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Magnesium chloride — (Chlor-3)

International Brand Names

None identified.

Drug Class Electrolyte replacements; Vitamins/minerals
Indications Hypomagnesemia
Mechanism Replacement
Dosage With Qualifiers Hypomagnesemia—4 g mixed in 250 mL of 5% dextrose IV no faster than 3 mL/min, dose range 1–40 g qd
NOTE: Serum magnesium measurements should guide replacement; keep calcium gluconate readily available to counteract potentially serious signs of magnesium intoxication.

  • Contraindications —hypersensitivity to drug or class, renal failure, impaired myocardial function

  • Caution —electrolyte disturbances, renal dysfunction

Maternal Considerations There are no adequate reports or well-controlled studies of magnesium chloride in pregnant women.
Side effects include flushing and sweating.
Fetal Considerations There are no adequate reports or well-controlled studies of magnesium chloride in human fetuses. Magnesium administered parenterally to the mother crosses the placenta. Rodent studies are reassuring.
Breastfeeding Safety Magnesium is normally present in human breast milk, and its concentration is stable throughout the first year of lactation. It is unknown whether magnesium chloride increases the magnesium content of breast milk. Considering the indications, limited use is unlikely to pose a clinically significant risk to the breastfeeding neonate.
Drug Interactions Calcium channel blocking agents should be avoided.
Doxercalciferol may increase the risk of hypermagnesemia.
References Martin RW, Perry KG Jr, Martin JN Jr, et al. J Miss State Med Assoc 1998; 39:180-2.
Meirowitz NB, Ananth CV, Smulian JC, Vintzileos AM. J Matern Fetal Med 1999; 8:177-83.
Nagra SA. J Trop Pediatr 1989; 35:126-8.
Oorschot DE. Magnes Res 2000; 13:265-73.
Usami M, Sakemi K, Tsuda M, Ohno Y. Eisei Shikenjo Hokoku 1996; 114:16-20.
Summary Pregnancy Category: B
Lactation Category: S

  • Magnesium chloride should be used during pregnancy and lactation only for the treatment of hypomagnesemia.

Magnesium citrate

International Brand Names

None identified.

Drug Class Laxatives
Indications Constipation
Mechanism Unknown
Dosage With Qualifiers Constipation—120–240 mL PO prn

  • Contraindications —hypersensitivity to drug or class, appendicitis, acute abdomen, GI obstruction

  • Caution —renal dysfunction, electrolyte disturbances

Maternal Considerations Magnesium citrate reduces the frequency of night leg cramps in nonpregnant patients. There are no adequate reports or well-controlled studies of magnesium citrate in pregnant women. Its use during pregnancy increases serum magnesium.
Side effects include abdominal cramps, flatulence, diarrhea, hypotension, hypermagnesemia, and respiratory disturbances.
Fetal Considerations There are no adequate reports or well-controlled studies of magnesium citrate in human fetuses. Magnesium ions freely cross the placenta.
Breastfeeding Safety Magnesium is normally present in human breast milk, and its concentration is stable throughout the first year of lactation. It is unknown whether magnesium citrate increases the magnesium content of breast milk. Considering the indications and dosing, limited use is unlikely to pose a clinically significant risk to the breastfeeding neonate.
Drug Interactions Calcium channel blocking agents should be avoided.
Doxercalciferol may increase the risk of hypermagnesemia.
References Ajayi GO, Fadiran EO. Clin Exp Obstet Gynecol 1998; 25:64-6.
Roffe C, Sills S, Crome P, Jones P. Med Sci Monit 2002; 8:CR326-30.
Summary Pregnancy Category: B
Lactation Category: S (likely)

  • Magnesium citrate should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Magnesium oxide

International Brand Names

None identified.

Drug Class Electrolyte replacements; Vitamins/minerals
Indications Hypomagnesemia
Mechanism Replacement
Dosage With Qualifiers Hypomagnesemia—1–2 tab PO bid or tid
NOTE: 400 mg tab = 241.3 mg of elemental magnesium.

  • Contraindications —hypersensitivity to drug or class, renal failure, impaired myocardial function

  • Caution —electrolyte disturbances, renal dysfunction

Maternal Considerations There are no adequate reports or well-controlled studies of magnesium oxide in pregnant women. Obstetricians have used oral magnesium as a tocolytic agent without demonstrable efficacy. It has also been advocated as a neuroprotectant for the acutely hypoxic fetus and to prevent preeclampsia. Neither indication can be substantiated.
Side effects include flushing and sweating.
Fetal Considerations There are no adequate reports or well-controlled studies of magnesium oxide in human fetuses. In one RCT, supplementation with magnesium oxide among women with gestational diabetes had beneficial effects on metabolic status and pregnancy outcomes including a significant reduction in neonatal hyperbilirubinemia and newborn hospitalization. Prior to this trial, the general conclusion was that there was not enough high-quality evidence to show that dietary magnesium supplementation during pregnancy is beneficial.
Breastfeeding Safety Magnesium is normally present in human breast milk, and its concentration is stable throughout the first year of lactation. It is unknown whether magnesium oxide increases the magnesium content of breast milk.
Drug Interactions Calcium channel blocking agents should be avoided.
Doxercalciferol may increase the risk of hypermagnesemia.
References Andreassi S, Teso A. Riv Eur Sci Med Farmacol 1992; 14:309-12.
Asemi Z, Karamali M, Jamilian M, et al. Am J Clin Nutr 2015; 102:222-9.
D’Almeida A, Carter JP, Anatol A, Prost C. Womens Health 1992; 19:117-31.
Makrides M, Crosby DD, Bain E, Crowther CA. Cochrane Database Syst Rev 2014;(4):CD000937.
Martin RW, Perry KG Jr, Martin JN Jr, et al. J Miss State Med Assoc 1998; 39:180-2.
Nagra SA. J Trop Pediatr 1989; 35:126-8.
Ridgway LE 3rd, Muise K, Wright JW, et al. Am J Obstet Gynecol 1990; 163:879-82.
Summary Pregnancy Category: B
Lactation Category: S

  • Magnesium oxide should be used during pregnancy and lactation for the treatment of hypomagnesemia. The efficacy of other applications cannot currently be substantiated.

Magnesium sulfate — (Tis U Sol)

International Brand Names

None identified.

Drug Class Anticonvulsants; Neuroprotection; Electrolyte replacements
Indications Ventricular arrhythmia, eclampsia, tocolysis, hypomagnesemia, preterm birth ≤32 weeks
Mechanism Inhibits Ca 2 + release from the intracytoplasmic storage deposits, blocks Ca 2 + influx through glutamate channels or through the NMDA receptor; may decrease the inflammatory response of white and gray matter to oxygen free radicals
Dosage With Qualifiers Ventricular arrhythmia—3–20 mg/min continuous IV × 6–48 h
Eclampsia, prevention and treatment—begin 4 g IV × 1 over 30 min; then 1 g/h IV maintenance rate for at least 24 h postpartum, or during diuresis > 200 mL/h; alternatively, 10 g IM loading dose followed by 5 g IM q4h until at least 24 h postpartum
Tocolysis—begin 6 g IV × 1 over 30 min, then 2–4 g/h IV × 48 h
Hypomagnesemia—1 g IM q4–6 h; alternative 5 g mixed in 1L NS IV over 3 h
NOTE: Renal dosing; measure serum magnesium every 4–6 h if infusion > 2 g/h or oliguria or maternal symptoms of toxicity; maintain between 4–7 mEq/L (4.8–8.4 mg/dL).

  • Contraindications —hypersensitivity to drug or class, renal failure, impaired myocardial function

