UTEROTONICS AND ADJUNCTIVE DRUG … AND ADJUNCTIVE DRUG THERAPY FOR POSTPARTUM HEMORRHAGE KATHY HALL, PHARMD, BCPS CRITICAL CARE PHARMACIST WESLEY MEDICAL CENTER OBJECTIVES Describe

UTEROTONICS AND ADJUNCTIVE DRUG THERAPY

FOR POSTPARTUM HEMORRHAGE

KATHY HALL, PHARMD, BCPS

CRITICAL CARE PHARMACIST

WESLEY MEDICAL CENTER

OBJECTIVES

Describe pharmacodynamics of uterotonics

Review warnings and precautions of uterotonics

Discuss adjunctive therapies for the treatment of post-partum

hemorrhage (PPH)

UTEROTONICS

Dinoprostone (Cervidil®)

Oxytocin (Pitocin®)

Misoprostol (Cytotec®)

Methylergonovine (Methergine®)

Carboprost (Hemabate®)

DINOPROSTONE (CERVIDIL®)

Lexicomp Database. 2016. Accessed June 2016.

Medications and Mother’s Milk Database. 2016. Accessed June 2016.

Mechanism of ActionSynthetic prostaglandin that induces uterine contractions and relaxes

cervical smooth muscle thus allowing dilation and passage of the fetus

Indication Cervical ripening

Contraindications

Inability for spontaneous labor/vaginal

delivery

Hx C-section/uterine rupture

Cephalopelvic disproportion

Vaginal bleeding during

pregnancy

≥ 6 term pregnancies

Epilepsy

Dosing 10 mg tablet intravaginally

Drug Interactions Carboprost, oxytocin Enhanced oxytocic effects

Adverse Reactions Postpartum DIC, uterine hypertonicity, vaginal warmth

Lactation Risk L3 probably compatible Clincally insignificant effect on breastmilk

Pearls Remove at the onset of labor or after 12 hours or 30 min prior to oxytocin

OXYTOCIN (PITOCIN®)

Mechanism of ActionActivates G-protein coupled receptors to increase intracellular calcium levels in

uterine myofibrils + increases local prostaglandin production = uterine contraction

IndicationInduction and augmentation of labor

Prevention and treatment postpartum hemorrhage

Contraindications

Cephalopelvic disproportion

Unfavorable fetal positions

Hypertonic/hyperactive uterus

Cord prolapse

Total placenta previa

Vasa previa

Cervical cancer

Active genital herpes

DosingInduction: 2 milliunits/min IV titrate Q15 mins as needed

PPH: 19.98 units IV over 20 min then 80 milliunits/hr until stable

Drug InteractionsCarboprost, dinoprostone, misoprostol Enhanced oxytocic effects

Ondansetron Prolonged QT

Adverse Reactions Arrhythmias, seizure, uterine hypertonicity, jaundice (neonate)

Lactation Risk L2 probably compatible oxytocin naturally increases during breast-feeding

PearlsRemove dinoprostone at least 30 minutes prior to oxytocin

Do not administer oxytocin within 4 hours of misoprostololLexicomp Database. 2016. Accessed June 2016.


MISOPROSTOL (CYTOTEC®)

Mechanism of Action Synthetic prostaglandin that induces uterine contractions

IndicationCervical ripening or induction of labor

Prevention and treatment postpartum hemorrhage

Contraindications Inability for spontaneous/vaginal delivery

DosingRipening/Induction: 25 mcg Q3-6 hours PRN

PPH: 400-600 mcg sublingually or rectally x1

Drug InteractionsCarboprost, oxytocin Enhanced oxytocic effects

Antacids Increased misoprostol effects

Adverse Reactions GI upset, uterine rupture

Lactation Risk L2 probably compatible Minimal excretion in milk due to fast elimination

PearlsBlack box warning: Risk of uterine rupture when used to induce labor after

eighth week of pregnancy



METHYLERGONOVINE (METHERGINE®)

Mechanism of ActionIncreases tone, rate and amplitude of uterine smooth muscle thus

producing sustained contractions shortening the third stage of labor

Indication Treatment postpartum hemorrhage

Contraindications Hypertension, pre-eclampsia

Dosing 0.2 mg IM every 20 minutes as needed

Drug InteractionsProtease inhibitors (boceprevir/telaprevir)/azole antifungals Increased

methylergonovine effects

Adverse Reactions HTN, chest pain, acute MI, CVA

Lactation Risk L2 probably compatible No difference in prolactin/milk production

PearlsSecond line for PPH compared to other uterotonics due to

adverse reactions



CARBOPROST (HEMABATE®)

Mechanism of ActionAnalog of naturally occurring prostaglandin F2 alpha thus stimulates

myometrial contractions

Indication Treatment of postpartum hemorrhage

Contraindications Active cardiac or pulmonary disease

Dosing 250 mg IM as directed Q15-90 min PRN (maximum 8 doses)

