proposal for inclusion of carbetocin in the ......general items 1. summary statement of the proposal...

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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

2

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

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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.

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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

or no treatment

Risk with

carbetocin

Risk difference with

carbetocin

Maternal

death

3.20 (0.13–77.79) ⨁◯◯◯

VERY LOW

1 per 1000

2 per 1000

1 more per 1000

(1 fewer to 77 more)

1 per 1000

(for vaginal birth)

2 per 1000

(for vaginal birth)

1 more per 1000


(for vaginal birth)

See commenta

(for caesarean

birth)

See commentb

(for caesarean

birth)

See commentc

PPH

≥ 1000 ml

0.52 (0.38–0.73) ⨁⨁⨁◯

MODERATE

27 per 1000

14 per 1000 13 fewer per 1000

(17 fewer to 7 fewer)

27 per 1000

(for vaginal birth)

14 per 1000

(for vaginal birth)

13 fewer per 1000


(for vaginal birth)

See commenta

(for caesarean

birth)

See commentb

(for caesarean

birth)

See commentc

(for caesarean birth)

Blood

transfusions

0.48 (0.26–0.89) ⨁⨁⨁◯

MODERATE

27 per 1000

13 per 1000 14 fewer per 1000


27 per 1000

(for vaginal birth)

13 per 1000

(for vaginal birth)

14 fewer per 1000


(for vaginal birth)

See commenta

(for caesarean

birth)

See commentb

(for caesarean

birth)

See commentc


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

5


RR (95% CI)

Certainty

Risk with placebo

or no treatment

Risk with

carbetocin


carbetocin

unit (ICU)

admissions

VERY LOW (2 fewer to 15 more)

2 per 1000

(for vaginal birth)

2 per 1000

(for vaginal birth)

0 fewer per 1000


(for vaginal birth)

See commenta

(for caesarean

birth)

See commentb

(for caesarean

birth)

See commentc


PPH ≥ 500 ml 0.42 (0.31–0.57) ⨁⨁⨁◯

MODERATE

255 per 1000

107 per 1000 148 fewer per 1000

(176 fewer to 110

fewer)

255 per 1000

(for vaginal birth)

107 per 1000

(for vaginal birth)

148 fewer per 1000

(176 fewer to 110

fewer)

320 per 1000

(for caesarean

birth)

134 per 1000

(for caesarean

birth)

186 fewer per 1000

(221 fewer to 138

fewer)

Use of

additional

uterotonics

0.19 (0.13–0.27) ⨁⨁◯◯

LOW

211 per 1000

40 per 1000

171 fewer per 1000

(184 fewer to 154

fewer)

193 per 1000

(for vaginal birth)

37 per 1000

(for vaginal birth)

156 fewer per 1000

(168 fewer to 141

fewer)

746 per 1000

(for caesarean

birth)

142 per 1000

(for caesarean

birth)

604 fewer per 1000

(649 fewer to 545

fewer)

Mean blood

loss (ml)

MD 138.37 lower

(193.24 lower to

83.50 lower)

⨁⨁⨁◯

MODERATE

The mean blood

loss was 295 ml

(range: 167.4–

853 ml)

The mean blood loss with carbetocin was on

average 138.37 lower (range: 193.24 ml

lower to 83.5 ml lower)

The mean blood

loss for vaginal

birth was 294 ml


average 138.37 ml lower (range: 193.24 ml


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RR (95% CI)

Certainty

Risk with placebo

or no treatment

Risk with

carbetocin


carbetocin

(range: 167.4–

680 ml)

The mean blood

loss for caesarean

birth 815 ml

(range: 800–

853 ml)


average 138.37 ml lower (range: 193.24 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

(absolute risk)

Carbetocin

Maternal death 1 per 1000 Probably similar effect

PPH ≥ 1000 ml 37 per 1000 Uncertain

Blood transfusion 22 per 1000 Probably similar effect

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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

Blood loss 301.5 ml

(98–1299 ml) Possibly superior

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 (oxytocin)

Risk with intervention (other uterotonics)

Risk difference with intervention

MATERNAL DEATH

Carbetocin 2.00 (0.37–10.92)

⨁⨁⨁◯ MODERATE

1 per 1000 2 per 1000 1 more per 1000 (1 fewer to 10 more)

0 per 1000 (for vaginal birth)