  • Caution —renal dysfunction, electrolyte disturbances

Maternal Considerations Magnesium sulfate is excreted by the kidney, with 90% of the dose excreted during the first 24 h after an IV infusion. The pharmacokinetic profile of magnesium sulfate after IV administration is best described by a two-compartment model with a rapid distribution (alpha) phase, followed by a relatively slow beta phase of elimination. The clinical effect and toxicity of magnesium is linked to its plasma concentration. A decreased GFR may lead to toxicity if not monitored closely. Use only half the usual load when the plasma Cr exceeds 1.3 mg/dL. DTRs are decreased as the concentration exceeds 4 mEq/L; they are lost as the level approaches 10 mEq/L. Potentially, lethal respiratory depression may occur at 12–15 mEq/L. Investigation suggests the measurement of total magnesium is not adequate for titration in women with either preeclampsia or preterm labor, as there is poor correlation between total magnesium and the physiologically active ionized magnesium. Calcium gluconate should always be readily available to counteract potential serious signs of magnesium intoxication.
Preeclampsia remains a leading cause of maternal and perinatal morbidity and death. Randomized trials demonstrate magnesium sulfate infusion halves the risk of eclampsia and is superior to both phenytoin and diazepam for the prevention of recurrent eclamptic seizures. The anticonvulsant effect is probably exerted on the cerebral cortex. It is also the drug of choice for the control of seizures. Magnesium sulfate is not an effective antihypertensive, though Mg 2 + concentrations between 2 and 4 mmol/L produce greater than half the maximal lowering of systolic and diastolic pressures. There remains controversy as to whether magnesium sulfate is beneficial for the treatment of mild preeclampsia. One analysis concluded that the risks and benefits of magnesium in this patient population counterbalance each other. Although a no-magnesium strategy results in a 15% reduction in neonatal mortality and avoids maternal drug toxicity, it leads to a twofold increase in maternal death and more neurologically compromised neonates compared with empiric magnesium. The clinical decision to use magnesium in women with mild preeclampsia for seizure prophylaxis should be determined by the physician or institution, considering patient values or preferences and the unique risk:benefit trade-off of each strategy. However, magnesium sulfate treatment clearly does not prevent the worsening of preeclampsia during labor. Approximately 10%–15% of eclamptic women convulsed despite prophylaxis. An additional 2-g loading dose is recommended if a woman convulses while receiving magnesium sulfate for the prevention of eclampsia. Magnesium sulfate may also be administered IM. Prospective studies comparing magnesium levels achieved with continuous IV infusion and IM reveal that therapeutically effective levels are achieved with both. Magnesium sulfate neither prolongs labor nor increases the oxytocin requirement in preeclamptic women. Magnesium sulfate is often continued for at least 24 h postpartum, but there is little scientific support for the practice. The duration of therapy may be individualized using maternal diuresis (> 200 mL/h for at least 2 h) as evidence the associated vasospasm has resolved. In one study, women with mild preeclampsia received shorter courses of magnesium sulfate (mean 9.5 ± 4.2 h) than those with severe preeclampsia alone (mean 16 ± 5.9 h), superimposed preeclampsia (mean 16 ± 5.8 h), or atypical preeclampsia (hemolysis, elevated liver enzymes, and low platelet count) (mean 20 ± 6.7 h). There was no eclampsia, and recovery room time was reduced 50%. Magnesium sulfate does not prolong the labor of preeclamptic women.
Preterm labor: No tocolytic agent has been proven to stop preterm labor and improve perinatal outcome. The demonstrable benefit of tocolysis is the time gained to administer corticosteroids. Magnesium sulfate depresses uterine contractility both in vitro and in vivo. Although it is the most commonly used parenteral tocolytic in the United States, the scientific support for this practice is weak, and several in-depth analyses conclude there is compelling evidence for the use of other agents with fewer side effects. For the primary outcome
of delivery within 48 h after intimation, there were no significant differences between women who received magnesium sulfate and women who did not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cyclo-oxygenase inhibitors, prostaglandin inhibitors, or human chorionic gonadotropin) (19 trials, 1913 women). Similarly for the primary outcome of serious infant outcome, there were no significant differences between infants exposed to magnesium sulfate and those not (whether placebo/no alternative tocolytic drug, betamimetics,
calcium channel blockers, COX inhibitors, prostaglandin inhibitors, human chorionic gonadotropin, or various tocolytic drugs) (18 trials, 2187 newborns). These reviewers conclude that magnesium sulfate is ineffective for delaying or preventing preterm birth, has no advantages for a range of neonatal and maternal outcomes as a tocolytic agent, and its use for this indication may be associated with an increased risk of total fetal, neonatal, or infant mortality (in contrast to its use in appropriate groups of women for maternal, fetal, neonatal, and infant neuroprotection where beneficial effects have been demonstrated). Pulmonary edema and CV problems occur at a frequency similar to that with beta mimetics (∼ 1%). Maternal infection, decreased colloid osmotic pressure, and fluid overload are each predisposing risk factors. A costs analysis concluded that nifedipine and indomethacin offered greater value as tocolytic agents.
Side effects include respiratory failure, CV collapse, hypothermia, depressed cardiac function, pulmonary edema, depressed reflexes, hypotension, drowsiness, N/V, hypocalcemia, hyperkalemia, flushing, blurred vision, sweating, muscle weakness, ECG changes, sedation, and confusion
Fetal Considerations Parenterally administered magnesium crosses the placenta and increases the fetal level. Though RCTs where the pediatricians were blind to magnesium sulfate therapy revealed no clear evidence of adverse effect, controversy persists. In a large retrospective chart review of 6654 women with preeclampsia treated with intravenous magnesium sulfate, 6% of neonates were diagnosed with hypotonia. Further, the rates of low 1- and 5-minute Apgar scores, intubation in the delivery room, admission to special care nursery, and hypotonia all significantly rose as maternal serum magnesium concentrations increased. Rodent studies suggest maternal seizures may be associated with fetal brain injury, an effect possibly ameliorated by magnesium sulfate.
Magnesium sulfate administered prior to preterm birth may act by one of several pathways to reduce perinatal neuronal damage. Meta-analysis of the trial data indicates that antenatal magnesium sulfate reduces the risk of cerebral palsy by a third, resulting in one fewer case for every 50 women treated. Treatment can be associated with discomfort and flushing, but maternal side effects are mostly transient and manageable. In one study, magnesium sulfate was given to > 500 women < 30 w who were expected to deliver within 24 h; the children were followed until a corrected age of 2 y. Children exposed to magnesium had a significantly lower rate of substantial gross motor function. In another RCT enrolling 2241 women at 24–31 w, magnesium sulfate reduced the rate of cerebral palsy in survivors. It remains controversial whether the intrapartum administration of magnesium sulfate reduces fetal heart variability and reactivity.
Breastfeeding Safety Some case reports describe engorgement and galactorrhea during tocolysis with IV magnesium sulfate. The mechanism remains unknown. Symptoms gradually subside after discontinuation. Magnesium is normally present in human breast milk, and its concentration is stable throughout the first year of lactation. It is unknown whether magnesium sulfate increases the magnesium content of breast milk. Considering the indication and dosing, limited use is unlikely to pose a clinically significant risk to the breastfeeding neonate.
Drug Interactions The dose of barbiturates, narcotics, hypnotics (or systemic anesthetics), or other CNS depressants should be adjusted because of the additive CNS depressant effects of magnesium.
CNS depression and peripheral transmission defects produced by magnesium may be antagonized by calcium.
References Abbassi-Ghanavati M, Alexander JM, McIntire DD, et al. Am J Perinatol 2012; 29:795-9.
Ascarelli MH, Johnson V, May WL, et al. Am J Obstet Gynecol 1998; 179:952-6.
Atkinson MW, Belfort MA, Saade GR, Moise KJ Jr. Obstet Gynecol 1994; 83:967-70.
Atkinson MW, Guinn D, Owen J, Hauth JC. Am J Obstet Gynecol 1995; 173:1219-22.
Belfort MA, Anthony J, Saade GR. Semin Perinatol 1999; 23:65-78.
Belfort MA, Saade GR, Moise KJ Jr. Acta Obstet Gynecol Scand 1993; 72:526-30.
Belfort MA, Saade GR, Moise KJ Jr. Am J Obstet Gynecol 1992; 167:1548-53.
Cahill AG, Macones GA, Odibo AO, Stamilio DM. Obstet Gynecol 2007; 110:601-7.
Chames MC, Livingston JC, Ivester TS, et al. Am J Obstet Gynecol 2002; 186:1174-7.
Crowther CA, Brown J, McKinlay CJ, Middleton P. Cochrane Database Syst Rev. 2014;(8):CD001060.
Crowther CA, Hiller JE, Doyle LW. In The Cochrane Library, Issue 2. Oxford, UK: Update Software, 2003.
Crowther CA, Hiller JE, Doyle LW, Balsam RR. JAMA 2003; 290:2669-76.
El-Sayed YY, Riley ET, Holbrook RH Jr, et al. Obstet Gynecol 1999; 93:79-83.
Ghidini A, Espada RA, Spong CY. Acta Obstet Gynecol Scand 2001; 80:126-9.
Gordon MC, Iams JD. Clin Obstet Gynecol 1995; 38:706-12.
Grether JK, Hoogstrate J, Selvin S, Nelson KB. Am J Obstet Gynecol 1998; 178:1-6.
Grether JK, Hoogstrate J, Walsh-Greene E, Nelson KB. Am J Obstet Gynecol 2000; 183:717-25.
Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Obstet Gynecol 1999; 94:869-77.
Hallak M, Hotra JW, Custodio D, Kruger ML. Am J Obstet Gynecol 2000; 18:793-8.
Hallak M, Martinez-Poyer J, Kruger ML, et al. Am J Obstet Gynecol 1999; 181:1122-7.
Hayes E, Moroz L, Pizzi L, Baxter J. Am J Obstet Gynecol 2007; 197:383.e1-6.
Hennessy A, Hill I. Aust NZ J Obstet Gynaecol 1999; 39:256-7.
Kimberlin DF, Hauth JC, Goldenberg RL, et al. Am J Perinatol 1998; 15:635-41.
Lewis DF, Bergstedt S, Edwards MS, et al. Am J Obstet Gynecol 1997; 177:742-5.
Livingston JC, Livingston LW, Ramsey R, et al. Obstet Gynecol 2003; 101:217-20.
Lu J, Pfister M, Ferrari P, et al. Clin Pharmacokinet 2002; 41:1105-13.
Lu JF, Nightingale CH. Clin Pharmacokinet 2000; 38:305-14.
Lucas MJ, Leveno KJ, Cunningham FG. N Engl J Med 1995; 333:201-5.
Lurie S, Rotmensch S, Feldman N, Glezerman M. Am J Perinatol 2002; 19:239-40.
Lyell DJ, Pullen K, Campbell L, et al. Obstet Gynecol 2007; 110:61-7.
Martin RW, Martin JN Jr, Pryor JA, et al. Am J Obstet Gynecol 1988; 158:1440-5.
Martin RW, Perry KG Jr, Martin JN Jr, et al. J Miss State Med Assoc 1998; 39:180-2.
Matsuda Y, Ikenoue T, Hokanishi H. Gynecol Obstet Invest 1993; 36:102-7.
Mittendorf R, Dambrosia J, Pryde PG, et al. Am J Obstet Gynecol 2002; 186:1111-8.
Nelson KB, Grether JK. Pediatrics 1995; 95:263-9.
[No authors]. Lancet 2002; 359:1877-90.
Odendaal HJ, Steyn DW, Norman K, et al. S Afr Med J 1995; 85:1071-6.
Pritchard JA, Cunningham FG, Pritchard SA. Am J Obstet Gynecol 1984; 148:951-63.
Rasch DK, Huber PA, Richardson CJ, et al. J Pediatr 1982; 100:272-6.
Repke JT, Power ML, Holzman GB, Schulkin J. J Reprod Med 2002; 47:472-6.
Ricci JM, Hariharan S, Helfgott A, et al. Am J Obstet Gynecol 1991; 165:603-10.
Roberts JM, Villar J, Arulkumaran S. BMJ 2002; 325:609-10.
Rouse DJ, Hirtz DG, Thom E, et al. N Engl J Med 2008; 359:895-905.
Saade GR, Taskin O, Belfort MA, et al. Obstet Gynecol 1994; 84:374-8.
Sibai BM. Am J Obstet Gynecol 1990; 162:1141-5.
Sibai BM, Graham JM, McCubbin JH. Am J Obstet Gynecol 1984; 150:728-33.
Szal SE, Croughan-Minihane MS, Kilpatrick SJ. Am J Obstet Gynecol 1999; 180:1475-9.
Taber EB, Tan L, Chao CR, et al. Am J Obstet Gynecol 2002; 186:1017-21.
Towers CV, Pircon RA, Heppard M. Am J Obstet Gynecol 1999; 180:1572-8.
Weiner CP, Renk K, Klugman M. Am J Obstet Gynecol 1988; 159:216-22.
Witlin AG, Sibai BM. Obstet Gynecol 1998; 92:883-9.
Summary Pregnancy Category: A
Lactation Category: S

  • Magnesium sulfate is superior to both phenytoin and diazepam for reducing the incidence of primary and secondary eclamptic convulsions.

  • Locales where eclampsia has a major impact on maternal mortality should institute policies to ensure that this inexpensive and lifesaving treatment is available and that care providers are trained to use it safely.

  • The controversy as to whether magnesium sulfate is as effective as other tocolytic agents or ineffective is now irrelevant. Magnesium sulfate is clearly not superior to other tocolytic agents and has worse safety and cost profiles. Both nifedipine and indomethacin (48-h course) have superior safety and cost profiles and greater efficacy. For these reasons, magnesium sulfate should not be used for tocolysis.

  • It appears that short-term infusion offers a high likelihood of neuroprotection for the newborn in high-risk pregnancies at 24 to 31 weeks gestation.

Mannitol — (Osmitrol; Resectisol)

International Brand Names

Acrosmosol (Ecuador); d -Mannitol (Korea); Manitol (Indonesia); Manitol Pisa (Mexico)

Drug Class Diuretics, osmotic
Indications Oliguria from acute renal failure (prevention and treatment), cerebral edema, diuresis (forced)
Mechanism Increases GFR
Dosage With Qualifiers Oliguria prevention—50–100 g IV over 2 h
Oliguria treatment—50–100 g IV over 2 h
Cerebral edema—100 g IV × 2–6 h
Diuresis, forced—25–100 g IV over 2 h
NOTE: Attempt to maintain urinary output > 100 mL/h.

