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Misoprostol versus methylergometrine: Pharmacokinetics in human milk
American Journal of Obstetrics and Gynecology (2004) 191, 2168e73
www.ajog.org
Misoprostol versus methylergometrine: Pharmacokinetics in human milk Danie`le Vogel,a Tilo Burkhardt, MD,a Katharina Rentsch, PhD,b Horst Schweer, PhD,c Bernhard Watzer,c Roland Zimmermann, MD,a Ursula von Mandach, PhDa,* Department of Obstetricsa and Institute of Clinical Chemistry,b Zurich University Hospital, Zurich, Switzerland, and Department of Pediatrics, Philipps University, Marburg, Germanyc Received for publication January 17, 2004; revised May 1, 2004; accepted May 5, 2004
KEY WORDS Misoprostol Methylergometrine Pharmacokinetics Human Lactation
Objective: The purpose of this study to compare breast milk pharmacokinetics between misoprostol 200 mg and methylergometrine 250 mg after single oral dosing in women who require postpartum uterotonic therapy. Study design: Open prospective randomized phase I study measuring misoprostol and methylergometrine on postpartum days 3 to 6 in milk 0.5, 1, 2, 3, 4, and 5 hours postdose, and in maternal serum at 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) in 10 lactating women per group. Results: Milk misoprostol levels rose and declined rapidly, which gave a milk elimination half-life of less than one half that of methylergometrine (mean G SE, 1.1 G 0.3 hours [median, 0.6 hours] vs 2.33 G 0.3 hours [median, 1.9 hours]; P Z .003). Milk/plasma ratios for misoprostol were one third of those for methylergometrine at 1 hour (P ! .0001) and 2 hours (P ! .0015). Conclusion: Misoprostol warrants further investigation as an alternative to postpartum methylergometrine because it enters and leaves breast milk at twice the rate, with one third of the milk/plasma ratio, which significantly lowers infant exposure and facilitates a timed dosing regimen. Ó 2004 Elsevier Inc. All rights reserved.
Methylergometrine, the conventional postnatal uterotonic, has several disadvantages: excessive uterine contraction in some cases, inhibition of lactation, and thermolability.1-4 A potential alternative is the prostaglandin E1 analogue, misoprostol. It has proved an effective uterotonic in the final stage and directly after delivery; it can be given by a variety of routes that * Reprint requests: Ursula von Mandach, PhD, Department of Obstetrics, University Hospital Zurich, Frauenklinikstrasse 10, CH8091 Zurich, Switzerland. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.05.008
include orally; it has fewer systemic side effects, does not inhibit lactation, and is heat stable.1,5 Oral methylergometrine is rapidly absorbed in the gut, with 60% of the dose entering the systemic circulation.6 Peak levels (maximum concentration [Cmax]) of 1.21 ng/mL appear 1 hour (time of maximum concentration [Tmax]) after single oral dosing of 125 mg. Because the plasma elimination half-life (t½b) is 1.4 hours, plasma levels of 0.2 ng/mL, with the use of highperformance liquid chromatography, remain present 6 hours after the dose is administered.7 Metabolism in the liver is followed by excretion mainly in bile and feces.
Vogel et al Table I
2169 Patient characteristics (n = 10 per group)
Characteristic
Misoprostol
Age (y)* Height (m)* Weight (kg)* Body surface area (m2)* Gravidity (n)* Parity (n)* Gestational age at delivery (wk)* Vaginal delivery or non-elective cesarean delivery (n) Elective cesarean delivery (n) Hemoglobin level, day 2 after delivery (g/dL)* Study day after delivery*
31.2 1.6 66.6 1.7 2.0 1.8 38.6
G G G G G G G
Methylergometrine
1.9 31.9 G 1.9 0.03 1.7 G 0.02 3.1 73.2 G 3.4 0.04 1.8 G 0.04 0.3 2.0 G 0.3 0.2 1.7 G 0.3 0.7 38.3 G 1.2
7
7
3
3
10.7 G 0.5
11.5 G 0.3
3.9 G 0.4
4.8 G 0.4
* Data are given as mean G SE; there were no significant differences between the groups.
Only 3% of an oral dose is excreted unchanged in the urine.6 After single oral dosing with 250 mg, the breast milk Cmax, which is determined by radioimmunoassay (RIA), is 1.3 ng/mL at a Tmax of 1 hour, with levels becoming undetectable after 8 hours.8 Oral misoprostol is 88% absorbed in the gut before rapid and virtually total conversion by de-esterification in the liver to its bioactive metabolite, misoprostol acid.9,10 It is detected in plasma within 2 minutes of oral ingestion, reaches Cmax (approximately 300 pg/mL) at 30 minutes, then declines rapidly.5,11-13 Misoprostol acid is 80% to 90% bound to serum protein, and its t½b is approximately 30 minutes;9,10 60% to 75% is eliminated in the urine and 15% in the gut as inactive polar metabolites.9 No accumulation occurs even after administration for several days.14 After single oral dosing with 600 mg, the breast milk Cmax, which is measured by gas chromatography/mass spectrometry, is 21 pg/mL at 1 hour, with levels becoming virtually unmeasurable after 5 hours.15 The current data indicate that the more rapid distribution and elimination of misoprostol results not only in substantially lower exposure of the infant than with methylergometrine but also allows an optimal time window between dosing and breastfeeding, hence further minimizing the risk of adverse infant effects. As a preliminary to the major efficacy and tolerability study required to test the clinical superiority of misoprostol as a postpartum uterotonic, we decided to characterize its pharmacokinetics versus methylergometrine in breast milk using state-of-the-art analytics in a representative clinical population.