0 fewer per 1000 (for vaginal birth)

10 per 1000 (for caesarean birth)


10 more per 1000 (6 fewer to 99 more) (for caesarean birth)

PPH ≥ 1000 ml

Carbetocin 0.87 (0.62–1.21)

⨁◯◯◯ VERY LOW

37 per 1000 32 per 1000 5 fewer per 1000 (from 14 fewer to 8 more)



4 fewer per 1000 (11 fewer to 6 more) (for vaginal birth)



17 fewer per 1000 (from 51 fewer to 28 more)

BLOOD TRANSFUSION

Carbetocin 0.81 (0.49–1.32)


22 per 1000 18 per 1000 4 fewer per 1000 (11 fewer to 7 more)






15 fewer per 1000 (41 fewer to 26 more) (for caesarean birth)

ICU ADMISSION

Carbetocin 1.16 (0.67–2.02)






No included studies or there is no event in included studies to estimate the baseline risk. (for caesarean birth)

Absolute risk with uterotonic cannot be estimated in the absence of absolute risk with oxytocin (for caesarean birth)

Risk difference cannot be estimated in the absence of absolute risks with intervention and oxytocin. (for caesarean birth)

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PPH ≥ 500 ml

Carbetocin 0.72 (0.56–0.93)


145 per 1000 104 per 1000 41 fewer per 1000 (from 64 fewer to 10 fewer)



34 fewer per 1000 (from 54 fewer to 9 fewer)



169 fewer per 1000 (from 266 fewer to 42 fewer)

USE ADDITIONAL UTEROTONICS

Carbetocin 0.45 (0.34–

0.59) ⨁⨁◯◯

LOW

135 per 1000 61 per 1000 74 fewer per 1000


116 per 1000

(for vaginal birth)

52 per 1000

(for vaginal birth)

64 fewer per 1000


(for vaginal birth)

304 per 1000


137 per 1000


167 fewer per 1000



MEAN BLOOD

LOSS (ml)

Carbetocin

81. 39

lower

(119.91

lower to

42.87

lower)

⨁⨁◯◯

LOW

301.53

(98.00–1299.00)

81.39 lower

(119.91 lower to 42.87 lower)

271.19 (98.00–535.00) (for vaginal birth)

81.39 lower


(for vaginal birth)

607.19

(188.00–1299.00)


81.39 lower



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.


RR (95% CI)

Certainty

Risk with placebo or no treatment

Risk with carbetocin

Risk difference with carbetocin

Nausea 0.88 (0.48–1.61) ⨁⨁◯◯ LOW

37 per 1000

33 per 1000 4 fewer per 1000 (19 fewer to 23 more)



4 fewer per 1000 (19 fewer to 23 more)




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RR (95% CI)

Certainty


Risk with carbetocin

Risk difference with carbetocin

Vomiting 0.91 (0.49–1.68) ⨁◯◯◯ VERY LOW

34 per 1000





See commenta


See commentb


See commentc

Headache 1.35 (0.65–2.82) ⨁⨁◯◯ LOW

12 per 1000

16 per 1000 4 more per 1000 (4 fewer to 22 more)

12 per 1000

(for vaginal birth)

16 per 1000

(for vaginal birth)

4 more per 1000 (4 fewer to 22 more)

See commenta


See commentb


See commentc

Abdominal pain

1.14 (0.75–1.73) ⨁⨁◯◯ LOW

339 per 1000





See commenta


See commentb


See commentc

Hypertension 1.04 (0.08–13.13) ⨁◯◯◯ VERY LOW

7 per 1000





See commenta


See commentb


See commentc

Shivering 0.54 (0.26–1.11) ⨁⨁⨁◯ MODERATE

148 per 1000





See commenta


See commentb


See commentc

Fever 1.14 (0.36–3.59) ⨁⨁⨁◯ MODERATE

29 per 1000





See commenta


See commentb


See commentc

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.

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

diarrhoea.


