Promethazine Compared With

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PROMETHAZINECOMPAREDWITH

METOCLOPRAMIDEFORHYPEREMESISGRAVIDARUM

A RANDOMIZEDCONTROLLEDTRIAL

Presenter Dr Surya Prasad rimal, Junior resident

Moderator Dr Pritha Basnet, Assistant professor


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OBSTETRICS & GYNECOLOGY

VOL. 115, NO. 5, MAY 2010

Peng Chiong Tan, Pwint Phyu Khine, NarayananVallikkannu, and Siti Zawiah Omar


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Location: Department of Obstetrics and Gynecology,

University of Malaya, Lembah Pantai, Kuala Lumpur,

Malaysia

Duration : From November 25, 2008,

to August 14, 2009

Subjects: A total of 73 and 76 women, randomized tometoclopramide and promethazine, respectively


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OBJECTIVES

To compare the effects of promethazine with

metoclopramide for hyperemesis gravidarum.


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OBJECTIVES

VERSUS


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INTRODUCTION

Hyperemesis gravidarum is practically defined as

pernicious vomiting in pregnancy that requires

hospitalization.

It typically is associated with dehydration, electrolyte

disturbances, and starvationwith consequent weight

loss.

It affects 0.3% to 2.3% of the pregnant population,

whereas nausea and vomiting of pregnancy is far

more common, affecting up to 85% of pregnant women.


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The mainstays of therapy: rehydration,

antiemetics, and enhancement of coping

mechanisms.

ACOG 2004 guidelines

dimenhydrinate,metoclopramide,or

promethazine as first-line antiemetic.


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Hyperemesis Gravidarum

When the joy of creating life turns

into a struggle for survival and hope

I wish that I had never tried to get

pregnant

I wish that in a few months I would

be able to hold my baby

I Wish . . .


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METOCLOPRAMIDE

increases the movements

or contractionsof the muscles

prokinetic
http://www.webmd.com/baby/guide/normal-labor-and-delivery-processhttp://www.webmd.com/baby/guide/normal-labor-and-delivery-process


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Side Effects

does not cause as many side effects as many other

medicines used to prevent nausea and vomiting.

May include:

Sleepiness or confusion.

Twitchingor muscle spasms.

Decreased blood pressure(hypotension).

Rapid or uncontrolled movements of lips and tongue.

Contra indications:

narrow-angle glaucoma, prostatedisease, severe low

blood pressure, or rapid, irregular heartbeats.
http://www.webmd.com/brain/tic-disorders-and_twitcheshttp://www.webmd.com/pain-management/muscle-spasms-cramps-charley-horsehttp://www.webmd.com/hypertension-high-blood-pressure/guide/diastolic-and-systolic-blood-pressure-know-your-numbershttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/oral-health/picture-of-the-tonguehttp://www.webmd.com/eye-health/glaucoma-eyeshttp://www.webmd.com/urinary-incontinence-oab/picture-of-the-prostatehttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/urinary-incontinence-oab/picture-of-the-prostatehttp://www.webmd.com/eye-health/glaucoma-eyeshttp://www.webmd.com/oral-health/picture-of-the-tonguehttp://www.webmd.com/heart/understanding-low-blood-pressure-basicshttp://www.webmd.com/hypertension-high-blood-pressure/guide/diastolic-and-systolic-blood-pressure-know-your-numbershttp://www.webmd.com/pain-management/muscle-spasms-cramps-charley-horsehttp://www.webmd.com/brain/tic-disorders-and_twitches