Figure A, Median milk misoprostol acid concentrations (picograms per milliliter) over the 5 hours after single oral dosing with misoprostol 200 mg in 10 lactating women. B, Median milk methylergometrine concentrations (picograms per milliliter) over the 5 hours after single oral dosing with 250 mg in 10 lactating women.
Patients and methods Patients After approval from the institutional review board of the Departments of Obstetrics and Urology at Zurich University Hospital, 20 lactating well-being women (10 per group) in lactation stage II (milk volume, R30 mL per feed after a 3-hour nursing interval; milk color, white) with the postpartum problem of uterine atony (putrid lochia, soft uterus !3 fingerbreadths below the umbilicus) who were normally treated in our department (2000 deliveries per year) with methylergometrine on postpartum days 3 through 6 (depending on the day of diagnosis) were recruited into the study, with informed consent in March/April 2003. The noninclusion criteria included multiple pregnancy, anemia (hemoglobin, % 8.0 g/dL on postpartum day 2), inadequate lactation (onset of lactation O48 hours after delivery; lactation stage 1; requirement for infant supplementation with
2170 Table II
Vogel et al Pharmacokinetics in human milk of misoprostol 200 mg versus methylergometrine 250 mg orally Misoprostol acid Mean G SE
AUC0-5 h (pg/mL ! h) Cmax (pg/mL) Tmax (h) t½b (h)
14.8 7.6 1.1 1.1
G G G G
5.3 2.8 0.2 0.30
Methylergometrine Median 8.2 3.6 1.0 0.6
Range
Mean G SE
3.0-48.4 1.9-30.7 0.5-2.0 0.4-2.2
1774.0 657.0 1.8 2.3
G G G G
139.5* 38.9* 0.3 0.3*
Median y
1686.3 645y 2.0 1.9y
Range 1140.0-2477.5 410-830 0.5-3.0 1.4-4.7
* Versus misoprostol: unpaired t test !0.0001 (AUC, Cmax) and !0.005 (t½b). y Versus misoprostol: Mann-Whitney U test !0.0005 (AUC, Cmax) and !0.05 (t½b).
glucose or other liquids), vegan or similar extreme diet, endometritis, essential hypertension, preeclampsia, severe disease, concomitant uterotonic therapy or medication likely to interfere with the study drugs, and participation in another clinical study in the previous 4 weeks.
Protocol According to the prospective open randomized design, treatments were allocated in a computer-generated random sequence with sealed opaque envelopes. After confirmation of the clinical indication (uterine atony) and before the first dose of uterotonic, the patient chose an envelope from the study box that allocated her to either misoprostol 200 mg orally (one 200-mg tablet) or methylergometrine 250 mg orally (two 125-mg tablets). The dose of misoprostol was selected on the basis of documented tolerability and uterine activity,12 while the dose of methylergometrine was approximated to the standard regimen for uterine atony that has been used in our Department for the past 20 years (250 mg, 3 times/d). Standardized milk sample collection (exactly 10 mL in a graduated plastic tube) was performed with an electric pump (Medela International, CH-6341, Baar, Switzerland; www.medela.ch). The baseline milk sample was taken 1 to 3 hours after a continental breakfast (bread, butter, marmalade, and coffee or tea) immediately after suckling the baby at the opposite breast, then the allocated drug was given. Further milk samples (10 mL) at the same breast were taken 0.5, 1, 2, 3, 4, and 5 hours after the dose was administered. Each milk sample was stored immediately at 4(C. Maternal blood samples (5 mL) were taken 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) after the dose was administered. Two-milliliter milk aliquots were pipetted into polypropylene tubes and stored at 70(C until analysis, along with 1-mL aliquots of centrifuged blood plasma (milk and plasma samples from the methylergometrine group were covered with aluminum foil). The sampling schedule was based on the pharmacokinetic data that were available in the literature that indicated that misoprostol levels in plasma and milk peak at around 1 hour, somewhat earlier than methylergometrine. Suckling was
not allowed (at the opposite breast) until at least 4 hours after the dose was administered.