Drug Interactions Oxytocin Increased oxytocic effects

Adverse ReactionsHTN, chest pain, nausea, vomiting, diarrhea, fever, uterine perforation,

uterine rupture, bronchospasm

Lactation RiskL3 probably compatible No data but unlikely to penetrate breastmilk

due to short half life

PearlsBlack box warning: Potent oxytocic agent

Consider premedication with anti-nausea/anti-diarrheal



ADJUNCTIVE THERAPIES FOR MASSIVE BLOOD LOSS

Tranexamic

acid

Fibrinogen

concentrateIron

TRANEXAMIC ACID (TXA)

Mechanism of Action Displaces plasminogen from fibrin thus inhibiting fibrinolysis

Indication Prevention and potential treatment postpartum hemorrhage

Contraindications Thromboembolic event

DosingPrevention: 1 gm IV once

Treatment: 1 gm IV once over 10 minutes then 1 gm IV over 8 hours

Drug Interactions None

Adverse Reactions GI upset, headache, blurred vision, risk of thrombosis

Lactation Risk L3 probably compatible No differences in infant growth/development

PearlsConsider administration prior to elective C-section

Optional administration during massive blood transfusion



TXA FOR CESAREAN SECTION PROPHYLAXIS

Study Methods Outcomes

Gungorduk, et al.

2011

Double-blind,

placebo-

controlled

RCT

Elective C-section

TXA 1 gm IV x1

(n = 330)

vs

Placebo (n = 330)

Yehia, et al.

2014

Double-blind, RCT

Elective C-section

TXA 1gm IV x1 +

oxytocin (n = 106)

vs

Oxytocin (n = 106)

Gungorduk, et al. Am J Perinatol. 2011; 28: 233-40.

Yehia, et al. Asian Pacific J of Reprod. 2014; 3: 53-56.

Outcome TXA Placebo P value

Mean EBL, ml 499.9 + 206.4 600.7 + 215.7 <0.001

Uterotonic agent, n (%) 7 (2.1) 19 (5.8) <0.03

Outcome TXA + Oxy Oxytocin P value

24-hr Hgb, mg/dL 11.2 + 1.5 9.6 + 1.2 0.01

PPH, n (%) 32 (31.1) 67 (63.2) <0.05

Iron replacement 1 (0.9) 7 (6.6) <0.05

TXA FOR CESAREAN SECTION PROPHYLAXIS

Study Design Methods Outcomes

Novikova, et al.

2015

Cochrane

review

TXA in C-section

and vaginal

deliveries

vs

Placebo or no

intervention

(n = 12 studies)

Blood loss >1000 mL less common with TXARR 0.4, 95% CI 0.23-0.71

- TXA effective in C-section but few outcomes in

vaginal birth

Additional uterotonics less with TXARR 0.48, 95% CI 0.34-0.68

Blood transfusion less with TXARR 0.24, 95% CI 0.11-0.53

Side effects more with TXARR 2.48, 95% CI 1.36-4.5

- Most common nausea, vomiting, diarrhea, dizziness

Novikova, et al. Cochrane Review. 2015; 6.

CRASH II

Randomized, placebo controlled, multicenter trial

Adult trauma patients with or at risk for significant bleeding

Tranexamic acid 1 gm IV over 10 minutes then 1 gm over 8 hours vs placebo

CRASH I Investigators. Lancet. 2010; 376: 23-32.

Mortality Outcome

n (%)

TXA

n = 10060

Placebo

n = 10067Statistics

All-cause 1463 (14.5) 1613 (16) p = 0.0035

Bleeding 489 (4.9) 574 (5.7) p = 0.0077

<1 hr from injury 509/3747 (13.6) 581/3704 (15.7) RR = 0.87 (0.75-1)

>1 to ≤ 3 hr from injury 463/3037 (15.2) 528/2996 (17.6) RR = 0.87 (0.75-1)

> 3 hr from injury 491/3272 (15) 502/3363 (14.9) RR = 1 (0.86-1.17)

WORLD MATERNAL ANTIFIBRINOLYTIC TRIAL (WOMAN TRIAL)

Randomized, double blind, placebo controlled

Effect of early TXA in PPH treatment following vaginal or cesarean delivery

TXA 1gm IV x1 (may repeat x1 if bleeding persists) vs placebo

Outcomes

Primary: Death or hysterectomy

Secondary: Death, surgical intervention, transfusion requirements, thromboembolic events, adverse events, length of stay, mechanical ventilation, lactation risk, health related quality of life, cost-effectiveness

Estimated completion May 2016

Shakur H, et al. The WOMAN Trial Study Protocol. Trials. 2010; 11: 40.

www.clinicaltrials.gov

TRANEXAMIC ACID FOR PREVENTING POSTPARTUM

HEMORRHAGE AFTER VAGINAL DELIVERY (TRAAP TRIAL)

Multicenter, randomized, double blind, placebo controlled

Effect of TXA immediately after vaginal delivery on PPH prevention

TXA 1gm IV x1 + oxytocin vs oxytocin + placebo

Outcomes

Primary: Incidence of PPH

Secondary: Blood loss, severe PPH, uterotonic administration, transfusion requirements, surgical intervention, hemoglobin/hematocrit change, thromboembolic events, adverse events

Estimated completion December 2016

Sentilhes L, et al. TRAAP Study Protocol. BMC Pregnancy and Childbirth. 2015; 15: 135.