  • Contraindications —hypersensitivity to drug or class, anuria, progressive renal failure after initiation, no response to the initial bolus, pulmonary edema, severe dehydration, intracranial hemorrhage, progressive heart failure

  • Caution —renal dysfunction

Maternal Considerations Mannitol is an osmotic diuretic. It is confined to the extracellular space after IV administration and is rapidly excreted by the kidneys (80% within 3 h). There are no adequate reports or well-controlled studies of mannitol in pregnant women. The published experience is limited to case reports of women often undergoing surgery for causes unrelated to pregnancy (intracranial hemorrhage or brain tumors) or for hypermagnesemia. Although mannitol has been used to treat posterior, reversible encephalopathy (PRES) in women with eclampsia, it is inferior to magnesium sulfate for the prevention of seizures.
Side effects include seizures, heart failure, CV collapse, pulmonary edema, acute renal failure, CNS depression, coma, fluid imbalance, tachycardia, dehydration, electrolyte disorders, acidosis, blurred vision, thrombophlebitis, urticaria, fever, infusion site infection, dryness of mouth, thirst, rhinitis, skin necrosis, angina, and water intoxication.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Mannitol crosses the human placenta by diffusion. Rodent teratogenicity studies have not been performed. Studies of pregnant ewes reveal that maternal hyperosmolality influences the fetal arginine vasopressin secretion and renal function, and thus the amount of AF.
Breastfeeding Safety There is no published literature in nursing women. It is unknown whether mannitol enters human breast milk.
Drug Interactions No clinically relevant interactions identified.
References Bain MD, Copas DK, Landon MJ, Stacey TE. J Physiol 1988; 399:313-9.
Bohman VR, Cotton DB. Obstet Gynecol 1990; 76:984-6.
Chang L, Looi-Lyons L, Bartosik L, Tindal S. Can J Anaesth 1999; 46:61-5.
Demir BC, Ozerkan K, Ozbek SE, et al. Arch Gynecol Obstet 2012; 286:287-93.
Ervin MG, Ross MG, Youssef A, et al. Am J Obstet Gynecol 1986; 155:1341-7.
Narbone MC, Musolino R, Granata F, et al. Neurol Sci 2006; 27:187-9.
Quraishi AN, Illsley NP. Placenta 1999; 20:167-74.
Summary Pregnancy Category: C
Lactation Category: U

  • Mannitol should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Maprotiline — (Ludiomil)

International Brand Names

Maprostad (Germany); Melodil (Israel); Mirpan (Germany); Psymion (Germany); Retinyl (Greece)

Drug Class Antidepressants; Tetracyclics
Indications Depression
Mechanism Unknown; inhibits reuptake of NE
Dosage With Qualifiers Depression—25–50 mg PO bid or tid; max 225 mg PO qd × 6 w

  • Contraindications —hypersensitivity to drug or class, MI, usage of MAOIs within 14 d

  • Caution —seizure disorders, arrhythmias, strokes, tachycardia

Maternal Considerations There are no adequate reports or well-controlled studies of maprotiline in pregnant women.
Side effects include seizures, neuroleptic malignant syndrome, constipation, dry mouth, blurred vision, dizziness, orthostatic hypotension, drowsiness, urinary retention, tachycardia, diaphoresis, renal failure, rash, edema, dyskinesia, diarrhea, bitter taste, abdominal cramps, dysphagia, decreased libido, weakness, fatigue, insomnia, agitation, hallucinations, nightmares, disorientation, delusions, restlessness, hypomania, mania, exacerbation of psychosis, decrease in memory, and feelings of unreality.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether maprotiline crosses the human placenta. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically. Rodent and chick studies suggest maprotiline is less embryo and organ toxic than imipramine and amitriptyline.
Breastfeeding Safety There is no published experience in nursing women. Maprotiline enters human breast milk and has a relative infant dose of < 2%.
Drug Interactions Close supervision and careful dosage adjustment are required when administering maprotiline with anticholinergic or sympathomimetic drugs because of the possibility of additive atropine-like effects.
Use with electroshock therapy should be avoided because of the lack of experience in this area.
Caution is advised with hyperthyroid patients or those on thyroid medication because of the potential for enhanced CV toxicity.
May block the pharmacologic effects of guanethidine .
The risk of seizures may be increased if taken with phenothiazines or when the dosage of benzodiazepines is rapidly tapered.
Plasma concentrations may be increased if given with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine ) and decreased if used with hepatic enzyme inducers (e.g., barbiturates, phenytoin ).
References Pinder RM, Brogden RN, Speight TM, Avery GS. Drugs 1977; 13:321-52.
Wirz-Justice A, Lichtsteiner M. J Pharm Pharmacol 1976; 28:172-5.
Summary Pregnancy Category: B
Lactation Category: S (probably)

  • Maprotiline should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Mebendazole — (Bendosan; Damaben; Drivermide; Fugacar; Ovex; Vermox)

International Brand Names

Amycil (Mexico); Anelmin (Israel); Anthex (South Africa); Antiox (Philippines); Bantenol (Spain); Benda (Thailand); Bestelar (Mexico); Cipex (South Africa); Combantrin-1 (New Zealand); Combantrin-1 with mebendazole (Australia); Conquer (Taiwan); D-Worm (South Africa); Gamax (Colombia); Helminzole (Mexico); Lomper (Spain); Mebex (India); Mindol (New Zealand); Noverme (Portugal); Noxworm (Thailand); Pantelmin (Austria, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Nicaragua, Panama, Peru, Portugal); Penalcol (Peru); Pharaxis M (Colombia); Revapol (Mexico); Soltric (Mexico); Sqworm (Australia); Surfont (Germany); Thelmox (Puerto Rico); Toloxim (Portugal); Vagaka (Thailand); Wormgo (South Africa); Wormin (South Africa, Israel, India); Zadomen (Malaysia); Zakor (Colombia)

Drug Class Anthelmintics
Indications Infection (pinworm, whipworm, hookworm, roundworm), capillariasis
Mechanism Inhibition of microtubule formation; causes glucose depletion
Dosage With Qualifiers Pinworm infection—100 mg PO × 1
Whipworm infection—100 mg PO bid × 3–5 d
Hookworm infection—100 mg PO bid × 3–5 d
Roundworm infection—100 mg PO bid × 3–5 d
Capillariasis—200 mg PO bid × 20 d

  • Contraindications —hypersensitivity to drug or class, pregnancy, children < 2 y

  • Caution —pregnancy

Maternal Considerations Mebendazole is an anthelmintic used to treat pinworm, a common childhood infection. Treatment of reproductive-age women is also strongly recommended in areas of widespread hookworm infection and its related anemia. In some endemic areas, treatment of all pregnant women after the first trimester effectively reduces the incidences of IUGR and perinatal death.
Side effects include angioedema, seizures, neutropenia, abdominal pain, N/V, diarrhea, fever, dizziness, headache, rash, pruritus, alopecia, and convulsions.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether mebendazole crosses the human placenta. Congenital helminthic infection in humans is rare. No increase in risk for congenital malformation or other adverse outcomes was noted in the largest prospective study with 140 first-trimester exposures. There are no reported sequelae from second- or third-trimester exposure. The Danish Fertility Database was used to identify all births in Denmark from 1997 to 2007, and maternal exposure to anthelmintics was identified through the Danish Prescription Registry. Of 713,667 births, 2567 mothers redeemed a prescription for mebendazole . There was no association between exposure to mebendazole and major congenital malformations (OR = 0.7 [CI 95% 0.5–1.1]) or other negative birth outcomes. No increased risk was found for a negative outcome regardless of the trimester of exposure. Rodent studies suggest mebendazole is embryotoxic and teratogenic at fairly low doses.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether mebendazole enters human breast milk. However, only about 2% of ingested drug is absorbed out of the gut. It is thus not surprising that several isolated case reports state the milk levels were undetectable after 3 d of treatment with 200 mg a day.
Drug Interactions No clinically relevant interactions identified.
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Gyorkos TW, Larocque R, Casapia M, Gotuzzo E. Pediatr Infect Dis J 2006; 25:791-4.
Kurzel RB, Toot PJ, Lambert LV, Mihelcic AS. NZ Med J 1994; 107:439.
Larocque R, Casapia M, Gotuzzo E, et al. Trop Med Int Health 2006; 11:1485-95.
Stephenson LS. Paediatr Drugs 2001; 3:495-508.
St. Georgiev V. Expert Opin Pharmacother 2001; 2:223-39.
Stoukides C. J Hum Lact 1994; 10:269.
Torp-Pedersen A, Jimenez-Solem E, Cejvanovic V, et al. J Obstet Gynaecol 2016; 36:1020-5.
Summary Pregnancy Category: C
Lactation Category: S (probably)

  • Mebendazole should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • Though mebendazole is not associated with significant increase in the rates of congenital defects, it is best avoided during the first trimester.

  • Treatment is beneficial for women in developing countries where intestinal helminthiases are endemic.

Mechlorethamine — (Mustargen)

International Brand Names

Mustine (Belgium, Netherlands, Turkey); Mustine Hydrochloride Boots (Malaysia)

Drug Class Antineoplastics, alkylating agent
Indications Hodgkin’s disease (stages III–IV), leukemia (chronic myelocytic and chronic lymphocytic), mycosis fungoides, polycythemia vera, lymphosarcoma
Mechanism Alkylating agent
Dosage With Qualifiers Malignancy—0.4 mg/kg/course; numerous dosing schedules exist reflecting the disease, patient response, and concomitant therapy

  • Contraindications —hypersensitivity to drug or class, suppurative inflammation

  • Caution —unknown

Maternal Considerations There are no adequate reports or well-controlled studies of mechlorethamine in pregnant women. Hodgkin’s disease does not affect the normal progress of pregnancy. Termination of pregnancy is usually unnecessary. Based on limited published experience, mechlorethamine may be used during pregnancy with a good outcome. Women treated during childhood or adolescence may experience decreased gonadal function.
Side effects include thrombosis, thrombophlebitis, anaphylaxis, N/V, depression, hemolytic anemia, skin eruption, delayed catamenia, oligomenorrhea, and amenorrhea.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether mechlorethamine crosses the human placenta. Children of women treated for hematologic malignancies during pregnancy with a variety of cytotoxic agents, including mechlorethamine, have normal birth weight as well as normal learning and educational performance. There is no increase in the prevalence of acute leukemia or congenital, neurologic, and psychological abnormalities. Mechlorethamine is teratogenic in rodents.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether mechlorethamine enters human breast milk.
Drug Interactions No clinically relevant interactions identified.
References Abboud J, Nasrallah T, Chahine G, Nasnas R. J Gynecol Obstet Biol Reprod 1993; 22:783-6.
Aviles A, Neri N. Clin Lymphoma 2001; 2:173-7.
Brice P, Pautier P, Marolleau JP, et al. Nouv Rev Fr Hematol 1994; 36:387-8.
van den Berg H, Furstner F, van den Bos C, Behrendt H. Pediatr Blood Cancer 2004; 42:210-5.
Summary Pregnancy Category: D
Lactation Category: U

  • If a pregnant patient has an aggressive hematologic malignancy, chemotherapy at full doses can be safely administered, even during the first trimester, if cure of the hematologic malignancy is considered reasonable.

Meclizine — (Ancolan; Antivert; Duramesan; En-Vert; Meclicot; Meclozine; Medivert; Yonyun)

International Brand Names

Bonamina (Argentina); Bonamine (Canada, Germany, Japan, Philippines, Taiwan); Chiclida (Spain); Dramine (Spain); Navicalm (Portugal); Postadoxin (Germany); Postadoxine (Philippines); Postafen (Denmark, Finland, Norway, Sweden); Postafene (Belgium, Hong Kong); Sea-Legs (New Zealand); Suprimal (Netherlands)

Drug Class Antiemetics; Antihistamines, H 1 ; Antivertigo agents
Indications Motion sickness
Mechanism Antagonizes ACh and H 1 receptors
Dosage With Qualifiers N/V and dizziness due to motion sickness—25–50 mg PO qd 1 h before travel; repeat q24h

  • Contraindications —hypersensitivity to drug or class

  • Caution —GI and GU obstruction, usage of drug with CNS-depressive effect

Maternal Considerations Meclizine effectively reduces N/V associated with emergency hormonal contraception (Yuzpe regimen). There are no adequate reports or well-controlled studies of meclizine in pregnant women. It is commonly used in several European countries for the treatment of first-trimester N/V.
Side effects include tachycardia, hallucinations, jaundice, ototoxicity, agitation, anxiety, hypotension, blurred vision, dry mouth, confusion, anorexia, N/V, diarrhea, rash, and constipation.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether meclizine crosses the human placenta. A large clinical experience reveals little evidence that meclizine is a significant human teratogen. A population-based study in Sweden with more than 16,000 first-trimester exposures reported improved pregnancy outcomes compared with the nonexposed population. Rodent studies conducted at 25–50 × the MRHD reveal cleft lip and palate.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. It is unknown whether meclizine enters human breast milk.
Drug Interactions No clinically relevant interactions identified.
References Källén B, Mottet I. Eur J Epidemiol 2003; 18:665-9.
Miklovich L, van den Berg BJ. Am J Obstet Gynecol 1976; 125:244-8.
Raymond EG, Creinin MD, Barnhart KT, et al. Obstet Gynecol 2000; 95:271-7.
Shapiro S, Kaufman DW, Rosenberg L, et al. Br Med J 1978; 1:483.
Summary Pregnancy Category: B
Lactation Category: S

  • Meclizine should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • Meclizine appears a reasonable choice for the management of N/V of pregnancy that has been unresponsive to vitamin B 6 .

