevance and evidence appraisal and synthesis

7. Treatment details

7.1 Dosing regimen

Withdraw 1 ml of the solution for injection containing 100 µg carbetocin and administer by intravenous injection or intramuscular injection. For intravenous administration carbetocin must be administered slowly, over 1 minute. Carbetocin must be administered as soon as possible after delivery, preferably before the delivery of the placenta.

7.2 Duration of treatment

Carbetocin is intended for single use administration only. No further doses of carbetocin should be administered for prevention of PPH.

8. Information supporting the public health relevance.

Obstetric haemorrhage, especially PPH, is responsible for more than a quarter of all maternal deaths worldwide.4 In most low-income countries, PPH is the leading cause of maternal deaths.

PPH is commonly defined as a blood loss of 500 ml or more within 24 hours after birth, and affects about 5% of all women giving birth around the world.5,6 Uterine atony is the most common cause of PPH and a leading cause of PPH-related maternal mortality worldwide.4

PPH could be prevented if prophylactic uterotonics are administered during the third stage of labour, and by timely and appropriate management.2 Oxytocin is the first choice uterotonic drug recommended by the WHO. However, oxytocin is sensitive to heat exposure and must be transported and store at 2-8 °C continuously. This represents a problem in low resource settings where the cold chain is difficult to

2 maintain. Carbetocin, in its heat stable formulation, does not require cold chain transport and storage and can stay at room temperature for a long period of time (30°C for 3 years, 40°C for 6 months, 50°C for 3 months and 60°C for 1 month).1 Based on the WHO CHAMPION trial results and on the updated WHO recommendations on uterotonics for the prevention of PPH, carbetocin is recommended for PPH prevention, especially in those settings where the cold storage of oxytocin is not possible.

9. Review of benefits: summary of evidence of comparative effectiveness.

This information is based on the Cochrane systematic review with a network meta-analysis of seven uterotonic options (NMA) and on the GRADE tables extracted from the WHO recommendations on uterotonics for the prevention of PPH.2,3

9.1 Carbetocin versus placebo or no treatment for the prevention of PPH.

Two small randomized trials (169 women) in the NMA directly compared carbetocin with placebo or no treatment for the prevention of PPH. Below a summary of the main outcomes.

Maternal death: evidence on whether the prophylactic use of carbetocin during the third stage of labour reduces maternal death when compared to placebo is of very low certainty.

PPH ≥1000 ml: when compared with placebo or not treatment, moderate certainty evidence suggests that carbetocin probably reduces PPH ≥1000 ml (RR 0.52, 95% CI from 0.38 to 0.72).

Blood transfusion: moderate certainty evidence suggests that carbetocin probably reduces the use of blood transfusion when compared to placebo or no treatment (RR 0.48, 95% CI from 0.26 to 0.89)

Severe maternal morbidity – intensive care unit admissions: it is uncertain whether carbetocin reduces maternal intensive care admission as the events were very few. No other severe maternal morbidity outcomes were reported in the NMA.

PPH ≥500 ml: when compared with placebo or no treatment, moderate certainty evidence suggests that carbetocin probably reduces PPH ≥500 ml when compared with placebo or not treatment (RR 0.42, 95% CI 0.31 to 0.57)

Use of additional uterotonics: low certainty of evidence suggests that the use of carbetocin may reduce the use of additional uterotonics when compared with placebo or no treatment (RR 0.19, 95% CI from 0.13 to 0.27)

Mean blood loss: moderate certainty evidence suggests that the use of prophylactic carbetocin probably reduces average blood loss compared with women receiving placebo or not treatment (Mean difference: 138.37 ml, 95% CI 193.24 ml lower to 83.50 ml lower)

In summary, Carbetocin is associated with a substantial reduction in PPH (≥500 ml), severe PPH (≥1000 ml), blood transfusion, and use of additional uterotonics when compared with placebo or no treatment. It makes little or no difference to the risks of experiencing side effects such as nausea, abdominal pain, headache, shivering, and fever. The quality assessment of the evidence is included in the GRADE tables below.