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PROMETHAZINE

Promethazine, a phenothiazine derivative,

Acts primarily as a strong antagonistof

the H1receptor(antihistamine) and a

moderate mACh receptorantagonist(anticholinergicand also has weak to

moderate affinityfor the 5-HT2A,[11]5-

HT2C,[11]D2,

[12][13]and 1-adrenergic

receptors,[14]where it acts as an antagonistat all sites, as well.
http://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/Antihistaminehttp://en.wikipedia.org/wiki/Muscarinic_acetylcholinehttp://en.wikipedia.org/wiki/Anticholinergichttp://en.wikipedia.org/wiki/Affinity_(pharmacology)http://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/D2_receptorhttp://en.wikipedia.org/wiki/D2_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Alpha-1_adrenergic_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/D2_receptorhttp://en.wikipedia.org/wiki/D2_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/5-HT2C_receptorhttp://en.wikipedia.org/wiki/Promethazinehttp://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/5-HT2A_receptorhttp://en.wikipedia.org/wiki/Affinity_(pharmacology)http://en.wikipedia.org/wiki/Anticholinergichttp://en.wikipedia.org/wiki/Muscarinic_acetylcholinehttp://en.wikipedia.org/wiki/Muscarinic_acetylcholinehttp://en.wikipedia.org/wiki/Muscarinic_acetylcholinehttp://en.wikipedia.org/wiki/Antihistaminehttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/H1_receptorhttp://en.wikipedia.org/wiki/Receptor_antagonist


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SIDEEFFECTS

Tardive dyskinesia

Confusion in the elderly

Drowsiness, dizziness, fatigue, more

rarely vertigoDry mouth

Constipation

Chest discomfort/pressure (typically in

cases when patient is already takingmedication for high blood pressure)
http://en.wikipedia.org/wiki/Tardive_dyskinesiahttp://en.wikipedia.org/wiki/Vertigo_(medical)http://en.wikipedia.org/wiki/Vertigo_(medical)http://en.wikipedia.org/wiki/Tardive_dyskinesiahttp://en.wikipedia.org/wiki/Tardive_dyskinesiahttp://en.wikipedia.org/wiki/Tardive_dyskinesia


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METHODOLOGY

Women hospitalized for the first time in their

current pregnancies with presumed hyperemesis

gravidarum were approached

Informed written consent.Ethical approval


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INCLUSIONCRITERIA

Clinical hyperemesis gravidarum with dehydration

and detectable ketonuria by urine dipstick at a

gestation of 16 weeks or less.


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EXCLUSIONCRITERIA

multiple gestation,

Established nonviable pregnancy,

preexisting medical condition that can cause

nausea and vomiting (eg, culture provensymptomatic urinary tract infection or dengue fever),

gastrointestinal causes of vomiting (eg,

gastroenteritis),medical causes of vomiting (eg, diabetic

ketoacidosis),

known allergy to metoclopramide /promethazine


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PRIMARYOUTCOME

well-beingvisual numerical rating scale score and

frequency of vomiting in the first 24 hours


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SECONDARYOUTCOMES

visual numerical rating scale scores for nausea at

enrolment and at 8, 16, and 24 hours;

adverse symptoms profile;

ketonuria status at the end of the 24-hour main studyperiod;

treatment curtailment during the main study period;

total doses of intravenous antiemetic needed during

hospitalization; admission- to-discharge interval; and

time needed for intravenous rehydration


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ASSIGNMENTTOTREATMENTGROUP

Participants were recruited by providers as they

were admitted to the gynecology ward.

After obtaining consent, participants were

assigned randomly by the sequentialopening ofnumbered, sealed, opaque envelopes stating

Drug A or Drug B.

These numbered envelopes were prepared by

an author (P.P.K.) in random blocks of four or

eight using a computer-generated randomization

sequence


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Study drugs were placed in identical vials.

Each vial contained a colorless 5-mL solution,

and the vial was labeled as A or B to effect

double blinding of drug allocation.

The solutions contained either 10 mg of

metoclopramide or 25 mg of promethazine.

The contents of vials A and B was swappedbetween metoclopramide and promethazine

periodically to strengthen blinding; that is, the

study drugs were in vials labeled differently at

different stages of the study.This was not revealed to providers.


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Antiemetic therapy as randomly allocated was

administered by slow injection into an indwelling

intravenous catheter over 1 to 2 minutes by

providersjust after randomization and 8, 16,and 24 hours later for a full course of four doses

as per trial protocol.

Participants were instructed to chart vomitingepisodes as they occurred during the 24-hour

study period and to mark the nausea visual

numerical rating scale (10 points, high score

denoting more severe nausea) before initialadministration of the study drug and 8, 16, and

24 hours after administration of the study drug.