Meclofenamate — (Meclomen)

International Brand Names

Ethos (Taiwan); Medomen (Singapore); Melvon (Korea); Movens (Italy)

Drug Class Analgesics, non-narcotic; NSAIDs
Indications Pain, dysmenorrhea, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout
Mechanism Inhibits cyclooxygenase and lipoxygenase, leading to reduced prostaglandin synthesis
Dosage With Qualifiers Pain—50 mg PO q4–6 h; max 400 mg/d
Dysmenorrhea—100 mg PO tid; max 6 d usage
Osteoarthritis—50–100 mg PO tid or qid
Rheumatoid arthritis—50–100 mg PO tid or qid
Ankylosing spondylitis—50–100 mg PO tid
Gout, acute—100 mg PO tid
NOTE: Take with food or milk.

  • Contraindications —hypersensitivity to drug or class, NSAID-induced asthma

  • Caution —nasal polyps, GI bleeding, hypertension, cardiac failure, asthma

Maternal Considerations Meclofenamate is a nonsteroidal agent with antiinflammatory, analgesic and antipyretic activities. It has little effect on human platelet function. There are no adequate reports or well-controlled studies of meclofenamate in pregnant women. In rodents, meclofenamate induces luteolysis followed by spontaneous labor. In contrast, in vitro studies reveal meclofenamate inhibits myometrial contractility. Meclofenamate is a popular analgesic for the treatment of postpartum pain after vaginal delivery.
Side effects include anaphylaxis, GI bleeding, bronchospasm, renal failure, interstitial nephritis, hepatic failure, Stevens-Johnson syndrome, agranulocytosis, abdominal pain, constipation, headache, dizziness, rash, urticaria, increased LFTs, drowsiness, edema, tinnitus, lupus, and serum sickness–like symptoms.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether meclofenamate crosses the human placenta. Similar-class agents do cross, causing fetal ductal constriction and decreased fetal urination. Because of the potential for premature closure of the fetal ductus arteriosus after maternal use of NSAIDs, chronic meclofenamate treatment during pregnancy is not recommended without fetal monitoring. Fetal exposure should be minimized until completion of future studies, as meclofenamate may affect fetal breathing movements and pulmonary vascular resistance. Rodent studies reveal that meclofenamate, like aspirin and other NSAIDs, can cause fetotoxicity and minor skeletal malformations (e.g., supernumerary ribs, delayed ossification) but no major teratogenicity.
Breastfeeding Safety There is no published experience in nursing women. Meclofenamate enters human breast milk, though the kinetics remain to be elucidated.
Drug Interactions Enhances the effect of warfarin, and the warfarin dose should be reduced to prevent excessive prolongation of the PT or INR.
Aspirin may lower meclofenamate plasma levels, possibly by competing for protein-binding sites. Greater fecal blood loss results from the use of both drugs.
References Cooke RG, Knifton A. Res Vet Sci 1980; 29:251-4.
Facchinetti F, De Pietri R, Giunchi M, Genazzani AR. Clin J Pain 1991; 7(Suppl 1):S60-3.
Gooneratne AD, Hartmann PE, Barker I. J Reprod Fertil 1982; 65:157-62.
Summary Pregnancy Category: C (first and second trimesters), D (third trimester)
Lactation Category: S (likely)

  • Similar to other NSAIDs, meclofenamate poses minimal risk when used occasionally.

Medroxyprogesterone — (Amen; Aragest; Asconale; Clinovir; Curretab; Cycrin; Depo-Provera; Med-Pro; Provera)

International Brand Names

Aragest 5 (Israel); Clinofem (Germany); Depo-Prodasone (France); Farlutal (Belgium, China, France, Italy, Netherlands); GestaPolar (Germany); Gestapuran (Finland, Sweden); Manodepa (Thailand); Medrone (Taiwan); Meges (Indonesia); Meprate (India); MPA (China); MPA Gyn 5 (Germany); Perlutex (Denmark, Norway); Perlutex Leo (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Panama); Prodafem (Austria, Switzerland); Progen (Korea); Progevera (Spain); Prothyra (Indonesia); Ralovera (Australia); Veraplex (Indonesia)

Drug Class Antineoplastics, hormone; Contraceptives; Hormones
Indications Amenorrhea, dysfunctional uterine bleeding, hormone replacement, contraception
Mechanism Inhibits gonadotropin release, stimulates transformation of proliferative into secretory endometrium
Dosage With Qualifiers Amenorrhea—5–10 mg PO qd × 5 on days 16–21 of the cycle or qmo
Dysfunctional uterine bleeding—5–10 mg PO qd × 5 on days 16–21 of the cycle or qmo
Hormone replacement—5–10 mg PO qd × 12–14 d
Contraception—150 mg IM q3mo

  • Contraindications —hypersensitivity to drug or class, thromboembolic disease, pregnancy, breast cancer, undiagnosed vaginal bleeding, thrombophlebitis, PE, retinal thrombosis, hepatic failure, missed abortion

  • Caution —cerebrovascular disorders, lactation, hepatic dysfunction, cardiac failure

Maternal Considerations Medroxyprogesterone is a popular and effective (0.42/1000 woman-years) contraceptive; irregular bleeding and amenorrhea are the most common side effects. It can be combined with an injectable estrogen. It is estimated that 68% of women who become pregnant after discontinuing conceive within 12 mo, 83% within 15 mo, and 93% within 18 mo. If bone density does decline, it is reversible and unlikely to adversely influence clinical events either acutely or later in reproductive-age women. Because of the indications, it is inevitable that pregnant women are exposed to medroxyprogesterone, as many pregnancies will not be recognized until after the first trimester. Progestational agents (i.e., not native progesterone ) such as medroxyprogesterone were long used during early pregnancy to prevent first-trimester spontaneous abortion. This practice cannot be substantiated. It is speculated that progestational agents may delay spontaneous abortion in women with defective embryos, but the evidence is soft. Although there are no adequate reports or well-controlled studies of medroxyprogesterone in pregnant women, epidemiologic studies are reassuring, as there is no demonstrable increase in the prevalence of ectopic pregnancy. Medroxyprogesterone is also commonly used as adjunctive therapy for endometrial cancer or adenomatous hyperplasia, especially in young women who wish to preserve fertility for the near term.
Side effects include thromboembolism, stroke, MI, hepatic adenoma, breast cancer, gallbladder disease, cholestatic jaundice, hypertension, stroke, amenorrhea, N/V, breast tenderness, weight gain, headache, edema, depression, rash, pruritus, libido changes, appetite changes, acne, hirsutism, galactorrhea, alopecia, and optic neuritis.
Fetal Considerations There are no adequate reports or well-controlled studies of medroxyprogesterone in human fetuses. In utero exposure of male fetuses to progestational agents may double the risk of hypospadias. Although there are insufficient data to quantify the risk for female fetuses, some progestational agents may cause mild virilization of the external genitalia. Defects outside the external genitalia are not reported in either humans or rodents. First-trimester exposure is an indication for a detailed anatomic ultrasound between 18 and 22 w.
Breastfeeding Safety Trace amounts of medroxyprogesterone are excreted into human breast milk. Early administration of medroxyprogesterone will probably remain controversial for at least the near future. When given 6 or more weeks postpartum, medroxyprogesterone increases prolactin and milk production in breastfeeding women. It has been suggested that women injected within 48 h postpartum may experience decreased or poor milk production. However, there are few objective data to support that conclusion. In contrast, it is clear contraceptive failures are far more numerous when the injection is delayed until 6 w.
Drug Interactions The literature suggests use with aminoglutethimide significantly reduces serum concentrations of medroxyprogesterone, likely by increasing clearance.
References Baheiraei A, Ardsetani N, Ghazizadeh S. Int J Gynaecol Obstet 2001; 74:203-5.
Borgatta L, Murthy A, Chuang C, et al. Contraception 2002; 66:169.
Carbone JP, Figurska K, Buck S, Brent RL. Teratology 1990; 42:121-30.
Danli S, Qingxiang S, Guowei S. Contraception 2000; 62:15-8.
Kennedy KI, Short RV, Tully MR. Contraception 1997; 55:347-50.
[No authors]. FDA Med Bull 1993; 23:6-7.
Prahalada S, Carroad E, Hendrickx AG. Contraception 1985; 32:497-515.
Ratchanon S, Taneepanichskul S. Obstet Gynecol 2000; 96:926-8.
Ushijima K, Yahata H, Yoshikawa H, et al. J Clin Oncol 2007; 25:2798-803.
Summary Pregnancy Category: X
Lactation Category: S
Medroxyprogesterone should not be administered during pregnancy.

  • First-trimester exposure is an indication for a detailed anatomic ultrasound between 18 and 22 w.

Mefenamic acid — (Coslan; Ponsfen; Ponstel)

International Brand Names

Algastel (Philippines); Algifort (Philippines); Alpain (Indonesia); Aprostal (Philippines); Atmose (Philippines); Beafemic (Malaysia); Benostan (Indonesia); Bonabol (Japan); Dolfenal (Thailand); Dysman (England); Dyspen (Malaysia, Thailand); Ecopan (Switzerland); Eurostan (Philippines); Femen (Thailand); Fenalac (Philippines); Fenamic (Israel); Fenamin (South Africa); Fenamol (Israel); Fengic (Philippines); Hamitan (Hong Kong); Hispen (Philippines); Hostan (Hong Kong); Johnstal (Taiwan); Kemostan (Indonesia); Lysalgo (Italy); Manic (Thailand); Manomic (Thailand); Masafen (Thailand); Mecid A (Philippines); Mefa (Hong Kong); Mefac (Ireland); Mefacap (Singapore); Mefacit (Poland); Mefalqic (South Africa); Mefast (Indonesia); Mefen (Malaysia); Mefic (New Zealand); Metmic (Philippines); Namic (Malaysia); Napan (Hong Kong); Parkemed (Austria, Germany); Passton (Taiwan); Pefamic (Thailand); Poncofen (Indonesia); Pondex (Indonesia); Pondnadysmen (Thailand); Ponser (Philippines, South Africa); Ponstan (Canada, Ecuador, England, Finland, Ghana, Greece, Israel, Japan, Kenya, Korea, Mauritius, Philippines, Portugal, South Africa, Switzerland, Tanzania, Turkey, Uganda, Venezuela, Zimbabwe); Ponstan (500 mg) (Colombia); Ponstan-500 (Mexico); Ponstan Forte (Israel, South Africa); Ponstil (Uruguay); Ponstyl (France, Mauritius); Pontacid (Hong Kong); Pontal (Japan, Korea); Pontyl (Singapore); Potarlon (Taiwan); Pynamic (Thailand); Ralgec (Philippines); Sefmic (Hong Kong); Selmac (Philippines); Sicadol (Chile, Paraguay); Solasic (Indonesia); Tanston (Peru); Tropistan (Indonesia); Vandifen (Philippines); Youfenam (Japan); Zerrmic (Philippines)

Drug Class Analgesics, non-narcotic; NSAIDs
Indications Pain, dysmenorrhea, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout
Mechanism Inhibits cyclooxygenase and lipoxygenase, reducing prostaglandin synthesis
Dosage With Qualifiers Pain—50 mg PO q4–6 h; max 400 mg/d
Dysmenorrhea—100 mg PO tid; max 6 d usage
Osteoarthritis—50–100 mg PO tid or qid
Rheumatoid arthritis—50–100 mg PO tid or qid
Ankylosing spondylitis—50–100 mg PO tid
Gout, acute—100 mg PO tid; alternatively 500 mg PO, then 250 mg PO q6h for not more than 7 d
NOTE: Take with food or milk.