Assays All samples were analyzed after collection was complete and were analyzed in duplicate. Each patient’s samples were analyzed in the same run. Misoprostol acid was quantified by gas chromatography/negative ion chemical ionization tandem mass spectrometry, with our published method.16 Methylergometrine was determined in breast milk and plasma with high-performance liquid chromatography tandem mass spectrometry (Finnigan TSQ 7000; ThermoQuest, San Jose, Calif). After the protein in the milk was precipitated with acetone, methylergometrine was extracted into dichloromethane/methanol by liquid-liquid extraction, and the lipids were removed from the organic phase by solid-phase extraction on silica columns. Methylergometrine was extracted from the plasma into ethyl acetate by liquid-liquid extraction. Quantification was performed with calibration samples that were prepared in the respective matrix.8
Statistics The data were entered into Excel (Microsoft Corporation, Redmond, Wash), analyzed with StatView 4.5 for Windows (SAS Institute Inc, Cary, NC), and expressed as means G SE (median). Misoprostol and methylergometrine levels were also expressed as medians in the Figures. Pharmacokinetic analysis Milk/plasma ratios were calculated from the respective concentrations. Areas under the milk concentrationtime curve from 0 to 5 hours (AUC0e5 h) were calculated by the trapezoidal rule; the Cmax was calculated from the fitted AUC0e5 h, along with the Tmax and the milk t½b (Stata 8.0 for Windows; Stata Corp, College Station, Tex). Statistical tests The Kolmogorov-Smirnov test was used for normality. Mean within-group differences were tested with the
Vogel et al
2171
Table III Milk and maternal plasma levels (picograms per milliliter) and milk/plasma ratio after single oral dosing with misoprostol 200 mg versus methylergometrine 250 mg (n = 10 per group) Misoprostol* Milk (pg/mL)
Plasma (pg/mL)
Milk/plasma ratio
Time post dose (h)
Mean G SE
0.5 1 2 0.5 1 2 0.5 1 2
5.2 4.8 d 174.3 104.4 d 0.04 0.06 d
Methylergometrine Median
G 2.9 G 1.0 G 53.5y G 16.0y G 0.02 G 0.01
2.4 3.6 d 123.7z 96z d 0.02 0.04 d
Mean G SE
Median
d
d 345 545 d 2545z 3140z d 0.16k 0.17
368 G 83.6 527 G 65.9 d 2594.4 3370 d 0.18 0.17
G 588.7y G 588.9y G 0.03x G 0.01
* The pharmacokinetics of misoprostol in breast milk suggest that it is a safer alternative to methylergometrine as a postpartum uterotonic in lactating mothers. y Versus milk: P ! .0001, paired t test. z Versus milk: P ! .01, Wilcoxon signed rank test. x Versus misoprostol at 1 hour: P ! .0001, unpaired t test. k Versus misoprostol at 1 hour: P ! .01, Mann-Whitney U test.
Wilcoxon signed-rank test and a paired t test of log values, and the mean between-group differences was tested with the Mann-Whitney U test and an unpaired t test of log values. A probability value of ! .5 was used in all tests. Bonferroni correction was used in the nonparametric tests.
Results The groups did not differ in demographic or obstetric variables (Table I). Milk and plasma concentrations were log-normally distributed in both groups.
Milk Misoprostol acid levels rose rapidly, peaked at 7.6 G 2.8 pg/mL (median, 3.6 pg/mL) at 1.1 G 0.2 hours (Table II), then rapidly declined to 0.20 pg/mL (median) at 5 hours (Figure, A). Methylergometrine levels rose less rapidly, peaked at 657.0 G 38.9 pg/mL (median, 645.0 pg/mL) at 1.8 G 0.3 hours (Table II), then steadily declined to 0.20 pg/mL (median) at 5 hours (Figure, B). AUC0e5 h and t½b values differed significantly between groups; the t½b of misoprostol was less than one-half that of methylergometrine (1.1 G 0.3 hours [median, 0.6 hours] vs 2.33 G 0.3 hours [median, 1.9 hours]; P =.003, unpaired t test; P =.02, Mann-Whitney U test; Table II).
Milk/plasma ratios Cmax with both drugs was significantly lower in milk than in plasma. Ratios for misoprostol acid (0.04 G 0.02 [range, 0.001-0.198] at 0.5 hours and 0.06 G 0.01 [range, 0.02-0.16] at 1 hour) were one third of the ratios for
methylergometrine (0.18 G 0.03 [range, 0.08-0.40] at 1 hour and 0.17 G 0.01 [range, 0.12-0.25] at 2 hours; P ! .0001, t test; P ! .0015, Mann-Whitney U test; Table III).
Comment Our data show that misoprostol enters and leaves breast milk at twice the rate of methylergometrine and has onethird the milk/plasma ratio, thus substantially lowering infant exposure to the drug. To keep demands on patients to a reasonable level (with respect to milk output and adequate provision for the child) and to maintain study feasibility, we could not investigate the pharmacokinetics in milk at shorter intervals or outside a 5-hour time frame. However, this time frame encompassed the pharmacokinetic profile of most women in our population under the behavioral circumstances that were described (clinical conditions, nutritional status, standardized conditions of milk sampling). In the misoprostol group at least, values had declined towards the detection limit after 5 hours, and in both groups the information on the distribution and elimination of the drugs in milk was sufficient to permit the computation of the milk/plasma ratio. In the misoprostol group, the mean milk Tmax was 1.1 G 0.2 hours. Because this included a Tmax of 2 hours in 2 of the women, the mean concentration at 1 hour was somewhat lower (4.8 G 1.0 pg/mL) than mean Cmax (7.6 G 2.8 pg/mL); the medians (3.6 pg/mL) did not differ. Similarly, the methylergometrine Tmax of 1.8 G 0.3 hours included 2 women with a Tmax at 3 hours, so that the mean concentration at 2 hours (527 G 65.9 pg/mL) was somewhat lower than the mean Cmax (657 G 38.9 pg/ mL); again, the medians (545 pg/mL) did not differ.