GRADE tables for maternal death, blood loss ≥1000 ml, blood transfusion, intensive care unit admission, blood loss ≥500 ml, use of additional uterotonics and mean blood loss.

Outcome Network meta-analysis Anticipated absolute effects for network meta-analysis estimate

RR (95% CI) Certainty Risk with placebo Risk with Risk difference with or no treatment carbetocin carbetocin

Maternal 3.20 (0.13–77.79) ⨁◯◯◯ 1 per 1000 2 per 1000 1 more per 1000 death VERY LOW (1 fewer to 77 more)

2 per 1000 1 more per 1000 1 per 1000 (for vaginal birth) (1 fewer to 77 more) (for vaginal birth) (for vaginal birth)

See commenta See commentb See commentc

(for caesarean (for caesarean birth) birth)

PPH 0.52 (0.38–0.73) ⨁⨁⨁◯ 27 per 1000 14 per 1000 13 fewer per 1000 ≥ 1000 ml MODERATE (17 fewer to 7 fewer)

14 per 1000 13 fewer per 1000 27 per 1000 (for vaginal birth) (17 fewer to 7 fewer) (for vaginal birth) (for vaginal birth)

See commenta See commentb See commentc

(for caesarean (for caesarean (for caesarean birth) birth) birth)

Blood 0.48 (0.26–0.89) ⨁⨁⨁◯ 27 per 1000 13 per 1000 14 fewer per 1000 transfusions MODERATE (20 fewer to 3 fewer)

13 per 1000 14 fewer per 1000 27 per 1000 (for vaginal birth) (20 fewer to 3 fewer) (for vaginal birth) (for vaginal birth)

See commenta See commentb See commentc

(for caesarean (for caesarean (for caesarean birth) birth) birth)

Intensive care 1.00 (0.11–8.74) ⨁◯◯◯ 2 per 1000 2 per 1000 0 fewer per 1000

Outcome Network meta-analysis Anticipated absolute effects for network meta-analysis estimate

RR (95% CI) Certainty Risk with placebo Risk with Risk difference with or no treatment carbetocin carbetocin

unit (ICU) VERY LOW (2 fewer to 15 more) admissions 2 per 1000 0 fewer per 1000 2 per 1000 (for vaginal birth) (2 fewer to 15 more) (for vaginal birth) (for vaginal birth)

See commenta See commentb See commentc

(for caesarean (for caesarean (for caesarean birth) birth) birth)

PPH ≥ 500 ml 0.42 (0.31–0.57) ⨁⨁⨁◯ 107 per 1000 148 fewer per 1000 255 per 1000 MODERATE (176 fewer to 110

fewer)

107 per 1000 148 fewer per 1000 255 per 1000 (for vaginal birth) (176 fewer to 110 (for vaginal birth) fewer)

320 per 1000 134 per 1000 186 fewer per 1000

(for caesarean (for caesarean (221 fewer to 138 birth) birth) fewer)

Use of 0.19 (0.13–0.27) ⨁⨁◯◯ 40 per 1000 171 fewer per 1000 211 per 1000 additional LOW (184 fewer to 154 uterotonics fewer)

37 per 1000 156 fewer per 1000 193 per 1000 (for vaginal birth) (168 fewer to 141 (for vaginal birth) fewer)

746 per 1000 142 per 1000 604 fewer per 1000

(for caesarean (for caesarean (649 fewer to 545 birth) birth) fewer)

Mean blood MD 138.37 lower ⨁⨁⨁◯ The mean blood The mean blood loss with carbetocin was on loss (ml) (193.24 lower to loss was 295 ml average 138.37 lower (range: 193.24 ml 83.50 lower) MODERATE (range: 167.4– lower to 83.5 ml lower) 853 ml)

The mean blood The mean blood loss with carbetocin was on loss for vaginal average 138.37 ml lower (range: 193.24 ml birth was 294 ml lower to 83.5 ml lower)

Outcome Network meta-analysis Anticipated absolute effects for network meta-analysis estimate

RR (95% CI) Certainty Risk with placebo Risk with Risk difference with or no treatment carbetocin carbetocin