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Also at 24 hours, participants were

asked to mark their perceived well-

being over the study period with a 10-point visual numerical rating scale

(higher score greater well-being) and

to answer a preset questionnaire(yes or no answers) on symptoms

experienced during the study

period.


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At the conclusion of the 24-hour main

study period, the allocated

intravenous study antiemetic could bestopped or continued as allocated or

open-label treatment (either

intravenous or oral) instituted at theproviders discretion.


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SAMPLESIZEESTIMATION

Based on the hypothesis that

metoclopramide will produce an overall

well-being visual numerical rating scale

score at 24 hours that is 1 unit better than

that produced by promethazine (using a10-point visual numerical rating scale),

assuming a visual numerical rating scale

standard deviation of 2, 0.05, and 80%power.

Sixty-four women were required in each

arm.


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Visual numerical rating scale score might not

be normal and that the Mann-Whitney U test

might have to be applied instead of theStudents t test, so, 10% increase to the

enrollment.

For 10% drop-out rate, it was planned toenroll a total of 158 women to perform a

suitably powered study.


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STATISTICALANALYSIS

SPSS 16

Students t test.

Two-by-two categorical data sets were analyzed

with the Fisher exact test and larger categorical

data sets with the 2 test; ordinal data and non

normally distributed continuous data were

analyzed with the Mann-Whitney U test


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Numbers needed to treat were generated using

GraphPad QuickCalc (GraphPad Software Inc., La

Jolla, CA).

P.05 was considered significant


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RESULTS

Primary outcome not significantly different.

Median vomitingfrequency one(range 026) compared

with two(range 026) (P.81) and

Well-beingvisual numerical rating scale score 8(range

110) compared with 7(range 210) (P.24) for themetoclopramide and promethazine arms, respectively


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SECONDARYOUTCOME

nausea visual numerical rating scale

very similar at each time point when

assessed individually.

Length of hospital stay, persistence of ketonuria at 24

hours, overall treatment curtailment, duration of

intravenous rehydration, and total doses of intravenous

antiemetic given during hospitalization were not

different between the trial arms.


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SECONDARYOUTCOME. Questionnaire on symptoms at the end of the 24-hour

main study period, the 3 Ds

drowsiness (58.6% compared with 83.6%,

P.001, number needed to treat to benefit[NNTb] 5),

dizziness (34.3% compared with 71.2%, P.001,

NNTb 3), and

dystonia (5.7% compared with 19.2%, P.02,

NNTb 8) were reported less frequently for

metoclopramide than for promethazine


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CONT.

Difficulty in sleeping, dry mouth, diarrhea,

headache, palpitations, and skin rash were reported

in similar proportions across the trial arms.


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DISCUSSION

A trial directly comparing promethazine with

metoclopramide for hyperemesis gravidarum has

not been done.

However, a three-armed trial of placebo compared

with metoclopramide compared with promethazine(with the first dose of pethidine) for labor analgesia

has shown that metoclopramide and promethazine

are equally effective in reducing the incidence of

nausea and vomiting but that the sedative effectwas more persistent in the promethazine group.

These findings are similar the data of this study .


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Metoclopramide has a desirable effect of

prokineticaction but this study indicate

that esophageal reflux is probably not animportant contributor to symptoms in

hyperemesis gravidarum

September 16, 2009, the U.S. FDAwarned of potential local tissue

damage, including gangrene, from

promethazine injection and mandated ablack box warning on the drug insert.


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LIMITATIONSOFTHESTUDY

The primary outcomes were over a 24-hour time scale

only

recruited on the basis of presumed hyperemesis

gravidarum before investigation results were available.

Later discovery of trial criteria infringements resulted in

postrandomization exclusion of 10 out of 159 (6.3%)

women

small number of participants whose data were

incomplete


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CONCLUSION

Intravenous metoclopramide or promethazine for

hospitalized hyperemesis gravidarum patients

produced similar therapeutic effects.

Metoclopramide resulted in fewer reported sideeffects and treatment curtailment owing to

adverse events.

Intravenous metoclopramide is preferred over

intravenous promethazine for the treatment ofhyperemesis gravidarum.