2172 As expected, the plasma misoprostol levels that are found in this study were somewhat lower than those measured by the same method after an oral dose of 400 mg (287.6 pg/mL [Cmax] at 27.5 minutes).16 In the only previous study that, to our knowledge, has investigated the pharmacokinetics of misoprostol in parallel breast milk and maternal plasma, with a single oral dose of 600 mg and our gas chromatography/mass spectrometry assay,16 the plasma Cmax was 344 pg/mL at 20 minutes; the milk Cmax was 21 pg/mL at 1 hour, and the milk AUC1e5 h was 51.4 pg/mL ! hour.15 The present study, which used a dose of 200 mg, naturally found lower values for all 3 parameters. Misoprostol has been used widely, off-label, as an uterotonic (eg, as an abortifacient in the first and second trimesters, for induction at term or after intrauterine fetal death, and for the prevention and therapy of atonicity-related postpartum hemorrhage). Dosing has been tested between the vaginal, rectal, sublingual, and oral routes.11-13,17-20 Plasma Cmax occurs later, and at a lower level, after vaginal versus oral dosing, but the drug remains detectable for longer in plasma.11,17 Sublingual dosing produces a Tmax similar to that of oral dosing, but a higher Cmax.17 Thus, the oral route is clearly ideal in lactating mothers because it generates rapidly declining levels, not only in maternal plasma, but also, as our present data confirm, in milk. The levels of methylergometrine that we found in plasma and milk were only marginally lower than those measured in 1978 by Erkkola et al,8 who used radioimmunoassay, in what to our knowledge is the only previous parallel pharmacokinetic study. After single oral dosing with 250 mg, they found Cmax values at 1 hour of 4.4 ng/mL in maternal plasma and 1.3 ng/mL in breast milk, which provided a milk/plasma ratio of 0.3. The adverse a-receptor and dopaminergic effects of methylergometrine (abdominal pain because of gut smooth muscle contraction, nausea, vomiting, diarrhea, headache, tachycardia1,2,8,20,21) often prevent its wider use. Convulsions and dyspnea have occurred on accidental administration in newborn infants.22,23 Thermolability is a further restriction in tropical developing countries.3,4 These substantial disadvantages make the identification of a safe and effective alternative a matter of some urgency. The lower drug levels that we have demonstrated in maternal plasma and milk, combined with the faster elimination from milk, are powerful pharmacokinetic arguments that favor the use of misoprostol in the special circumstances of the lactating mother. We estimate that the maximum amount of drug that is delivered in breast milk (108 pg in a nursing volume of 30 mL [3.6 pg/mL]) represents a dose of 3 ! 105 mg/kg in a 3.5-kg neonate (ie, 1/100 that in the mother [0.2 mg/60 kg or 1 ! 103 mg/kg]). In recommending a safe dosing regimen for lactating women, we can say that, on the basis of the present data, misoprostol should be taken immediately
Vogel et al after a feed and that the next feed may safely be given after 4 hours, or even at the earliest after 3 hours, by which time misoprostol levels in milk have fallen below 1 pg/mL. Further advantages, such as absent cardiovascular effects5,24,25 (no hypertensive effects, which makes it an ideal oral drug for women with continuing postpartum hypertension) and stability even at fairly high temperatures5,17,26 are additional reasons for undertaking a large efficacy and tolerability study of misoprostol as a postpartum uterotonic in lactating women.
References 1. Gru¨nberger W. Postpartum uterus involution and lactation levels in randomized comparison between prostin E2 tablets and methergine dragees [in German]. Gynakol Rundsch 1983;23:100-7. 2. Arabin B, Ru¨ttgers H, Kubli F. Effects of routine administration of methylergometrin during puerperium on involution, maternal morbidity and lactation [in German]. Geburtshilfe Frauenheilkd 1986;46:215-20. 3. de Groot AN. The role of oral (methyl)ergometrine in the prevention of postpartum haemorrhage. Eur J Obstet Gynecol Reprod Biol 1996;69:31-6. 4. Hogerzeil HV, Walker GJ. Instability of (methyl)ergometrine in tropical climates: an overview. Eur J Obstet Gynecol Reprod Biol 1996;69:25-9. 5. el Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Use of oral misoprostol in the prevention of postpartum haemorrhage. BJOG 1997;104:336-9. 6. Ma¨ntyla¨ R, Kleimola T, Kanto J. Methylergometrine (methylergonovine) concentrations in the human plasma and urine. Int J Clin Pharmacol Biopharm 1978;16:254-7. 7. de Groot AN, Vree TB, Hekster YA, van den Biggelaar Martea M, van Dongen PW, van Roosmalen J. Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women. Int J Clin Pharmacol Ther 1995;33:328-32. 8. Erkkola R, Kanto J, Allonen H, Kleimola T, Mantyla R. Excretion of methylergometrine (methylergonovine) into the human breast milk. Int J Clin Pharmacol Biopharm 1978;16:579-80. 9. Arns PA. Misoprostol. Am J Med Sci 1991;301:133-7. 10. Davies NM, Longstreth J, Jamali F. Misoprostol therapeutics revisited. Pharmacotherapy 2001;21:60-73. 11. Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88-92. 12. Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PY, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275-80. 13. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38-47. 14. Garris RE, Kirkwood CF. Misoprostol: a prostaglandin E1 analogue. Clin Pharm 1989;8:627-44. 15. Abdel-Aleem H, Villar J, Gu¨lmezoglu MA, Mostafa SA, Youssef AA, Shokry M, et al. The pharmacokinetics of the prostaglandin E1 analogue misoprostol in plasma and colostrum after postpartum oral administration. Eur J Obstet Gynecol 2003;108:25-8. 16. Watzer B, Seyberth HW, Schweer H. Determination of misoprostol free acid in human breast milk and serum by gas chromatography/negative ion chemical ionization tandem mass spectrometry. J Mass Spectrom 2002;37:927-33.