  • Contraindications —hypersensitivity to drug or class, NSAID-induced asthma

  • Caution —nasal polyps, GI bleeding, hypertension, cardiac failure, asthma

Maternal Considerations Mefenamic acid is a nonsteroidal agent with antiinflammatory, analgesic and antipyretic action. There are no adequate reports or well-controlled studies of mefenamic acid in pregnant women. In one small, randomized trial, the prevalence of preterm labor was significantly reduced by mefenamic acid compared with placebo. This observation has not subsequently been tested adequately. If the effect of mefenamic acid is similar to that for other NSAIDs, it is unlikely to be effective. Mefenamic acid rapidly decreases uterine contractility in women with dysmenorrhea.
Side effects include anaphylaxis, GI bleeding, bronchospasm, renal failure, interstitial nephritis, hepatic failure, Stevens-Johnson syndrome, agranulocytosis, abdominal pain, constipation, headache, dizziness, rash, urticaria, elevated LFTs, drowsiness, edema, tinnitus, lupus, and serum sickness–like symptoms.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Mefenamic acid crosses the human placenta, achieving an F:M ratio approximating 0.32 in the second trimester. There are case reports of ductal closure reported as with other NSAIDs. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically. Embryotoxicity is noted in some species. Because of the potential for premature closure of the fetal ductus arteriosus after maternal use of NSAIDs, chronic mefenamic acid treatment during pregnancy is not recommended without fetal monitoring.
Breastfeeding Safety Only trace amounts of mefenamic acid are excreted into breast milk, posing no clinical risk to the nursing infant.
Drug Interactions Mefenamic acid is a CYP2C9 substrate, and a number of compounds are recognized inhibitors of CYP2C9. However, drug interaction studies of mefenamic acid and these compounds have not been conducted.
May reduce the natriuretic effect of furosemide and thiazides presumably by the inhibition of renal prostaglandin synthesis. The patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
NSAIDs can increase plasma lithium levels (15%) by decreasing renal lithium clearance, presumably by inhibiting renal prostaglandin synthesis. Patients should be observed carefully for signs of lithium toxicity.
NSAIDs competitively inhibit methotrexate accumulation in rabbit kidney slices. Caution is advised when NSAIDs are administered with methotrexate.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Antacids containing magnesium hydroxide may increase the C max and AUC of mefenamic acid by 125% and 36%, respectively.
May prolong PT. Frequent monitoring of PT is necessary when mefenamic acid is given to patients receiving oral anticoagulant drugs.
A false-positive reaction for urinary bile, using the diazo tablet test, may result after mefenamic acid. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed.
References Adverse Drug Reactions Advisory Committee. Med J Aust 1998; 169:270-1.
Buchanan RA, Eaton CJ, Koeff ST, Kinkel AW. Curr Ther Res Clin Exp 1968; 10:592-7.
MacKenzie IZ, Graf AK, Mitchell MD. Int J Gynaecol Obstet 1985; 23:455-8.
Mital P, Garg S, Khuteta RP, et al. J R Soc Health 1992; 112:214-6.
Smith RP, Powell JR. Am J Obstet Gynecol 1982; 143:286-92.
Summary Pregnancy Category: C
Lactation Category: S (probably)

  • Mefenamic acid should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • Occasional use during pregnancy appears safe, though continuous use likely has the same adverse effects as other NSAIDs.

Mefloquine — (Lariam)

International Brand Names

Lariam (Canada, Chile, China, Hong Kong, Korea, Peru, Philippines, Taiwan, Uruguay); Laricam (Japan); Mefliam (Israel, South Africa); Mephaquin (Colombia, Hong Kong, Israel, Thailand); Mephaquine (Switzerland); Mequin (Thailand); Tropicur (Argentina)

Drug Class Antiprotozoals
Indications Malaria (prophylaxis and treatment)
Mechanism Unknown; acts as schizonticide
Dosage With Qualifiers Malaria prophylaxis—250 mg PO qw beginning 1 w before and continuing until 4 w after possible exposure
Malaria treatment—1250 mg PO × 1 followed by treatment with primaquine
NOTE: Take with food and water.

  • Contraindications —hypersensitivity to drug or class, depression, psychosis, serious life-threatening infections

  • Caution —seizures, psychiatric disorder, hepatic dysfunction, cardiac conduction diseases, cardiac arrhythmia

Maternal Considerations Malaria remains an important cause of maternal and perinatal morbidity and mortality in endemic countries. P. falciparum drug resistance increasingly limits the effectiveness of antimalarial therapy. Mefloquine is the most effective agent for the prevention of chloroquine-resistant falciparum malaria. The WHO favors mefloquine prophylaxis during pregnancy from 16 w onward. Yet for some reason the safety of mefloquine in pregnancy is a continuing subject of debate. Gonzales and colleagues reviewed 18 relevant articles; only one was double blind and placebo controlled. They found no differences in the risk of adverse pregnancy outcomes in women exposed to mefloquine compared with those exposed to other antimalarials or to the general population. Mefloquine (15 mg/kg) may have more side effects than sulfadoxine - pyrimethamine during pregnancy.
Mefloquine and quinine are the only antimalarials generally available during pregnancy for the treatment of multidrug-resistant P. falciparum . Prospective studies show mefloquine (25 mg/kg) in combination with artesunate (4 mg/kg/d for 3 d) is more effective than quinine (10 mg/kg q8h). Many of the adverse effects of mefloquine reflect primary hepatic damage or symptomatic thyroid disturbances that could occur either independently or secondary to hepatocellular injury. Routine intermittent treatment of women in endemic locales has been suggested.
Side effects include seizures, hallucinations, ECG conduction abnormalities, erythema multiforme, Stevens-Johnson syndrome, encephalopathy, dizziness, syncope, extrasystoles, myalgia, N/V, fever, headache, chills, diarrhea, pruritus, asthenia, transient emotional disturbances, and hair loss.
Fetal Considerations Prophylactic (250 mg/w) mefloquine during early pregnancy is not associated with an increased risk of malformations and is not an indication for pregnancy termination. Similarly, second-trimester exposure is not associated with adverse reactions. Mefloquine is associated with an increased risk of stillbirth perhaps because of maternal malaria, as the rates of abortion, IUGR, neurodevelopmental compromise, and congenital malformations are not altered. Rodent studies at high doses reveal that mefloquine is teratogenic and embryotoxic.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. The relative infant dose of mefloquine is < 0.2%, too small to be clinically relevant.
Drug Interactions Use with related compounds (e.g., chloroquine, quinidine, quinine ) may produce ECG abnormalities and increase the risk of convulsions. If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 h after the last dose.
Because of the potential for fatal prolongation of the QTc interval, halofantrine should not be given simultaneously with or subsequent to mefloquine.
Theoretically, use with other drugs known to alter cardiac conduction (e.g., antiarrhythmic or β-adrenergic blocking agents, antihistamines or H 1 -blocking agents, calcium channel blockers, phenothiazines, TCAs) might also contribute to prolongation of the QTc interval. There are no data.
May reduce seizure control by lowering the plasma levels of anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, valproic acid ). Monitor blood levels and adjust the dose appropriately.
May attenuate the immune response to oral live typhoid vaccine. Vaccinations composed of attenuated live bacteria should be completed at least 3 d before the first dose.
References Bounyasong S. J Med Assoc Thai 2001; 84:1289-99.
Briand V, Cottrell G, Massougbodji A, Cot M. Malar J 2007; 6:160.
Croft AM, Herxheimer A. BMC Public Health 2002; 2:6.
Edstein MD, Veenendaal JR, Hyslop R. Chemotherapy 1988; 34:165-9.
McGready R, Brockman A, Cho T, et al. Trans R Soc Trop Med Hyg 2000; 94:689-93.
[No authors]. Prescrire Int 2000; 9:180-1.
Nosten F, van Vugt M, Price R, et al. Lancet 2000; 356:297-302.
Nosten F, Vincenti M, Simpson J, et al. Clin Infect Dis 1999; 28:808-15.
Orton LC, Orton AA. Cochrane Database Syst Rev 2008; (4):CD004912.
Rosenblatt JE. Mayo Clin Proc 1999; 74:1161-75.
Summary Pregnancy Category: C
Lactation Category: S

  • Mefloquine is the most effective agent for prevention of chloroquine-resistant falciparum malaria.

  • Mefloquine has not been associated with an increased rate of birth defects, but the incidence of stillbirths may be increased. The WHO favors mefloquine prophylaxis in pregnant women from 16 w onward.

  • Mefloquine should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Megestrol — (Magace; Megace; Niagestine)

International Brand Names

Endace (India); Maygace (Spain); Megace (Argentina, Australia, Austria, Canada, Chile, Czech Republic, Ecuador, England, Greece, Hungary, Ireland, Netherlands, Peru, Poland, Russia, Uruguay); Megace OS (Canada); Megaplex (Indonesia, Thailand); Megastrol (Paraguay); Megejohn (Taiwan); Megestat (Brazil, Germany); Mestrel (Mexico, Thailand)

Drug Class Antineoplastics; Hormone/hormone modifier; Hormones, other gynecologic; Progestins
Indications Breast cancer, endometrial cancer (palliative), AIDS wasting syndrome
Mechanism Inhibition of pituitary gonadotropin release; stimulates transformation of proliferative endometrium to secretory; antineoplastic
Dosage With Qualifiers Breast cancer—40 mg PO qid
Endometrial cancer palliation—10–80 mg PO qid
AIDS wasting syndrome—800 mg PO qd; alternative 400 mg PO bid

  • Contraindications —hypersensitivity to drug or class, first-trimester pregnancy, concurrent use of dofetilide due to increased risk of cardiac arrhythmias and cardiac arrest

  • Caution —recurrent or metastatic cancer, thromboembolic disease

Maternal Considerations Megestrol is a synthetic, progestational drug. It is used as an implantable contraceptive. There are no adequate reports or well-controlled studies of megestrol in pregnant women, nor are there any indications for its use. Megestrol is used to treat early endometrial cancer in young women who wish to preserve their fertility when possible. The largest study, 141 women with stage IA, grade 1 endometrial adenocarcinoma of the uterus, had complete remission after megestrol treatment. Seventy (49.6%) tried to conceive; 44 (62.9%) required fertility agents. The median interval to attempted pregnancy after treatment was 5 months (range: 1–31 months). The median age at the time of the attempted pregnancy was 32.4 y. Fifty-one (73%) conceived and 46 (66%) delivered 58 liveborns. The spontaneous abortion rate, ectopic pregnancy rate, and preterm delivery rate in the cohort were 24%, 2.8%, and 11.5%, respectively. The 5-y disease-free survival was similar between patients who received fertility drugs (n = 44) and those who did not (n = 97) (73% compared with 62%, P = NS). The rate was significantly higher in patients who achieved at least one pregnancy (n = 51) than in those who did not (n = 90) (76% compared with 62%, P = 0.028). Although the proportion of patients with a history of subfertility or infertility was high, the pregnancy outcomes were good using assisted reproductive technology. The use of fertility drugs was not associated with a higher incidence of cancer recurrence. As a treatment for weight loss in cancer patients, megestrol should be started only after other treatable causes are sought and addressed.
Side effects include weight increase, thrombophlebitis, PE, adrenal suppression, stroke, abdominal pain, amenorrhea, N/V, breast tenderness, weight gain, headache, edema, depression, rash, pruritus, libido changes, appetite changes, acne, hirsutism, alopecia, constipation, and cardiomyopathy.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether megestrol crosses the human placenta. There are case reports of abnormalities, including hypospadias.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. Small quantities of megestrol are excreted into human breast milk. However, megestrol has no clinically relevant effect on breast milk when used for contraception. Other progestins used for contraception appear compatible with breastfeeding.
Drug Interactions Use with indinavir results in an ∼ 36% decrease in the C max and ∼ 28% decrease for the AUC of indinavir. A higher dose is indicated. Pharmacokinetics studies reveal no significant alterations for either zidovudine or rifabutin.
References Abdel-Aleem H, Abol-Oyoun el-SM, Shaaban MM, et al. Contraception 1996; 54:281-6.
Farrar DJ, Aromin I, Uvin SC, et al. Genitourin Med 1997; 73:226.
Kowalczyk CL, Malone J Jr, Peterson EP, et al. J Reprod Med 1999; 44:57-60.
Lonnerdal B, Forsum E, Hambraeus L. Am J Clin Nutr 1980; 33:816-24.
Lowe MP, Bender D, Sood AK, et al. Fertil Steril 2002; 77:188-9.
Park JY, Seong SJ, Kim TJ, et al. Obstet Gynecol 2013; 121:136-42.
Summary Pregnancy Category: D (tablet), X (suspension)
Lactation Category: S (possibly)

  • There are no indications for megestrol use during pregnancy.