(range: 167.4– 680 ml)

The mean blood The mean blood loss with carbetocin was on loss for caesarean average 138.37 ml lower (range: 193.24 ml birth 815 ml lower to 83.5 ml lower) (range: 800– 853 ml)

Note: The assumed risks in the placebo group are based on weighted means of baseline risks from the studies with placebo groups in the network meta-analysis. The corresponding risks in the carbetocin group (and their 95% confidence interval) are based on the assumed risks in the placebo or no treatment group and the relative effects of carbetocin (and its 95% CI) derived from the network meta-analysis. a There were no included studies or there were no events in the included studies to estimate the baseline risk. b Absolute risk with carbetocin cannot be estimated in the absence of absolute risk with placebo or no treatment. c Risk difference cannot be estimated in the absence of absolute risks with placebo or no treatment and carbetocin. CI: confidence interval; Hb: haemoglobin; MD: mean difference RR: risk ratio

Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group grades of evidence Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

9.2 Carbetocin versus oxytocin for the prevention of PPH

Carbetocin has similar desirable effects compared with oxytocin though it may likely be superior to oxytocin in reducing PPH of at least 500 ml (41 fewer events per 1000 women), use of additional uterotonics (74 fewer per 1000 women) and blood loss after birth (82 ml less on average). There is no clear difference between carbetocin and oxytocin in terms of undesirable effects.

Summary of treatment effects of carbetocin versus oxytocin on beneficial outcomes

Desirable outcomes Oxytocin Carbetocin (absolute risk)

Maternal death 1 per 1000 Probably similar effect

PPH ≥ 1000 ml 37 per 1000 Uncertain

Blood transfusion 22 per 1000 Probably similar effect

Intensive care unit admissions 2 per 1000 Probably similar effect

PPH ≥ 500 ml 145 per 1000 Probably superior Additional uterotonics 135 per 1000 Possibly superior 301.5 ml Blood loss Possibly superior (98–1299 ml) Note: Probably superior or probably similar effect: moderate-certainty evidence of different effect or no effect Possibly superior or possibly similar effect: low-certainty evidence of different effect or no effect Uncertain: very low-certainty evidence (regardless of effect)

The quality assessment of the evidence is included in the GRADE tables below.

GRADE tables for maternal death, blood loss ≥1000 ml, blood transfusion, intensive care unit admission, blood loss ≥500 ml, use of additional uterotonics and mean blood loss.

Uterotonic agent Network meta-analysis Anticipated absolute effects for network meta-analysis estimate

RR (95% CI) Certainty Risk with control Risk with intervention Risk difference with intervention (oxytocin) (other uterotonics)

MATERNAL DEATH Carbetocin 2.00 (0.37– ⨁⨁⨁◯ 1 per 1000 2 per 1000 1 more per 1000 10.92) MODERATE (1 fewer to 10 more) 0 per 1000 0 per 1000 0 fewer per 1000 (for vaginal birth) (for vaginal birth) (for vaginal birth) 10 per 1000 20 per 1000 10 more per 1000 (for caesarean birth) (for caesarean birth) (6 fewer to 99 more) (for caesarean birth) PPH ≥ 1000 ml Carbetocin 0.87 (0.62– ⨁◯◯◯ 37 per 1000 32 per 1000 5 fewer per 1000 1.21) VERY LOW (from 14 fewer to 8 more) 30 per 1000 26 per 1000 4 fewer per 1000 (for vaginal birth) (for vaginal birth) (11 fewer to 6 more) (for vaginal birth) 133 per 1000 116 per 1000 17 fewer per 1000 (for caesarean birth) (for caesarean birth) (from 51 fewer to 28 more) BLOOD TRANSFUSION Carbetocin 0.81 (0.49– ⨁⨁⨁◯ 22 per 1000 18 per 1000 4 fewer per 1000 1.32) MODERATE (11 fewer to 7 more) 15 per 1000 12 per 1000 3 fewer per 1000 (for vaginal birth) (for vaginal birth) (5 fewer to 4 more) (for vaginal birth) 81 per 1000 66 per 1000 15 fewer per 1000 (for caesarean birth) (for caesarean birth) (41 fewer to 26 more) (for caesarean birth) ICU ADMISSION Carbetocin 1.16 (0.67– ⨁⨁⨁◯ 2 per 1000 2 per 1000 0 fewer per 1000 2.02) MODERATE (1 fewer to 2 more) 2 per 1000 2 per 1000 0 fewer per 1000 (for vaginal birth) (for vaginal birth) (1 fewer to 2 more) (for vaginal birth) No included studies or Absolute risk with Risk difference cannot be estimated there is no event in uterotonic cannot be in the absence of absolute risks included studies to estimated in the absence with intervention and oxytocin. (for estimate the baseline risk. of absolute risk with caesarean birth) (for caesarean birth) oxytocin (for caesarean birth)