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Patient had metabolic and

biochemical characteristics

comparable with other women inreported studies of hyperemesis

gravidarum. Hence, findings can

be generalized.


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REFERENCES

1. Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG. Hyperemesisgravidarum, a literature review. Hum Reprod Update 2005;11:52739.

2. Tan PC, Jacob R, Quek KF, Omar SZ. The fetal sex ratio andmetabolic, biochemical, haematological and clinical indicators ofseverity of hyperemesis gravidarum. BJOG 2006;113:7337.

3. Nausea and vomiting of pregnancy. Practice Bulletin No. 52.American College of Obstetricians and Gynecologists. ObstetGynecol 2004;103:80314.

4. Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK,Morrison JC. A pilot study of intravenous ondansetron forhyperemesis gravidarum. Am J Obstet Gynecol 1996;174: 15658.

5. Safari HR, Fassett MJ, Souter IC, Alsulyman OM, Goodwin TM.The efficacy of methylprednisolone in the treatment ofhyperemesis gravidarum: a randomized, double-blinblind,controlled study. Am J Obstet Gynecol 1998;179:9214.


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CONT.

6. Ziaei S, Hosseiney FS, Faghihzadeh S. Theefficacy low dose of prednisolone in the treatmentof hyperemesis gravidarum. Acta Obstet GynecolScand 2004;83:2725

7. Lacasse A, Lagoutte A, Ferreira E, Berard A.Metoclopramide and diphenhydramine in thetreatment of hyperemesis gravidarum: effectivenessand predictors of rehospitalisation. Eur J ObstetGynecol Reprod Biol 2009;143:439.

8. Yost NP, McIntire DD, Wians FH Jr, Ramin SM,Balko JA, Leveno KJ. A randomized, placebo-controlled trial of corticosteroids for hyperemesisdue to pregnancy. Obstet Gynecol 2003;102:12504.


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CONT..

9. Buttino L Jr, Coleman SK, Bergauer NK, Gambon C, StanzianoGJ. Home subcutaneous metoclopramide therapy forhyperemesis gravidarum. J Perinatol 2000;20:35962.

10. Bondok RS, El Sharnouby NM, Eid HE, Abd Elmaksoud AM.Pulsed steroid therapy is an effective treatment for intractablehyperemesis gravidarum. Crit Care Med 2006;34:27813.

11. Neri I, Allais G, Schiapparelli P, Blasi I, Benedetto C, FacchinettiF. Acupuncture versus pharmacological approach to reduceHyperemesis gravidarum discomfort. Minerva Ginecol2005;57:4715.

12. Jewell D, Young G. Interventions for nausea and vomiting inearly pregnancy. The Cochrane Database of Systematic Reviews2003, Issue 4. Art. No.: CD000145. DOI: 10.1002/14651858.CD000145.

13. Bsat FA, Hoffman DE, Seubert DE. Comparison of threeoutpatient regimens in the management of nausea and vomitingin pregnancy. J Perinatol 2003;23:5315.


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CONT..

14. Tan PC, Yow CM, Omar SZ. A placebo-controlled trial of oralpyridoxine in hyperemesis gravidarum. Gynecol Obstet Invest2009;67:1517.

15. Tan PC, Jacob R, Quek KF, Omar SZ. Indicators ofprolonged hospital stay in hyperemesis gravidarum. Int JGynaecol Obstet 2006;93:2467.

16. Tan PC, Tan NC, Omar SZ. Effect of high levels of humanchorionic gonadotropin and estradiol (E2) on the severity ofhyperemesis gravidarum. Clin Chem Lab Med 2009;47: 16571.

17. Vella L, Francis D, Houlton P, Reynolds F. Comparison of theantiemetics metoclopramide and promethazine in labour. Br

Med J (Clin Res Ed) 1985;290:11735.18. Brock-Utne JG, Rubin J, Welman S, Dimopoulos GE, Moshal

MG, Downing JW. The action of commonly used antiemeticson the lower oesophageal sphincter. Br J Anaesth 1978;50:2958.


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CONT..

19. Sandhya, Yaddanapudi LN. Evaluation of two antiemetic agents duringoutpatient gynaecological surgery. Singapore Med J 1994;35:2713.