  • Megestrol appears compatible with breastfeeding.

Melatonin

International Brand Names

Many.

Drug Class Hormones, antioxidant
Indications Sleep promotion (jet lag), insomnia, seasonal affective disorder
Mechanism Secreted by the suprachiasmatic nuclei of the hypothalamus and directly influences circadian rhythms
Dosage With Qualifiers Sleep promotion (jet lag)—5 mg PO qd × 5 d
Insomnia—0.3–1 mg PO bid; should be given at 6 and 8 pm
NOTE: Melatonin is not regulated by the FDA and is sold OTC.

  • Contraindications— hypersensitivity to drug or class

  • Caution— CV disease

Maternal Considerations There are no adequate reports or well-controlled studies of melatonin in pregnant women. Melatonin is a natural hormone ( N -acetyl-5-methoxytryptamine) produced by the pineal gland with antioxidant properties. Its secretion is stimulated by the dark and inhibited by light. Secretion disturbances have been associated with depression. Rodent studies suggest that melatonin is involved in the initiation of parturition without having a direct effect on progesterone secretion. In humans, melatonin may also modulate myometrial function, as receptors are present.
Side effects include fatigue, depression, constriction of the coronary arteries, possible effects on fertility, and pruritus.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Melatonin rapidly crosses the isolated human placenta equal to the freely diffusible marker antipyrine. It stimulates glutathione peroxidase in the human chorion and inhibits the vasospastic effects of oxidized lipids. It also crosses the rodent placenta, and fetal rodents respond to the maternal melatonin rhythm. Melatonin may offer some protection for ischemia/reperfusion-induced oxidative mitochondrial damage to the fetal rat brain.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. In both human and rodent breast milk, melatonin is undetectable in the light but increases rapidly after dark. The M:P ratio ranges from 0.35 to 0.8, and melatonin is believed responsible for shifting the newborn to the circadian rhythm of the mother.
Drug Interactions No clinically relevant interactions identified.
References Goldman BD. Sci STKE 2003; 2003(192):PE29.
Illnerova H, Buresova M, Presl J. J Clin Endocrinol Metab 1993; 77:838-41.
Okatani Y, Wakatsuki A, Watanabe K, et al. J Pineal Res 2000; 29:74-80.
Parry BL, Meliska CJ, Sorenson DL, et al. Am J Psychiatry 2008; 165:1551-8.
Rowe SA, Kennaway DJ. Am J Physiol Regul Integr Comp Physiol 2002; 282:R797-804.
Schenker S, Yang Y, Perez A, et al. Clin Nutr 1998; 17:159-67.
Schlabritz-Loutsevitch N, Hellner N, Middendorf R, et al. J Clin Endocrinol Metab 2003; 88:908-13.
Wakatsuki A, Okatani Y, Shinohara K, et al. J Pineal Res 2001; 31:167-72.
Summary Pregnancy Category: B
Lactation Category: S

  • Melatonin should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Meloxicam

International Brand Names

Aflamid (Mexico); Artrilox (Indonesia); Dormelox (Brazil); Ecax (Chile); Exel (Mexico); Flodin (Peru); Loxibest (Mexico); Loxicam (Colombia); Masflex (Mexico); Mecox (Indonesia); Melcox (Korea); Melicam (Taiwan); Melocam (Colombia); Melocox (Korea); Mel-OD (India); Melosteral (Mexico); Melox (Hong Kong, Israel, Malaysia, Singapore, Thailand); Meloxin (Indonesia); Merapiran (Argentina); Mevamox (Brazil); Mexican (Colombia); Mexpharm (Indonesia); Mobec (Germany); Mobic (Colombia, England, Hong Kong, Ireland, Israel, Korea, New Zealand, Philippines, Singapore, South Africa, Taiwan, Thailand); Mobicox (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama); Mobiflex (Indonesia); Mopik (Taiwan); Movalis (Bulgaria, Czech Republic, Hungary, Poland); Movi-Cox (Indonesia); Movicox (Netherlands); Mowin (Peru); Muvera (India); Ostelox (Indonesia); Rafree (Malaysia); Rumonal (Colombia); Selektine (Israel)

Drug Class Analgesics, non-narcotic; NSAIDs
Indications Osteoarthritis
Mechanism Inhibits PGHS-II
Dosage With Qualifiers Osteoarthritis—7.5–15 mg PO qd; max 15 mg/d

  • Contraindications —hypersensitivity to drug or class, NSAID-induced asthma

  • Caution —nasal polyps, GI bleeding, hypertension, cardiac failure, asthma

Maternal Considerations Meloxicam is a nonsteroidal agent with antiinflammatory, analgesic and antipyretic activities. It has a long half-life compared with more popular NSAIDs. There is no published clinical experience during pregnancy. In the ewe, meloxicam is an inhibitor of uterine contractions. It is a modest inhibitor of preterm labor in rats treated with LPS. In vitro, meloxicam relaxes myometrial strips from pregnant and nonpregnant women, but it is less potent than celecoxib.
Side effects include anaphylaxis, GI bleeding, bronchospasm, renal failure, interstitial nephritis, hepatic failure, Stevens-Johnson syndrome, agranulocytosis, abdominal pain, constipation, headache, dizziness, rash, urticaria, elevated LFTs, drowsiness, edema, tinnitus, lupus, and serum sickness–like symptoms.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Meloxicam crosses the human placenta. The administration of high doses to rodents is associated with cardiac septal defects and embryotoxicity. Meloxicam attenuates RU486-stimulated labor in sheep. Because of the potential for premature closure of the fetal ductus arteriosus after maternal use of NSAIDs, chronic meloxicam treatment during pregnancy is not recommended without fetal monitoring.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether meloxicam enters human breast milk. It does enter rodent milk.
Drug Interactions NSAIDs may decrease the antihypertensive effect of ACEIs.
Use with aspirin (1000 mg tid) in healthy volunteers tends to increase the AUC (10%) and C max (24%) of meloxicam. The clinical significance is not known. As with other NSAIDs, concomitant use of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. The use of low-dose aspirin with meloxicam may increase the rate of GI ulceration or other complications.
Cholestyramine for 4 d increased the clearance of meloxicam by 50%, decreasing the t/2 from 19.2 h to 12.5 h, and the AUC 35%. This suggests the existence of a recirculation pathway for meloxicam in the GI tract.
NSAIDs reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. However, the pharmacokinetics and pharmacodynamics of both single and multiple doses of furosemide are unaffected by multiple doses of meloxicam.
Increases the mean predose lithium level and the AUC by 21% in healthy subjects compared to controls receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis.
Anticoagulant activity should be monitored, particularly the first few days after initiating or changing meloxicam therapy, in patients receiving warfarin or similar agents, as these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in healthy subjects receiving doses of warfarin that produced an INR between 1.2 and 1.8. In these subjects, meloxicam did not alter either warfarin pharmacokinetics or the the average anticoagulant effect of warfarin as determined by PT.
References Lee PR, Kim SR, Jung BK, et al. Am J Obstet Gynecol 2003; 189:261-6.
McKeown KJ, Challis JR, Small C, et al. Biol Reprod 2000; 63:1899-904.
Slattery MM, Friel AM, Healy DG, Morrison JJ. Obstet Gynecol 2001; 98:563-9.
Yousif MH, Thulesius O. J Pharm Pharmacol 1998; 50:681-5.
Summary Pregnancy Category: C
Lactation Category: U

  • Meloxicam should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • There are alternative agents for which there is more experience regarding use during pregnancy and lactation.

Melphalan — (Alkeran)

International Brand Names

Alkeran (Brazil, Canada, Chile, China, Colombia, Ecuador, Hong Kong, India, Indonesia, Japan, Korea, Mexico, Philippines, Taiwan, Thailand, Uruguay); Alkerana (Argentina)

Drug Class Antineoplastics, alkylating agent
Indications Multiple myeloma, ovarian cancer
Mechanism Alkylates and cross-links DNA
Dosage With Qualifiers Multiple myeloma—varies depending on tumor and protocol
Ovarian cancer—varies depending on tumor and protocol
NOTE: The most commonly recommended dose is 10 mg/d × 7–10 d. Continuous maintenance therapy with 2 mg/d is instituted when the WBC > 4000 cells/mL and the PLT > 100,000 cells/mL.

  • Contraindications —hypersensitivity to drug or class, hypersensitivity to chlorambucil, resistance to drug

  • Caution— renal failure, leukopenia, thrombocytopenia, anemia, leukemia

Maternal Considerations Melphalan is an alkylating agent. Although methotrexate is the primary choice for uncomplicated malignant trophoblastic disease, occasional resistance to methotrexate requires alternative drug regimens that may include melphalan (e.g., melphalan, actinomycin D, and methotrexate ). These regimens are more frequently associated with life-threatening hematologic toxicity compared with those regimens that include methotrexate. Women cured of either trophoblastic disease or ovarian cancer (usually stage 1A–C) using a drug regimen that includes melphalan can have successful pregnancies. Melphalan is also used to treat primary thrombocythemia and for marrow conditioning prior to allogeneic marrow transplantation. Women treated after age 32 are less likely to resume menstruation than younger women. There are no adequate reports or well-controlled studies of melphalan in pregnant women. There are only case reports of its use during an ongoing pregnancy.
Side effects include bone marrow suppression, N/V, diarrhea, pulmonary fibrosis and interstitial pneumonitis, skin hypersensitivity, vasculitis, alopecia, hemolytic anemia, anaphylaxis, stomatitis, and sterility.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether melphalan crosses the human placenta. Rodent studies reveal both embryotoxicity and teratogenicity. Anomalies include CNS and skeletal defects.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether melphalan enters human breast milk.
Drug Interactions Severe renal failure has been reported after a single dose of IV melphalan followed by standard oral doses of cyclosporine.
Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. The incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients when nalidixic acid and IV melphalan are given simultaneously.
References Curry SL, Blessing JA, DiSaia PJ, et al. Obstet Gynecol 1989; 73:357-62.
Maciejewska M, Snarski E, Wiktor-Jędrzejczak W. Exp Clin Transplant 2016; 14:665-9.
Schilder JM, Thompson AM, DePriest PD, et al. Gynecol Oncol 2002; 87:1-7.
Wiqvist N, Lundstrom V, Eneroth P. Acta Obstet Gynecol Scand 1976; 55:275-8.
Summary Pregnancy Category: D
Lactation Category: NS (possibly)

  • Melphalan is an effective part of multidrug regimens for the treatment of GTDs.

  • It should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • If possible, delay administration until the second trimester.