Vogel et al 17. Tang OS, Schweer H, Seyberth HW, Lee SW, Ho PC. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17:332-6. 18. Bamigboye AA, Merrell DA, Hofmeyr GJ, Mitchell R. Randomized comparison of rectal misoprostol with syntometrine for management of third stage of labor. Acta Obstet Gynecol Scand 1998;77:178-81. 19. Abdel Aleem H, el Nashar I, Abdel Aleem A. Management of severe postpartum hemorrhage with misoprostol. Int J Gynaecol Obstet 2001;72:75-6. 20. Zu¨st S, Ho¨sli I, Surbek D, Holzgreve W. Adverse effects of misoprostol in pregnancy [in German]. Z Geburtshilfe Neonatol 2001;205:43-8 . 21. Ma¨ntyla¨ R, Kanto J. Clinical pharmacokinetics of methylergometrine (methylergonovine). Int J Clin Pharmacol Ther Toxicol 1981;19:386-91.
2173 22. Donatini B, Le Blaye I, Krupp P. Inadvertent administration of uterotonics to neonates. Lancet 1993;341:839-40. 23. Baum CR, Hilpert PL, Bhutani VK. Accidental administration of an ergot alkaloid to a neonate. Pediatrics 1996;98:457-8. 24. Ramsey PS, Hogg BB, Savage KG, Winkler DD, Owen J. Cardiovascular effects of intravaginal misoprostol in the mid trimester pregnancy. Am J Obstet Gynecol 2000;183:1100-2. 25. Amant F, Spitz B, Timmerman D, Corremans A, Van Assche FA. Misoprostol compared with methylergometrine for the prevention of postpartum haemorrhage: a double-blind randomised trial. BJOG 1999;106:1066-70. 26. de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J. Ergot alkaloids: current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology. Drugs 1998;56:523-35.
www.ajog.org
Misoprostol versus methylergometrine: Pharmacokinetics in human milk Danie`le Vogel,a Tilo Burkhardt, MD,a Katharina Rentsch, PhD,b Horst Schweer, PhD,c Bernhard Watzer,c Roland Zimmermann, MD,a Ursula von Mandach, PhDa,* Department of Obstetricsa and Institute of Clinical Chemistry,b Zurich University Hospital, Zurich, Switzerland, and Department of Pediatrics, Philipps University, Marburg, Germanyc Received for publication January 17, 2004; revised May 1, 2004; accepted May 5, 2004
KEY WORDS Misoprostol Methylergometrine Pharmacokinetics Human Lactation
Objective: The purpose of this study to compare breast milk pharmacokinetics between misoprostol 200 mg and methylergometrine 250 mg after single oral dosing in women who require postpartum uterotonic therapy. Study design: Open prospective randomized phase I study measuring misoprostol and methylergometrine on postpartum days 3 to 6 in milk 0.5, 1, 2, 3, 4, and 5 hours postdose, and in maternal serum at 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) in 10 lactating women per group. Results: Milk misoprostol levels rose and declined rapidly, which gave a milk elimination half-life of less than one half that of methylergometrine (mean G SE, 1.1 G 0.3 hours [median, 0.6 hours] vs 2.33 G 0.3 hours [median, 1.9 hours]; P Z .003). Milk/plasma ratios for misoprostol were one third of those for methylergometrine at 1 hour (P ! .0001) and 2 hours (P ! .0015). Conclusion: Misoprostol warrants further investigation as an alternative to postpartum methylergometrine because it enters and leaves breast milk at twice the rate, with one third of the milk/plasma ratio, which significantly lowers infant exposure and facilitates a timed dosing regimen. Ó 2004 Elsevier Inc. All rights reserved.
Methylergometrine, the conventional postnatal uterotonic, has several disadvantages: excessive uterine contraction in some cases, inhibition of lactation, and thermolability.1-4 A potential alternative is the prostaglandin E1 analogue, misoprostol. It has proved an effective uterotonic in the final stage and directly after delivery; it can be given by a variety of routes that * Reprint requests: Ursula von Mandach, PhD, Department of Obstetrics, University Hospital Zurich, Frauenklinikstrasse 10, CH8091 Zurich, Switzerland. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.05.008
include orally; it has fewer systemic side effects, does not inhibit lactation, and is heat stable.1,5 Oral methylergometrine is rapidly absorbed in the gut, with 60% of the dose entering the systemic circulation.6 Peak levels (maximum concentration [Cmax]) of 1.21 ng/mL appear 1 hour (time of maximum concentration [Tmax]) after single oral dosing of 125 mg. Because the plasma elimination half-life (t½b) is 1.4 hours, plasma levels of 0.2 ng/mL, with the use of highperformance liquid chromatography, remain present 6 hours after the dose is administered.7 Metabolism in the liver is followed by excretion mainly in bile and feces.
Vogel et al Table I
2169 Patient characteristics (n = 10 per group)
Characteristic
Misoprostol
Age (y)* Height (m)* Weight (kg)* Body surface area (m2)* Gravidity (n)* Parity (n)* Gestational age at delivery (wk)* Vaginal delivery or non-elective cesarean delivery (n) Elective cesarean delivery (n) Hemoglobin level, day 2 after delivery (g/dL)* Study day after delivery*
31.2 1.6 66.6 1.7 2.0 1.8 38.6
G G G G G G G
Methylergometrine
1.9 31.9 G 1.9 0.03 1.7 G 0.02 3.1 73.2 G 3.4 0.04 1.8 G 0.04 0.3 2.0 G 0.3 0.2 1.7 G 0.3 0.7 38.3 G 1.2
7
7
3
3
10.7 G 0.5
11.5 G 0.3
3.9 G 0.4
4.8 G 0.4
* Data are given as mean G SE; there were no significant differences between the groups.