RR (95% CI)

Certainty


Risk with carbetocin Risk difference with carbetocin

NAUSEA

Carbetocin 1.00 (0.71–1.41)

⨁⨁◯◯ LOW








VOMITING

Carbetocin 0.93 (0.64–1.35)









HEADACHE


1.33) ⨁⨁◯◯

LOW

171 per 1000 161 per 1000 10 fewer per 1000


167 per 1000

(for vaginal birth)

157 per 1000

(for vaginal birth)

10 fewer per 1000


(for vaginal birth)

175 per 1000


164 per 1000


11 fewer per 1000



ABDOMINAL

PAIN

Carbetocin 1.13 (0.90–1.44)

⨁⨁⨁◯–MODERATE




27 more per 1000 (21 fewer to 92 more) (for vaginal birth)




HYPERTENSION

Carbetocin 1.24 (0.28–5.56)

⨁◯◯◯ VERY LOW








SHIVERING


1.29) ⨁⨁◯◯

LOW

91 per 1000 70 per 1000 21 fewer per 1000

(from 49 fewer to 26 more)

89 per 1000

(for vaginal birth)

69 per 1000

(for vaginal birth)

20 fewer per 1000


(for vaginal birth)

103 per 1000


79 per 1000


24 fewer per 1000


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FEVER

Carbetocin 1.07 (0.43–2.69)









DIARRHOEA

Carbetocin Not reported

– There were no included studies or there were no events in the included studies to estimate the baseline risk.

Absolute risk with uterotonic cannot be estimated in the absence of absolute risk with oxytocin.

Risk difference cannot be estimated in the absence of absolute risks with intervention and oxytocin.

There were no included studies or there were no events in the included studies to estimate the baseline risk (for vaginal birth)

Absolute risk with uterotonic cannot be estimated in the absence of absolute risk with oxytocin. (for vaginal birth)

Risk difference cannot be estimated in the absence of absolute risks with intervention and oxytocin. (for vaginal birth)

There were no included studies or there were no events in the included studies to estimate the baseline risk (for caesarean birth)

Absolute risk with uterotonic cannot be estimated in the absence of absolute risk with oxytocin. (for caesarean birth)

Risk difference cannot be estimated in the absence of absolute risks with intervention and oxytocin. (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

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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

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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

1. Malm M, Madsen I, Kjellstrom J. Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries. J Pept Sci 2018; 24(6). 2. WHO. WHO recommendations: Uterotonics for the prevention of postpartum haemorrhage - In Press. Geneva: World Health Organization, 2018. 3. Gallos ID WH, Price MJ, Merriel A, Gee H, Lissauer D, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev 2018 04;4:CD011689 PubMed PMID: 29693726 Epub 2018/04/25 eng 2018. 4. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014; 2(6): e323-33. 5. Souza JP, Gulmezoglu AM, Vogel J, et al. Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet 2013; 381(9879): 1747-55. 6. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol 2008; 22(6): 999-1012. 7. Lawrie TA RE, Vogel JP, Oladapo OT. The cost-effectiveness of uterotonic agents to prevent postpartum haemorrhage: a systematic review. (unpublished). 2018.

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8. Henriquez-Trujillo AR, Lucio-Romero RA, Bermudez-Gallegos K. Analysis of the cost-effectiveness of carbetocin for the prevention of hemorrhage following cesarean delivery in Ecuador. J Comp Effect Res 2017; 6(6): 529-36. 9. Voon HY, Shafie AA, Bujang MA, Suharjono HN. Cost effectiveness analysis of carbetocin during cesarean section in a high volume maternity unit. J Obstet Gynaecol Res 2018; 44(1): 109-16. 10. van der Nelson HA, Draycott T, Siassakos D, Yau CWH, Hatswell AJ. Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An economic impact analysis. Eur J Obstet Gyn R B 2017; 210: 286-91. 11. Luni Y, Borakati A, Matah A, Skeats K, Eedarapalli P. A prospective cohort study evaluating the cost-effectiveness of carbetocin for prevention of postpartum haemorrhage in caesarean sections. Journal of Obstetrics and Gynaecology 2017; 37(5): 601-4. 12. Caceda SI, Ramos RR, Saborido CM. Pharmacoeconomic study comparing carbetocin with oxytocin for the prevention of hemorrhage following cesarean delivery in Lima, Peru. J Comp Effect Res 2018; 7(1): 49-55. 13. Higgins L, Mechery J, Tomlinson AJ. Does carbetocin for prevention of postpartum haemorrhage at caesarean section provide clinical or financial benefit compared with oxytocin? J Obstet Gynaecol 2011; 31(8): 732-9.

proposal for inclusion of carbetocin in the ......general items 1. summary statement of the proposal...

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