Meperidine — (Demerol; Doloneurin)

International Brand Names

Alodan “Gerot” (Austria); Centralgin (Switzerland); Cluyer (Argentina); Demero (Uruguay, Venezuela); Demerol HCl (Canada, Chile, Mexico, Philippines); Dolantin (Germany); Dolantina (Spain); Dolantine (Belgium); Dolargan (Hungary, Poland); Dolestine (Israel); Dolosal (Brazil); Dolsin (Czech Republic); Lydol (Bulgaria); Meperdol (Paraguay); Neomochin (Japan); Opistan (Japan); Pethidine (England, India, Korea); Pethidine Roche (South Africa); Pethidine Tablet (New Zealand); Petidin (Denmark, Finland, Norway, Sweden)

Drug Class Analgesics, narcotic; Anesthetics, adjunct
Indications Pain, preoperative sedation, obstetric analgesia
Mechanism Binds opioid receptors in the CNS
Dosage With Qualifiers Pain—50–150 mg PO/SC/IM q3–4 h; IM preferred over SC/IV
Preoperative sedation—50–100 mg SC/IM × 1, 30–60 min before surgery
Obstetric analgesia—50–100 mg SC/IM/IV q3–4 h; approximately 75 mg parenteral meperidine = 10 mg parenteral morphine
NOTE: Available in liquid, tablet, and parenteral forms; may be combined with promethazine; administer slowly and adjust dose based on CrCl.

  • Contraindications —hypersensitivity to drug or class, MAOI < 14 d

  • Caution —respiratory, hepatic, or renal dysfunction; seizure disorder; head injury; hypothyroidism; atrial flutter; convulsions

Maternal Considerations Meperidine is a synthetic narcotic qualitatively similar to morphine. It is metabolized to another active form, normeperidine. Historically, meperidine was perhaps the most commonly used parenteral opioid during labor for pain relief. Well-designed studies demonstrate that the incidence of cesarean delivery in nulliparous women with epidural analgesia is similar to IV meperidine though epidural has superior analgesia, less maternal sedation, and no need for neonatal naloxone. Fentanyl given SC is as effective for labor pain relief as IM meperidine , and it is associated with greater satisfaction, less sedation, shorter labors, fewer nursery admissions, and fewer difficulties establishing breastfeeding. When used for early labor analgesia, meperidine increases the prevalence of neonatal acidemia. It does not improve outcome when given for dystocia. Meperidine does not have in vitro a significant effect on the spontaneous contractions of gravid human myometrium. Postoperatively, PCEA with meperidine offers high-quality pain relief with few side effects.
Side effects include respiratory arrest and depression, cardiac arrest, tachydysrhythmias, dependency, abuse, vomiting, sweating, shock, agitation, disorientation, euphoria, dysphoria, weakness, dry mouth, flushing, visual disturbances, constipation, biliary tract spasm, palpitation, hypotension, syncope, pruritus, skin rashes, and pain at the site of injection.
Fetal Considerations Meperidine crosses the human placenta and significantly decreases the number of FHR accelerations. Maternal sedation may cause insufficient fetomaternal gas exchange and fetal acidemia. Meperidine achieves its highest concentration in fetal tissues 2–3 h after administration, correlating with the clinical observation that the maximal risk of neonatal depression occurs 2–3 h after maternal injection. Neonatal respiratory depression requiring resuscitation at delivery occurs. The greater the drug-to-delivery interval, the higher the fetal concentration of normeperidine and the lower the newborn’s performance on the Brazelton Neonatal Behavioral Assessment Scale. Spontaneous behavior and cognitive performance in exposed rhesus monkeys at 3–12 mo of age is altered by meperidine.
Breastfeeding Safety Meperidine is excreted into human breast milk, with peak levels occurring about 2 h after administration and a relative infant dose ranging from 1.1%–13.3%. The elimination half-life is also prolonged in infants (13 h). Although a single dose of meperidine has little impact on the nursing infant, repeated administration negatively affects the newborn. Nursing infants repeatedly exposed to morphine are more alert and oriented than those exposed repeatedly to meperidine. This makes morphine the preferred narcotic for lactating mothers.
Drug Interactions Use with caution and consider starting with a lower dose in patients who are concurrently receiving other CNS depressants, including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and ethanol. Drug-drug interactions may result in respiratory depression, hypotension, profound sedation, or coma if these drugs are taken in combination with the usual doses of meperidine.
Employ caution giving an agonist-antagonist analgesic (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine ) to a patient who has had or is receiving a pure opioid agonist analgesic such as meperidine. Mixed agonist-antagonist analgesics may reduce the analgesic effect of meperidine and/or precipitate withdrawal symptoms.
Acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
Cimetidine reduces both the clearance and volume of distribution of meperidine and the formation of normeperidine in healthy subjects.
Phenytoin may enhance the hepatic metabolism of meperidine and thus reduce its t/2 and bioavailability in healthy subjects.
Ritonavir increases the plasma concentrations of normeperidine and should be avoided.
May enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
References Belfrage P, Boreus LO, Hartvig P, et al. Acta Obstet Gynecol Scand 1981; 60:43-9.
Chestnut DH. Reg Anesth 1997; 22:495-9.
Clark A, Carr D, Loyd G, et al. Am J Obstet Gynecol 1998; 179:1527-33.
Fleet J, Belan I, Jones MJ, et al. BJOG 2015; 122:983-92.
Gambling DR, Sharma SK, Ramin SM, et al. Anesthesiology 1998; 89:1336-44.
Golub MS, Donald JM. Biol Neonate 1995; 67:140-8.
Head BB, Owen J, Vincent RD Jr, et al. Obstet Gynecol 2002; 99:452-7.
Herbst A, Wolner-Hanssen P, Ingemarsson I. Obstet Gynecol 1997; 90:125-30.
Kariniemi V, Rosti J. J Perinat Med 1986; 14:131-5.
Kuhnert BR, Kuhnert PM, Philipson EH, Syracuse CD. Am J Obstet Gynecol 1985; 151:410-5.
Kuhnert BR, Linn PL, Kennard MJ, Kuhnert PM. Anesth Analg 1985; 64:335-42.
Lurie S, Feinstein M, Heifetz C, Mamet Y. Int J Gynaecol Obstet 1999; 65:125-7.
Ngan Kee WD, Lam KK, Chen PP, Gin T. Anesth Analg 1997; 85:380-4.
Ngan Kee WD, Lam KK, Chen PP, Gin T. Anesthesiology 1996; 85:289-94.
Nguyen Thi TV, Orliaguet G, Ngu TH, Bonnet F. Reg Anesth 1994; 19:386-9.
Paech MJ, Moore JS, Evans SF. Anesthesiology 1994; 80:1268-76.
Peiker G, Muller B, Ihn W, Noschel H. Zentralbl Gynakol 1980; 102:537-41.
Ramin SM, Gambling DR, Lucas MJ, et al. Obstet Gynecol 1995; 86:783-9.
Sharma SK, Alexander JM, Messick G, et al. Anesthesiology 2002; 96:546-51.
Sharma SK, Sidawi JE, Ramin SM, et al. Anesthesiology 1997; 87:487-94.
Sheiner E, Shoham-Vardi I, Sheiner EK, et al. Arch Gynecol Obstet 2000; 263:95-8.
Solt I, Ganadry S, Weiner Z. Isr Med Assoc J 2002; 4:178-80.
Sosa CG, Balaguer E, Alonso JG, et al. Am J Obstet Gynecol 2004; 191:1212-8.
Sosa CG, Buekens P, Hughes JM, et al. Eur J Obstet Gynecol Reprod Biol 2006; 129:135-9.
Spigset O, Hagg S. Paediatr Drugs 2000; 2:223-38.
Thorp JA, Hu DH, Albin RM, et al. Am J Obstet Gynecol 1993; 169:851-8.
Vincent RD Jr, Chestnut DH. Am Fam Physician 1998; 58:1785-92.
Wittels B, Glosten B, Faure EA, et al. Anesth Analg 1997; 85:600-6.
Yoo KY, Lee J, Kim HS, Jeong SW. Anesth Analg 2001; 92:1006-9.
Summary Pregnancy Category: B
Lactation Category: NS (possibly)

  • There is a long clinical experience with meperidine during pregnancy and lactation that is reassuring overall.

  • Repeated use during labor leads to the accumulation of meperidine and normeperidine in fetal tissues, reaching a maximum about 3 h after administration.

  • Shorter-acting agents such as fentanyl are preferable to meperidine for labor analgesia.

  • Neonatal depression may occur 2–3 h after maternal administration.

  • Morphine is preferable to meperidine for postpartum analgesia in breastfeeding women.

Mephentermine — (This drug is not distributed in the United States.)

International Brand Names

Mephentermin (Bulgaria); Mephentine (India); Wyamine (Czech Republic, Greece)

Drug Class Adrenergic agonists; Pressors
Indications Hypotension
Mechanism Stimulates the release of NE/epinephrine
Dosage With Qualifiers Hypotension shock—1 mg/mL IV solution in D 5 W; may also be given as a stock solution of 30 mg/mL IV × 1
Hypotension spinal anesthesia—15 mg IV push × 1; may be repeated in 30 min; maintenance of BP accomplished by a continuous infusion of a 0.1% solution of mephentermine in D 5 W (1 mg/mL solution)

  • Contraindications —hypersensitivity to drug or class, hypotension induced by chlorpromazine, MAOI < 14 d

  • Caution —general anesthesia, CV diseases, hypertension, hyperthyroidism

Maternal Considerations Mephentermine is a synthetic sympathomimetic used to treat hypotension. It increases stroke volume and thus increases both systolic and diastolic BP. There is also a variable degree of peripheral vasoconstriction. Mephentermine increases HR by the release of epinephrine. There are no adequate reports or well-controlled studies of mephentermine in pregnant women. It has been used during pregnancy to restore or support uteroplacental blood flow after spinal or epidural analgesia. Though an RCT concluded ephedrine and mephentermine had similar efficacy, it has largely been abandoned in favor of ephedrine.
Side effects include nervousness, anxiety, arrhythmias, transient extrasystoles, AV block, and hypertension.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether mephentermine crosses the human placenta. Rodent teratogenicity studies have not been performed. Studies in animals and humans reveal fetal hypoxia after mephentermine presumably secondary to uterine artery constriction and decreased uterine blood flow. Transient fetal hypertension (mean arterial BP > 20% of control) is also reported.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether mephentermine enters human breast milk.
Drug Interactions Cyclopropane and halothane anesthetics increase cardiac automatic irritability and therefore seem to sensitize the myocardium to the action of catecholamine. Hence, use during cyclopropane and halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or VF. The same type of cardiac arrhythmias may result from catecholamines in patients with profound hypoxia or hypercarbia.
References Chestnut DH, Ostman LG, Weiner CP, et al. Anesthesiology 1988; 68:363-6.
James FM 3rd, Greiss FC Jr, Kemp RA. Anesthesiology 1970; 33:25-34.
Kansal A, Mohta M, Sethi AK, et al. Anaesthesia 2005; 60:28-34.
Lauckner W, Schwarz R, Retzke U. Zentralbl Gynakol 1978; 100:217-21.
Ralston DH, Shnider SM, DeLorimier AA. Anesthesiology 1974; 40:354-70.
Senties L, Arellano G, Casellas A, et al. Am J Obstet Gynecol 1970; 107:892-7.
Summary Pregnancy Category: C
Lactation Category: U

  • Mephentermine is an alternative to ephedrine for the management or prevention of hypotensive episodes following spinal and epidural analgesia.