Only 3% of an oral dose is excreted unchanged in the urine.6 After single oral dosing with 250 mg, the breast milk Cmax, which is determined by radioimmunoassay (RIA), is 1.3 ng/mL at a Tmax of 1 hour, with levels becoming undetectable after 8 hours.8 Oral misoprostol is 88% absorbed in the gut before rapid and virtually total conversion by de-esterification in the liver to its bioactive metabolite, misoprostol acid.9,10 It is detected in plasma within 2 minutes of oral ingestion, reaches Cmax (approximately 300 pg/mL) at 30 minutes, then declines rapidly.5,11-13 Misoprostol acid is 80% to 90% bound to serum protein, and its t½b is approximately 30 minutes;9,10 60% to 75% is eliminated in the urine and 15% in the gut as inactive polar metabolites.9 No accumulation occurs even after administration for several days.14 After single oral dosing with 600 mg, the breast milk Cmax, which is measured by gas chromatography/mass spectrometry, is 21 pg/mL at 1 hour, with levels becoming virtually unmeasurable after 5 hours.15 The current data indicate that the more rapid distribution and elimination of misoprostol results not only in substantially lower exposure of the infant than with methylergometrine but also allows an optimal time window between dosing and breastfeeding, hence further minimizing the risk of adverse infant effects. As a preliminary to the major efficacy and tolerability study required to test the clinical superiority of misoprostol as a postpartum uterotonic, we decided to characterize its pharmacokinetics versus methylergometrine in breast milk using state-of-the-art analytics in a representative clinical population.
Figure A, Median milk misoprostol acid concentrations (picograms per milliliter) over the 5 hours after single oral dosing with misoprostol 200 mg in 10 lactating women. B, Median milk methylergometrine concentrations (picograms per milliliter) over the 5 hours after single oral dosing with 250 mg in 10 lactating women.
Patients and methods Patients After approval from the institutional review board of the Departments of Obstetrics and Urology at Zurich University Hospital, 20 lactating well-being women (10 per group) in lactation stage II (milk volume, R30 mL per feed after a 3-hour nursing interval; milk color, white) with the postpartum problem of uterine atony (putrid lochia, soft uterus !3 fingerbreadths below the umbilicus) who were normally treated in our department (2000 deliveries per year) with methylergometrine on postpartum days 3 through 6 (depending on the day of diagnosis) were recruited into the study, with informed consent in March/April 2003. The noninclusion criteria included multiple pregnancy, anemia (hemoglobin, % 8.0 g/dL on postpartum day 2), inadequate lactation (onset of lactation O48 hours after delivery; lactation stage 1; requirement for infant supplementation with
2170 Table II
Vogel et al Pharmacokinetics in human milk of misoprostol 200 mg versus methylergometrine 250 mg orally Misoprostol acid Mean G SE
AUC0-5 h (pg/mL ! h) Cmax (pg/mL) Tmax (h) t½b (h)
14.8 7.6 1.1 1.1
G G G G
5.3 2.8 0.2 0.30
Methylergometrine Median 8.2 3.6 1.0 0.6
Range
Mean G SE
3.0-48.4 1.9-30.7 0.5-2.0 0.4-2.2
1774.0 657.0 1.8 2.3
G G G G
139.5* 38.9* 0.3 0.3*
Median y
1686.3 645y 2.0 1.9y
Range 1140.0-2477.5 410-830 0.5-3.0 1.4-4.7
* Versus misoprostol: unpaired t test !0.0001 (AUC, Cmax) and !0.005 (t½b). y Versus misoprostol: Mann-Whitney U test !0.0005 (AUC, Cmax) and !0.05 (t½b).
glucose or other liquids), vegan or similar extreme diet, endometritis, essential hypertension, preeclampsia, severe disease, concomitant uterotonic therapy or medication likely to interfere with the study drugs, and participation in another clinical study in the previous 4 weeks.
Protocol According to the prospective open randomized design, treatments were allocated in a computer-generated random sequence with sealed opaque envelopes. After confirmation of the clinical indication (uterine atony) and before the first dose of uterotonic, the patient chose an envelope from the study box that allocated her to either misoprostol 200 mg orally (one 200-mg tablet) or methylergometrine 250 mg orally (two 125-mg tablets). The dose of misoprostol was selected on the basis of documented tolerability and uterine activity,12 while the dose of methylergometrine was approximated to the standard regimen for uterine atony that has been used in our Department for the past 20 years (250 mg, 3 times/d). Standardized milk sample collection (exactly 10 mL in a graduated plastic tube) was performed with an electric pump (Medela International, CH-6341, Baar, Switzerland; www.medela.ch). The baseline milk sample was taken 1 to 3 hours after a continental breakfast (bread, butter, marmalade, and coffee or tea) immediately after suckling the baby at the opposite breast, then the allocated drug was given. Further milk samples (10 mL) at the same breast were taken 0.5, 1, 2, 3, 4, and 5 hours after the dose was administered. Each milk sample was stored immediately at 4(C. Maternal blood samples (5 mL) were taken 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) after the dose was administered. Two-milliliter milk aliquots were pipetted into polypropylene tubes and stored at 70(C until analysis, along with 1-mL aliquots of centrifuged blood plasma (milk and plasma samples from the methylergometrine group were covered with aluminum foil). The sampling schedule was based on the pharmacokinetic data that were available in the literature that indicated that misoprostol levels in plasma and milk peak at around 1 hour, somewhat earlier than methylergometrine. Suckling was
not allowed (at the opposite breast) until at least 4 hours after the dose was administered.