PPH ≥ 500 ml Carbetocin 0.72 (0.56– ⨁⨁⨁◯ 145 per 1000 104 per 1000 41 fewer per 1000 0.93) MODERATE (from 64 fewer to 10 fewer) 122 per 1000 87 per 1000 34 fewer per 1000 (for vaginal birth) (for vaginal birth) (from 54 fewer to 9 fewer) 604 per 1000 435 per 1000 169 fewer per 1000 (for caesarean birth) (for caesarean birth) (from 266 fewer to 42 fewer) USE ADDITIONAL UTEROTONICS Carbetocin 0.45 (0.34– ⨁⨁◯◯ 135 per 1000 61 per 1000 74 fewer per 1000 0.59) LOW (89 fewer to 55 fewer) 116 per 1000 52 per 1000 64 fewer per 1000 (for vaginal birth) (for vaginal birth) (77 fewer to 48 fewer) (for vaginal birth) 304 per 1000 137 per 1000 167 fewer per 1000 (for caesarean birth) (for caesarean birth) (201 fewer to 125 fewer) (for caesarean birth) MEAN BLOOD LOSS (ml) 81. 39 ⨁⨁◯◯ 301.53 81.39 lower Carbetocin lower LOW (98.00–1299.00) (119.91 lower to 42.87 lower) (119.91 lower to 42.87 271.19 81.39 lower lower) (98.00–535.00) (119.91 lower to 42.87 lower) (for vaginal birth) (for vaginal birth) 607.19 81.39 lower (188.00–1299.00) (119.91 lower to 42.87 lower) (for caesarean birth) (for caesarean birth)

10. Review of harms and toxicity: summary of evidence of safety.

10.1 Carbetocin versus placebo or no treatment for the prevention of PPH

When used for PPH prevention, carbetocin has little or no difference to the risks of experiencing side effects. The quality assessment of the evidence is included in the GRADE tables below.

GRADE tables for nausea, vomiting, headache, abdominal pain, hypertension, shivering, fever and diarrhoea.

Nausea 0.88 (0.48–1.61) ⨁⨁◯◯ 37 per 1000 33 per 1000 4 fewer per 1000 LOW (19 fewer to 23 more) 37 per 1000 33 per 1000 4 fewer per 1000 (for vaginal birth) (for vaginal birth) (19 fewer to 23 more) 67 per 1000 59 per 1000 8 fewer per 1000 (for caesarean (for caesarean (35 fewer to 41 more) birth) birth)