Mephobarbital

International Brand Names

Prominal (Australia, England, Spain)

Drug Class Anticonvulsants; Barbiturates; Hypnotics; Sedatives
Indications Seizure disorder (grand mal and petit mal epilepsy), anxiety
Mechanism Alters sensory cortex, cerebellar, and motor activities; induces sedation, hypnosis, and anesthesia
Dosage With Qualifiers Seizure disorder—400–600 mg PO qd
Anxiety—50 mg PO tid or qid

  • Contraindications —hypersensitivity to drug or class, porphyria, psychological dependence on barbiturates

  • Caution —rickets, osteomalacia, vitamin K or C deficiencies, hepatic dysfunction

Maternal Considerations Seizure control should be sought prior to pregnancy. There are no adequate reports or well-controlled studies of mephobarbital in pregnant women. Clearance is altered by pregnancy and may require frequent adjustment through the puerperium. Barbiturates are hepatic enzyme inducers and alter the clearance of many other drugs. The dose of mephobarbital must be increased in 85% of pregnancies to maintain therapeutic levels.
Side effects include drowsiness, sedation, hypnosis, marked excitement, depression, confusion, respiratory depression, erythema multiforme, Stevens-Johnson syndrome, angioedema, megaloblastic anemia, TTP, urticaria, blood dyscrasias, thrombophlebitis, necrosis, dependence, hepatitis, and swelling.
Fetal Considerations There are no adequate reports or well-controlled studies of mephobarbital in human fetuses. Barbiturates rapidly cross the human placenta, reaching F:M ratios approaching unity. Retrospective case-control studies suggest a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. The great majority of women on anticonvulsant medication deliver normal infants. Rodent teratogenicity studies have not apparently been conducted with mephobarbital.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether mephobarbital enters human breast milk. Small amounts of other barbiturates are excreted.
Drug Interactions Most reports of clinically significant drug interactions with the barbiturates have involved phenobarbital. However, the application of this experience to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies.
May lower the plasma levels of dicumarol (name previously used: bishydroxycoumarin ), thus causing a decrease in the PT. Barbiturates induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response to oral anticoagulants (e.g., acenocoumarol, dicumarol, phenprocoumon, warfarin ). Patients stabilized on anticoagulant therapy may require dose adjustments should a barbiturate be added or withdrawn from their regimen.
May enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added or withdrawn.
May interfere with the absorption of oral griseofulvin, decreasing the blood level.
May shorten the t/2 of doxycycline, probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic, for as long as 2 w after barbiturate therapy is discontinued. The clinical response to doxycycline should be monitored closely.
Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be measured more frequently if these drugs are given concurrently. Valproate and valproic acid appear to decrease barbiturate metabolism; therefore barbiturate blood levels should be monitored and appropriate adjustments made as indicated.
Use with other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or ethanol, may produce additive depressant effects.
MAOIs prolong the effects of barbiturates probably because metabolism of the barbiturate is inhibited.
Pretreatment or concurrent use may decrease the effect of estradiol by increasing its metabolism. There have been reports of women treated with phenobarbital who become pregnant while taking oral contraceptives.
References Lander CM, Eadie MJ. Epilepsia 1991; 32:257-66.
Summary Pregnancy Category: D
Lactation Category: U

  • Mephobarbital should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • There are alternative agents for which there is more experience during pregnancy and lactation.

Meprobamate — (Amosene; Atacin; Disatral; Equanil; Mepriam; Meproban-400; Meprospan; Miltown; Neuramate; Oasil-Simes; Probate; Procalmadiol; Sinanin; Trancot; Tranmep)

International Brand Names

Andaxin (Hungary); Ansiowas (Spain); Apo-Meprobamate (Canada); Atraxin (Japan); Distoncur (Argentina); Epikur (Austria); Harmonin (Japan); Meprin (Argentina); Mepro (Israel); Meprodil (Switzerland); Miltaun (Austria, Germany); Oasil (Belgium); Pertranquil (Austria, Belgium); Placidon (Argentina); Praol (Greece); Procalmidol (Belgium); Quanil (Italy); Restenil (Sweden); Sycropaz (Argentina); Visanon (Germany)

Drug Class Anxiolytics
Indications Anxiety
Mechanism Unknown; has effects on multiple CNS sites, including thalamus and limbic system
Dosage With Qualifiers Anxiety—400 mg PO bid; max 2400 mg/d

  • Contraindications —hypersensitivity to drug or class, alcohol consumption

  • Caution —job requiring driving or operating machinery

Maternal Considerations There are no adequate reports or well-controlled studies of meprobamate in pregnant women. Meprobamate decreases clearance of alcohol in rodents during pregnancy.
Side effects include dependence, ataxia, slurred speech, vertigo, anxiety, anorexia, insomnia, vomiting, tremors, muscle twitching, confusional states, hallucinosis, convulsive seizures, paresthesias, impairment of visual accommodation, euphoria, overstimulation, paradoxic excitement, palpitation, tachycardia, arrhythmia, transient ECG changes, syncope, hypotension, maculopapular rash, leukopenia, acute nonthrombocytopenic purpura, petechiae, ecchymoses, eosinophilia, peripheral edema, adenopathy, fever, anaphylaxis, exfoliative dermatitis, stomatitis, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, thrombocytopenic purpura, coma, shock, and vasomotor and respiratory collapse.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Meprobamate crosses the human placenta. Several studies suggest an increased prevalence of malformations associated with the first-trimester use of tranquilizers such as meprobamate, chlordiazepoxide, and diazepam. However, there was no clear evidence of either teratogenicity or fetotoxicity following attempted maternal suicide with very large doses. Use monotherapy given at the lowest effective dose given divided to minimize the peaks. Although rodent studies reveal that meprobamate reduces the learning ability of mature rodent offspring, this effect is not seen in humans.
Breastfeeding Safety Meprobamate is concentrated in breast milk (about 2–4 times higher than maternal plasma), leading to neonatal sedation. There are better alternatives such as alprazolam and lorazepam .
Drug Interactions No clinically significant interactions identified.
References Belafsky HA, Breslow S, Hirsch LM, et al. Obstet Gynecol 1969; 34:378-86.
Hartz SC, Heinonen OP, Shapiro S, et al. N Engl J Med 1975; 292:726-8.
Leonard BE. Arch Toxicol Suppl 1982; 5:48-58.
Nordeng H, Zahlsen K, Spigset O. Ther Drug Monit 2001; 23:298-300.
Rawat AK. Adv Exp Med Biol 1980; 132:561-8.
Rosenberg JM. N Y State J Med 1975; 75:1334-5.
Timmermann G, Acs N, Banhidy F, Czeizel AE. Toxicol Ind Health 2008; 24:97-107.
Summary Pregnancy Category: D
Lactation Category: NS (possibly)

  • Meprobamate should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • It is rarely required during pregnancy and should be avoided at least during the first trimester.

Mercaptopurine — (Purinethol)

International Brand Names

Classen (Japan); Empurine (Philippines, Thailand); Ismipur (Italy); Leukerin (Japan); Mercaptopurina (Spain); Puri-Nethol (Austria, Belgium, Brazil, Bulgaria, China, Czech Republic, Denmark, Ecuador, England, Finland, Germany, Hong Kong, India, Indonesia, Ireland, Korea, Malaysia, Norway, Paraguay, Sweden, Switzerland, Taiwan, Thailand, Uruguay); Purinethol (Argentina, Australia, Canada, Chile, France, Greece, Italy, Mexico, Netherlands, Philippines, Poland, Russia)

Drug Class Antineoplastics, antimetabolite; Immunomodulators
Indications Leukemia (acute lymphocytic and acute myelogenous), Crohn’s disease, ulcerative colitis
Mechanism Unknown; multiple biochemical effects leading to cell death
Dosage With Qualifiers Acute lymphocytic leukemia—numerous dosing schedules depending on disease, response, and concomitant therapy
AML—numerous dosing schedules depending on disease, response, and concomitant therapy
Crohn’s disease—75–125 mg PO qd; max 1.5 mg/kg/d
Ulcerative colitis—begin with 50 mg PO qd; typical dose 75–125 mg PO qd; max 1.5 mg/kg/d
NOTE: Monitor CBC qw × 4 then qmo and LFTs q3mo after induction or during maintenance of remission; discontinue temporarily with evidence of an abnormally large decrease in WBC or platelet count, or Hb concentration.

  • Contraindications —hypersensitivity to drug or class, renal dysfunction

  • Caution —bone marrow suppression

Maternal Considerations Azathioprine is metabolized to 6-mercaptopurine. Mercaptopurine and azathioprine are the most commonly used immunomodulatory agents and are therefore the most commonly used agents during pregnancy in women with inflammatory bowel disease (IBD). In addition to the listed indications, mercaptopurine is used as an adjunct to prevent organ rejection after transplantation. There are no adequate reports or well-controlled studies in pregnant women. IBD can be challenging during pregnancy. Women with quiescent disease are likely to have an uncomplicated pregnancy, whereas those with active disease are more likely to suffer spontaneous abortion, stillbirth, IUGR, and exacerbation of disease. Treatment with either azathioprine or mercaptopurine does not increase the risks of an adverse pregnancy outcome. In women considering pregnancy, an active episode should be treated aggressively and remission accomplished before pregnancy is attempted. Women who unexpectedly conceive while the disease is active should be treated aggressively, as remission provides the greatest hope for a favorable outcome. The treatment of AML typically involves a complex drug regimen that includes mercaptopurine. Multiple case reports suggest the use of mercaptopurine can produce a complete and sustained remission while ending with the delivery of a normally developed infant.
Side effects include leukopenia, thrombocytopenia, anemia, hepatotoxicity, urate nephropathy, nephrolithiasis, diarrhea, fever, N/V, anorexia, jaundice, abdominal pain, edema, and bleeding.
Fetal Considerations There are no adequate reports or well-controlled studies of mercaptopurine in human fetuses. It likely crosses the human placenta, as transient but severe neonatal bone marrow hypoplasia is reported. The impact of mercaptopurine use during the first trimester on development is controversial. Retrospective studies conclude there is no increased prevalence of anomalies. However, more recent population-based cohort studies conclude the risk of malformation is increased more than sixfold. In another study, the incidence of fetal loss was higher in women with IBD previously treated with mercaptopurine compared with those who had not been so treated. Whether this was related to their older age at conception, longer duration of disease, initially more severe disease, or use of mercaptopurine could not be determined. Although it was suggested mercaptopurine increases the risk of spontaneous first-trimester abortion, it proved a poor abortifacient in one prospective trial. Exposure during the second and third trimesters does affect the fetal immune system, and birth weight may be reduced. Toxic effects on the neonatal pancreas, liver, and lymphocytes are reported. Rodent studies reveal teratogenicity perhaps mediated by DNA modification or drug-induced changes in mineral metabolism (zinc). Malformations include cleft palate, micrognathia and agnathia, microglossia, short limbs, and gut herniation. Zinc supplementation reduces the risk of an adverse effect.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether mercaptopurine enters human breast milk. Until such data become available, it is perhaps best to avoid immunosuppressive medications while breastfeeding. Infliximab may be a reasonable alternative.
Drug Interactions Reduce the dose of mercaptopurine one-third to one-fourth when allopurinol and mercaptopurine are used together to avoid severe toxicity.
There is usually complete cross-resistance between mercaptopurine and thioguanine.
Dose may need to be reduced if combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.
Inhibition of the anticoagulant effect of warfarin has been reported when given with mercaptopurine .
There is in vitro evidence that aminosalicylate derivatives (e.g., mesalamine, olsalazine, sulphasalazine ) inhibit the TPMT enzyme. They should be used cautiously in patients receiving mercaptopurine.
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Summary Pregnancy Category: D
Lactation Category: NS (possibly)

  • Mercaptopurine is one of the most commonly used drugs for the treatment of inflammatory bowel disease (IBD).

  • Women with ulcerative colitis should be advised to conceive when their disease is quiescent.

  • Mercaptopurine should be used during pregnancy only if the benefit justifies the potential perinatal risk. It is contraindicated during lactation.

  • Zinc supplementation may reduce the risk of an adverse perinatal effect.

Meropenem — (Merrem IV)

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