Assays All samples were analyzed after collection was complete and were analyzed in duplicate. Each patient’s samples were analyzed in the same run. Misoprostol acid was quantified by gas chromatography/negative ion chemical ionization tandem mass spectrometry, with our published method.16 Methylergometrine was determined in breast milk and plasma with high-performance liquid chromatography tandem mass spectrometry (Finnigan TSQ 7000; ThermoQuest, San Jose, Calif). After the protein in the milk was precipitated with acetone, methylergometrine was extracted into dichloromethane/methanol by liquid-liquid extraction, and the lipids were removed from the organic phase by solid-phase extraction on silica columns. Methylergometrine was extracted from the plasma into ethyl acetate by liquid-liquid extraction. Quantification was performed with calibration samples that were prepared in the respective matrix.8
Statistics The data were entered into Excel (Microsoft Corporation, Redmond, Wash), analyzed with StatView 4.5 for Windows (SAS Institute Inc, Cary, NC), and expressed as means G SE (median). Misoprostol and methylergometrine levels were also expressed as medians in the Figures. Pharmacokinetic analysis Milk/plasma ratios were calculated from the respective concentrations. Areas under the milk concentrationtime curve from 0 to 5 hours (AUC0e5 h) were calculated by the trapezoidal rule; the Cmax was calculated from the fitted AUC0e5 h, along with the Tmax and the milk t½b (Stata 8.0 for Windows; Stata Corp, College Station, Tex). Statistical tests The Kolmogorov-Smirnov test was used for normality. Mean within-group differences were tested with the
Vogel et al
2171
Table III Milk and maternal plasma levels (picograms per milliliter) and milk/plasma ratio after single oral dosing with misoprostol 200 mg versus methylergometrine 250 mg (n = 10 per group) Misoprostol* Milk (pg/mL)
Plasma (pg/mL)
Milk/plasma ratio
Time post dose (h)
Mean G SE
0.5 1 2 0.5 1 2 0.5 1 2
5.2 4.8 d 174.3 104.4 d 0.04 0.06 d
Methylergometrine Median
G 2.9 G 1.0 G 53.5y G 16.0y G 0.02 G 0.01
2.4 3.6 d 123.7z 96z d 0.02 0.04 d
Mean G SE
Median
d
d 345 545 d 2545z 3140z d 0.16k 0.17
368 G 83.6 527 G 65.9 d 2594.4 3370 d 0.18 0.17
G 588.7y G 588.9y G 0.03x G 0.01
* The pharmacokinetics of misoprostol in breast milk suggest that it is a safer alternative to methylergometrine as a postpartum uterotonic in lactating mothers. y Versus milk: P ! .0001, paired t test. z Versus milk: P ! .01, Wilcoxon signed rank test. x Versus misoprostol at 1 hour: P ! .0001, unpaired t test. k Versus misoprostol at 1 hour: P ! .01, Mann-Whitney U test.
Wilcoxon signed-rank test and a paired t test of log values, and the mean between-group differences was tested with the Mann-Whitney U test and an unpaired t test of log values. A probability value of ! .5 was used in all tests. Bonferroni correction was used in the nonparametric tests.
Results The groups did not differ in demographic or obstetric variables (Table I). Milk and plasma concentrations were log-normally distributed in both groups.
Milk Misoprostol acid levels rose rapidly, peaked at 7.6 G 2.8 pg/mL (median, 3.6 pg/mL) at 1.1 G 0.2 hours (Table II), then rapidly declined to 0.20 pg/mL (median) at 5 hours (Figure, A). Methylergometrine levels rose less rapidly, peaked at 657.0 G 38.9 pg/mL (median, 645.0 pg/mL) at 1.8 G 0.3 hours (Table II), then steadily declined to 0.20 pg/mL (median) at 5 hours (Figure, B). AUC0e5 h and t½b values differed significantly between groups; the t½b of misoprostol was less than one-half that of methylergometrine (1.1 G 0.3 hours [median, 0.6 hours] vs 2.33 G 0.3 hours [median, 1.9 hours]; P =.003, unpaired t test; P =.02, Mann-Whitney U test; Table II).
Milk/plasma ratios Cmax with both drugs was significantly lower in milk than in plasma. Ratios for misoprostol acid (0.04 G 0.02 [range, 0.001-0.198] at 0.5 hours and 0.06 G 0.01 [range, 0.02-0.16] at 1 hour) were one third of the ratios for
methylergometrine (0.18 G 0.03 [range, 0.08-0.40] at 1 hour and 0.17 G 0.01 [range, 0.12-0.25] at 2 hours; P ! .0001, t test; P ! .0015, Mann-Whitney U test; Table III).