Outcome Network meta-analysis Anticipated absolute effects for network meta-analysis estimate RR (95% CI) Certainty Risk with placebo Risk with Risk difference with or no treatment carbetocin carbetocin Vomiting 0.91 (0.49–1.68) ⨁◯◯◯ 34 per 1000 31 per 1000 3 fewer per 1000 VERY LOW (17 fewer to 23 more) 34 per 1000 31 per 1000 3 fewer per 1000 (for vaginal birth) (for vaginal birth) (17 fewer to 23 more) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Headache 1.35 (0.65–2.82) ⨁⨁◯◯ 12 per 1000 16 per 1000 4 more per 1000 LOW (4 fewer to 22 more) 12 per 1000 16 per 1000 4 more per 1000 (4 fewer to 22 more) (for vaginal birth) (for vaginal birth) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Abdominal 1.14 (0.75–1.73) ⨁⨁◯◯ 339 per 1000 383 per 1000 47 more per 1000 pain LOW (85 fewer to 247 more) 339 per 1000 383 per 1000 47 more per 1000 (for vaginal birth) (for vaginal birth) (85 fewer to 247 more) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Hypertension 1.04 (0.08–13.13) ⨁◯◯◯ 7 per 1000 7 per 1000 0 fewer per 1000 VERY LOW (6 fewer to 84 more) 7 per 1000 7 per 1000 0 fewer per 1000 (for vaginal birth) (for vaginal birth) (6 fewer to 84 more) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Shivering 0.54 (0.26–1.11) ⨁⨁⨁◯ 148 per 1000 80 per 1000 68 fewer per 1000 MODERATE (110 fewer to 16 more) 148 per 1000 80 per 1000 68 fewer per 1000 (for vaginal birth) (for vaginal birth) (110 fewer to 16 more) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Fever 1.14 (0.36–3.59) ⨁⨁⨁◯ 29 per 1000 33 per 1000 4 more per 1000 MODERATE (19 fewer to 75 more) 29 per 1000 33 per 1000 4 more per 1000 (for vaginal birth) (for vaginal birth) (19 fewer to 75 more) See commenta See commentb See commentc (for caesarean (for caesarean birth) birth) Diarrhoea _ _ _ _ _ a There were no included studies or there were no events in the included studies to estimate the baseline risk. b Absolute risk with carbetocin cannot be estimated in the absence of absolute risk with placebo or no treatment. c Risk difference cannot be estimated in the absence of absolute risks with placebo or no treatment and carbetocin.

10.2 Carbetocin versus oxytocin for the prevention of PPH

There is no clear difference between carbetocin and oxytocin in terms of undesirable effects. The quality assessment of the evidence is included in the GRADE tables below.

GRADE tables for nausea, vomiting, headache, abdominal pain, hypertension, shivering, fever and diarrhoea.

Outcome Network meta-analysis Anticipated absolute effects for network meta-analysis estimate RR (95% Certainty Risk with placebo or Risk with carbetocin Risk difference with CI) no treatment carbetocin

NAUSEA

Carbetocin 1.00 (0.71– ⨁⨁◯◯ 102 per 1000 102 per 1000 0 fewer per 1000 1.41) LOW (30 fewer to 42 more) 86 per 1000 86 per 1000 0 fewer per 1000 (for vaginal birth) (for vaginal birth) (25 fewer to 35 more) (for vaginal birth) 163 per 1000 163 per 1000 0 fewer per 1000 (for caesarean birth) (for caesarean birth) (47 fewer to 67 more) (for caesarean birth) VOMITING Carbetocin 0.93 (0.64– ⨁⨁⨁◯ 28 per 1000 26 per 1000 2 fewer per 1000 1.35) MODERATE (10 fewer to 10 more) 13 per 1000 12 per 1000 1 fewer per 1000 (for vaginal birth) (for vaginal birth) (5 fewer to 5 more) (for vaginal birth) 97 per 1000 91 per 1000 6 fewer per 1000 (for caesarean birth) (for caesarean birth) (34 fewer to 35 more) (for caesarean birth) HEADACHE Carbetocin 0.94 (0.66– ⨁⨁◯◯ 171 per 1000 161 per 1000 10 fewer per 1000 1.33) LOW (58 fewer to 56 more) 167 per 1000 157 per 1000 10 fewer per 1000 (for vaginal birth) (for vaginal birth) (57 fewer to 55 more) (for vaginal birth) 175 per 1000 164 per 1000 11 fewer per 1000 (for caesarean birth) (for caesarean birth) (59 fewer to 58 more) (for caesarean birth) ABDOMINAL PAIN Carbetocin 1.13 (0.90– ⨁⨁⨁◯– 241 per 1000 272 per 1000 31 more per 1000 1.44) MODERATE (24 fewer to 106 more) 210 per 1000 237 per 1000 27 more per 1000 (for vaginal birth) (for vaginal birth) (21 fewer to 92 more) (for vaginal birth) 364 per 1000 411 per 1000 47 more per 1000 (for caesarean birth) (for caesarean birth) (36 fewer to 160 more) (for caesarean birth) HYPERTENSION Carbetocin 1.24 (0.28– ⨁◯◯◯ 82 per 1000 102 per 1000 20 more per 1000 5.56) VERY LOW (59 fewer to 374 more) 76 per 1000 94 per 1000 18 more per 1000 (for vaginal birth) (for vaginal birth) (55 fewer to 347 more) (for vaginal birth) 167 per 1000 207 per 1000 40 more per 1000 (for caesarean birth) (for caesarean birth) (120 fewer to 762 more) (for caesarean birth) SHIVERING Carbetocin 0.77 (0.46– ⨁⨁◯◯ 91 per 1000 70 per 1000 21 fewer per 1000 1.29) LOW (from 49 fewer to 26 more) 89 per 1000 69 per 1000 20 fewer per 1000 (for vaginal birth) (for vaginal birth) (from 48 fewer to 26 more) (for vaginal birth) 103 per 1000 79 per 1000 24 fewer per 1000 (for caesarean birth) (for caesarean birth) (from 56 fewer to 30 more)