20. U.S. Food and Drug Administration. Information for healthcareprofessionals-intravenous promethazine and severe tissue injury,including gangrene. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcare

Professionals/ucm182169.htm. Retrieved October 3 2009.21. Tan PC, Jacob R, Quek KF, Omar SZ. Readmission risk and metabolic,

biochemical, haematological and clinical indicators of severity inhyperemesis gravidarum. Aust N Z J Obstet Gynaecol 2006;46:44650.

22. Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism andhyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol1992;167:64852.

23. Bashiri A, Neumann L, Maymon E, Katz M. Hyperemesis gravidarum:epidemiologic features, complications and outcome. Eur J ObstetGynecol Reprod Biol 1995;63:1358.
http://www.fda.gov/http://www.fda.gov/


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Metoclopramide Promethazine P


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(n73) (n76)

Weight (kg) 54.3 9.1 54.210.5 .95

Body mass index

(kg/m2)

23.0 3.5 22.5 4.2 .45

Coexisting medical

condition

4 (5.5) 6 (7.9) .75

At recruitmentKetonuria(dipstick)

1+ 16 (21.9) 16 (21.1)

2+ 15 (20.5) 12 (15.8)

3+ 32 (43.8) 43 (56.6)

4+ 10 (13.7) 5 (6.6)



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Metoclopramide

(n73)

Promethazine

(n76)

P

Nausea score* 5 (2.757) 5 (1.57) .85 .85

Serum sodium

(mmol/L)

134 4 134 2 .78

Serum potassium

(mmol/L)

3.9 0.5 3.9 0.5 .86

Hematocrit 0.39 0.04 0.39 0.03 .57

Pulse 84 13 82 12 .37

Systolic blood

pressure

(mmHg)

114 11 117 12 .15

Diastolic blood

pressuremmH

69 10 71 11 .24


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Primary outcomes

Metoclopramide

(n73)

Promethazine

(n76)

P Relative

Risk

(95% CI)

NNTb*

(95% CI)

Primary

outcomes

Vomiting

episodes

(n144)

1 (05) 2 (03) .81

Well-beingVNRS

(n142)

8 (610) 7 (5.259) .24

7.62.2 7.12.3 .24



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Metoclopramide

(n73)

Promethazine

(n76)

P

Secondary outcomes

Nausea score

At recruitment (n143) 5 (2.757 5 (1.57) .85

8 h (n143) 4 (1.55 4 (1.756) .54

16 h (n137) 3 (15) 3 (15) .80

24 h (n126) 2 (15) 2 (14) .99

Metoclopramid Promethazine


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Metoclopramid

e

(n73)

Promethazine

(n76)

Hospital stay (d) (n149) 1.8 (1.52.5) 1.7 (1.52.4)

Ketonuria (dipstick) at the end of

the

study period (n148)

Nil 54 (75.0)) 61 (80.3)

1+ 6 (8.3) 7 (9.2)

2+ 9 (12.5) 5 (6.6)

3+ 3 (4.2) 3 (3.9)



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etoc op a de

(n73)

o et a e

(n76)

Intravenous

rehydration (h)

(n147)

42 (3359) 39 (3348.75) .23

Full study drug course

not completed

4/73 (5.5) 9/76 (11.8) .25

Full study drug course

not completed

owing to adverse

events

0/73 (0) 7/76 (9.2) .014

Intravenous antiemetic

doses

4 (44) 4 (44.75) .98

Metoclopramide Promethazine P Relative Risk NNTb*


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Metoclopramide

(n73)

Promethazine

(n76)

P Relative Risk

(95% CI)

NNTb

(95% CI)

Symptoms profile

by questionnaire

(n143)

Felt drowsy 41/70 (58.6) 61/73 (83.6) .001 0.7 (95% CI 0.60.9) 5 (39)

Unable to sleep 12/70 (17.1) 16/73 (21.9) .53 0.8 (0.41.5)

Had dry mouth 28/70 (40.0) 32/73 (43.8) .74 0.9 (0.61.3)

Felt dizzy 24/70 (34.3) 52/73 (71.2)


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Promethazine Compared With

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