TOPICAL TRANEXAMIC ACID IN CESAREAN SECTION (TXACS)

Single center, randomized, double-blind placebo controlled

Effect of topical TXA on surgical hemostasis during cesarean delivery

TXA 2 gm/120 mL vs placebo

60 mL to placenta bed

30 mL to open incision wound

30 mL to closed incision wound

Outcomes

Primary: Intraoperative blood loss

Secondary: Transfusion requirements, hemoglobin trends

Estimated completion December 2016


FIBRINOGEN CONCENTRATE (RIASTAP™)

Mechanism of Action Replaces missing or low plasma fibrinogen thus acting as substrate in the

clotting cascade

Indication Alternative to cryoprecipitate in treatment of postpartum hemorrhage

Contraindications Active thrombosis

Dosing 3 gm IV once

Drug Interactions None

Adverse Reactions Allergic reactions, thrombosis, transmission of infectious agents

Lactation Risk Not studied

Pearls Widely utilized in Europe


FIBRINOGEN CONCENTRATE IN POSTPARTUM HEMORRHAGE

Study Methods Outcomes

Ahmed, et al.2012

Prospective,

observational study

Major obstetric hemorrhage + fibrinogen <200 mg/dL

Cryo (n = 14)

vsFib conc (n = 20)

Mallaiah, et al.2015

Prospective cohort

Major obstetric hemorrhage + fibrinogen < 200 mg/dL

Cryo (n = 42) vs

Fib conc 3 gm IV x1 (n = 51)

Ahmed, et al. Transfus Med. 2012; 22: 344-9.

Mallaiah, et al. Anaesthesia. 2015; 70: 166-175.

Outcome Cryo Fib conc P value

EBL (L) 5.19 3.34 NS

RBCs (units) 7.12 5.9 NS

FFP (units) 4.07 3.15 NS

Post fibrinogen (mg/dL) 305 334 NS

Outcome Cryo Fib conc P value

RBCs (median units) 4 3 NS

FFP (median units) 4.25 0 NS

TACO (n, %) 4 (9) 0 0.367

TRALI (n, %) 0 0 NS

Hysterectomy (n, %) 6 (14) 3 (6) NS

FIBRINOGEN CONCENTRATE VS CRYOPRECIPITATE

Fibrinogen Concentrate

2-4 gm = ~100 mg/dL fibrinogen

Standard fibrinogen components

No ABO compatibility

Decreased risk of immune-mediated complications

No risk of transfusion reactions

Costly

Cryoprecipitate

10 units = ~70 mg/dL fibrinogen

Familiarity of care

Inexpensive

IRON REPLACEMENT

PO

Cheap

Easy administration

IV

Absorption

Tolerance

Hgb (g/dL) IV PO P-value

Day 0 7.3 7.5 NS

Day 5 9.9 7.9 <0.01

Day 14 11.1 9 <0.01

Day 40 11.5 11.2 NS

Ferritin (mcg/L) IV PO P-value

Day 0 13 11 NS

Day 5 48 12 <0.01

Day 14 37.9 16 <0.01

Day 40 42.2 15 <0.05

IV VS ORAL IRON

Single center, randomized controlled trial

Effect of IV vs PO iron on postpartum anemia

Ferrous sucrose 200 mg IV on day 2 and 4 postpartum (n = 22)

Ferrous sulfate 200 mg PO BID x 6 weeks (n = 21)

Bhandal, et al. BJOG. 2006; 113: 1248-1252.

Markova V, et al. Cochrane Review. 2015; 8.

FERRIC GLUCONATE



Litton E, et al. BMJ. 2013; 347.

Mechanism of Action Source of elemental iron

Indication Iron deficiency anemia

Contraindications Hypersensitivity reaction

Dosing 250 mg IV over 2 hrs daily x4 days

Drug Interactions No major interactions

Adverse Reactions Hypotension, headache, chest pain, GI upset

Lactation Risk L1 compatible Low Fe secretion in breastmilk but high bioavailability

Pearls Doses > 125 mg increases risk of adverse reactions

Potential for increased infection

SUMMARY

Remove dinoprostone 30 min prior to oxytocin

Risk of uterine rupture with misoprostol after eighth week of pregnancy

Methylergonovine contraindicated in HTN and pre-eclampsia

Carboprost contraindicated in active cardiac disease or asthma

Consider TXA prior to C-section or in massive blood loss

Consider fibrinogen concentrate for fibrinogen <200 mg/dL and massive blood loss

IV iron quickly achieves increased Hgb and ferritin

UTEROTONICS AND ADJUNCT DRUG THERAPY

FOR POSTPARTUM HEMORRHAGE

KATHY HALL, PHARMD, BCPS

CRITICAL CARE PHARMACIST

WESLEY MEDICAL CENTER

Documents

UTEROTONICS AND ADJUNCTIVE DRUG … AND ADJUNCTIVE DRUG THERAPY FOR POSTPARTUM HEMORRHAGE KATHY HALL, PHARMD, BCPS CRITICAL CARE PHARMACIST WESLEY MEDICAL CENTER OBJECTIVES Describe