(for caesarean birth) FEVER Carbetocin 1.07 (0.43– ⨁⨁⨁◯ 29 per 1000 31 per 1000 2 more per 1000 2.69) MODERATE (17 fewer to 49 more) 24 per 1000 26 per 1000 2 more per 1000 (for vaginal birth) (for vaginal birth) (14 fewer to 41 more) (for vaginal birth) 55 per 1000 59 per 1000 4 more per 1000 (for caesarean birth) (for caesarean birth) (31 fewer to 93 more) (for caesarean birth) DIARRHOEA Carbetocin Not – There were no included Absolute risk with Risk difference cannot be reported studies or there were uterotonic cannot be estimated in the absence of no events in the estimated in the absence of absolute risks with included studies to absolute risk with oxytocin. intervention and oxytocin. estimate the baseline risk. There were no included Absolute risk with Risk difference cannot be studies or there were uterotonic cannot be estimated in the absence of no events in the estimated in the absence of absolute risks with included studies to absolute risk with oxytocin. intervention and oxytocin. estimate the baseline (for vaginal birth) (for vaginal birth) risk (for vaginal birth) There were no included Absolute risk with Risk difference cannot be studies or there were uterotonic cannot be estimated in the absence of no events in the estimated in the absence of absolute risks with included studies to absolute risk with oxytocin. intervention and oxytocin. estimate the baseline (for caesarean birth) (for caesarean birth) risk (for caesarean birth)

11. Summary of available data on comparative cost and cost-effectiveness of the medicine.

11.1 Range of cost of the proposed medicine

Commercial price (information provided by Ferring Pharmaceuticals):

Carbetocin is sold under various brand names (PABAL, DURATOCIN, LONACTENE and DURATOBAL) by FERRING Pharmaceuticals across the world. In Europe, the ex-factory prices range from €18 to €40 per unit (100mcg). In Asia, the ex-factory prices range from €15 to €27. In Latin America, ex-factory the prices range from €18 to €22. In Middle East, Turkey and Africa, the ex-factory prices range from €8 to 18€. Carbetocin is not sold in the US. Price differences reflect discrepancies between country’s economic situations.

Access program

In 2013, WHO was approached by Merck for Mothers (a philanthropic initiative of Merck, known outside the USA as Merck Sharpe & Dohme [MSD]) and Ferring Pharmaceuticals to explore the potential value of heat-stable carbetocin for reducing the incidence of maternal death. WHO convened an international panel of stakeholders who identified the need for demonstration of non-inferiority of heat-stable carbetocin before a change in guidance and practice could be considered. If non-inferior to oxytocin, the heat-stable formulation of carbetocin would be made available in public-sector health care facilities in high-burden countries at an affordable and sustainable “access price” (comparable to the United Nations Population

Fund [UNFPA] price of oxytocin), according to a memorandum of understanding (MoU) signed by representatives of WHO, Ferring Pharmaceuticals and Merck. This price is a subsidized price of $0.31 +/- 10% per ampoule of 100 µg heat-stable carbetocin (the UNFPA current price of Oxytocin is $0.27 per unit (10 I.U.)).