Comment Our data show that misoprostol enters and leaves breast milk at twice the rate of methylergometrine and has onethird the milk/plasma ratio, thus substantially lowering infant exposure to the drug. To keep demands on patients to a reasonable level (with respect to milk output and adequate provision for the child) and to maintain study feasibility, we could not investigate the pharmacokinetics in milk at shorter intervals or outside a 5-hour time frame. However, this time frame encompassed the pharmacokinetic profile of most women in our population under the behavioral circumstances that were described (clinical conditions, nutritional status, standardized conditions of milk sampling). In the misoprostol group at least, values had declined towards the detection limit after 5 hours, and in both groups the information on the distribution and elimination of the drugs in milk was sufficient to permit the computation of the milk/plasma ratio. In the misoprostol group, the mean milk Tmax was 1.1 G 0.2 hours. Because this included a Tmax of 2 hours in 2 of the women, the mean concentration at 1 hour was somewhat lower (4.8 G 1.0 pg/mL) than mean Cmax (7.6 G 2.8 pg/mL); the medians (3.6 pg/mL) did not differ. Similarly, the methylergometrine Tmax of 1.8 G 0.3 hours included 2 women with a Tmax at 3 hours, so that the mean concentration at 2 hours (527 G 65.9 pg/mL) was somewhat lower than the mean Cmax (657 G 38.9 pg/ mL); again, the medians (545 pg/mL) did not differ.
2172 As expected, the plasma misoprostol levels that are found in this study were somewhat lower than those measured by the same method after an oral dose of 400 mg (287.6 pg/mL [Cmax] at 27.5 minutes).16 In the only previous study that, to our knowledge, has investigated the pharmacokinetics of misoprostol in parallel breast milk and maternal plasma, with a single oral dose of 600 mg and our gas chromatography/mass spectrometry assay,16 the plasma Cmax was 344 pg/mL at 20 minutes; the milk Cmax was 21 pg/mL at 1 hour, and the milk AUC1e5 h was 51.4 pg/mL ! hour.15 The present study, which used a dose of 200 mg, naturally found lower values for all 3 parameters. Misoprostol has been used widely, off-label, as an uterotonic (eg, as an abortifacient in the first and second trimesters, for induction at term or after intrauterine fetal death, and for the prevention and therapy of atonicity-related postpartum hemorrhage). Dosing has been tested between the vaginal, rectal, sublingual, and oral routes.11-13,17-20 Plasma Cmax occurs later, and at a lower level, after vaginal versus oral dosing, but the drug remains detectable for longer in plasma.11,17 Sublingual dosing produces a Tmax similar to that of oral dosing, but a higher Cmax.17 Thus, the oral route is clearly ideal in lactating mothers because it generates rapidly declining levels, not only in maternal plasma, but also, as our present data confirm, in milk. The levels of methylergometrine that we found in plasma and milk were only marginally lower than those measured in 1978 by Erkkola et al,8 who used radioimmunoassay, in what to our knowledge is the only previous parallel pharmacokinetic study. After single oral dosing with 250 mg, they found Cmax values at 1 hour of 4.4 ng/mL in maternal plasma and 1.3 ng/mL in breast milk, which provided a milk/plasma ratio of 0.3. The adverse a-receptor and dopaminergic effects of methylergometrine (abdominal pain because of gut smooth muscle contraction, nausea, vomiting, diarrhea, headache, tachycardia1,2,8,20,21) often prevent its wider use. Convulsions and dyspnea have occurred on accidental administration in newborn infants.22,23 Thermolability is a further restriction in tropical developing countries.3,4 These substantial disadvantages make the identification of a safe and effective alternative a matter of some urgency. The lower drug levels that we have demonstrated in maternal plasma and milk, combined with the faster elimination from milk, are powerful pharmacokinetic arguments that favor the use of misoprostol in the special circumstances of the lactating mother. We estimate that the maximum amount of drug that is delivered in breast milk (108 pg in a nursing volume of 30 mL [3.6 pg/mL]) represents a dose of 3 ! 105 mg/kg in a 3.5-kg neonate (ie, 1/100 that in the mother [0.2 mg/60 kg or 1 ! 103 mg/kg]). In recommending a safe dosing regimen for lactating women, we can say that, on the basis of the present data, misoprostol should be taken immediately
Vogel et al after a feed and that the next feed may safely be given after 4 hours, or even at the earliest after 3 hours, by which time misoprostol levels in milk have fallen below 1 pg/mL. Further advantages, such as absent cardiovascular effects5,24,25 (no hypertensive effects, which makes it an ideal oral drug for women with continuing postpartum hypertension) and stability even at fairly high temperatures5,17,26 are additional reasons for undertaking a large efficacy and tolerability study of misoprostol as a postpartum uterotonic in lactating women.
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2173 22. Donatini B, Le Blaye I, Krupp P. Inadvertent administration of uterotonics to neonates. Lancet 1993;341:839-40. 23. Baum CR, Hilpert PL, Bhutani VK. Accidental administration of an ergot alkaloid to a neonate. Pediatrics 1996;98:457-8. 24. Ramsey PS, Hogg BB, Savage KG, Winkler DD, Owen J. Cardiovascular effects of intravaginal misoprostol in the mid trimester pregnancy. Am J Obstet Gynecol 2000;183:1100-2. 25. Amant F, Spitz B, Timmerman D, Corremans A, Van Assche FA. Misoprostol compared with methylergometrine for the prevention of postpartum haemorrhage: a double-blind randomised trial. BJOG 1999;106:1066-70. 26. de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J. Ergot alkaloids: current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology. Drugs 1998;56:523-35.