11.2 Cost-effectiveness

A systematic review of the literature found no direct evidence on the costs and cost–effectiveness of carbetocin compared with no uterotonic for PPH prevention.7 However, the review found a cost– effectiveness analysis from the United Kingdom of Great Britain and Northern Ireland (United Kingdom) that compared carbetocin with other uterotonic agents.3 This analysis concluded that carbetocin might be the most cost-effective uterotonic agent for vaginal and caesarean birth in high-income country (HIC) settings when the relatively high costs of managing PPH and side-effects associated with other options are considered. No cost–effectiveness analysis from LMICs was identified.

In the same review,7 six other studies that evaluated economic outcomes related to carbetocin use following caesarean section were identified: five were cost–effectiveness analyses8-12 and one was a service evaluation study;13 three were from an HIC (the United Kingdom) and three were from middle-income countries (Ecuador, Malaysia and Peru). All six studies compared carbetocin (100 μg) with oxytocin (5 international units [IU] or 10 IU, if dose was reported). Findings were somewhat inconsistent across the cost–effectiveness studies with several suggesting that carbetocin might be cost-effective following caesarean section compared with oxytocin, and others indicating that uncertainty around the supply cost and other resource data made it difficult to determine whether it might be cost-effective or not.10,12 In addition, the United Kingdom service evaluation study reported a significant increase in the cost of care during the period from birth of baby to transfer to the postnatal ward of low-risk women undergoing elective caesarean birth (from approximately US$ 104.27 before the introduction of carbetocin, to US$ 128.35 following this; P < 0.01), but economic modelling was not performed in this study.13 In general, the certainty of the evidence overall was undermined by methodological limitations and uncertainty in the underlying data of the studies.

Findings from one prospective study included in the review suggested that the cost–effectiveness of carbetocin might be greater following emergency caesarean section than for elective caesarean section, due to a larger reduction observed in the use of additional uterotonics with emergency caesarean section, which could be investigated further.11

In summary, the cost-effectiveness of carbetocin varies across settings. Carbetocin may be cost-effective in some high-income settings (where the cost of managing PPH and its complications is high), however, there is no direct evidence to suggest that carbetocin is cost-effective in settings where the cost of PPH care is moderate.2 Given the substantial beneficial effects and minimal side effects, carbetocin would probably be cost-effective if the unit cost is comparable to other effective uterotonics and in settings where the cost of PPH care is substantial.2

Regulatory information

12. Summary of regulatory status and market availability of the medicine.

Carbetocin was first registered in Canada in June 1997 and subsequently in UK in October 1997. Via Mutual Recognition Procedure in EU, carbetocin is now approved in 23 countries via the national EU authorities (i.e. not EMA). Globally, carbetocin is today approved in more than 80 countries worldwide, not including US and Japan. In most of the countries carbetocin is approved for prevention of uterine atony following delivery of the infant by Caesarean Section. In a few countries, primarily in Latin America and recently in Australia, carbetocin is also approved for prevention of uterine atony following vaginal delivery. The product has been launched in 79 countries.

The currently approved product is manufactured in Germany, where the primary packaging material is vials. The product Ferring will make available in LIC/LMIC countries at access price will be manufactured in China and India, and the primary packaging material is ampoules. Ferring started the registration process of the ampoule product in September 2018, where the first application was submitted to Swissmedic, via their procedure for Global Health Products (MAGHP). The approval by Swissmedic is anticipated in Q2 2020, where after Ferring will pursue registrations in the LIC/LMIC (defined by the world bank) and Ferring will seek WHO PQ.

The countries of origin for the ampoule product are China and India. Ferring currently has a registration of carbetocin (product manufactured in vials in Germany) in China, while an application in India is planned to be submitted in Q1 2019.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia).

Carbetocin is not listed in any of the pharmacopoeia.

Reference list

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