L - Clinical Tree

Labetalol — (Coreton; Normadate; Normodyne; Trandate)

International Brand Names

Abetol (Italy); Albetol (Finland); Amipress (Italy); Biascor (Argentina); Hybloc (New Zealand); Ipolab (Italy); Labelol (Argentina); Labesine (Korea); Lamitol (Slovenia); Liondox (Argentina); Presolol (Australia, Taiwan); Pressalolo (Italy); Salmagne (Greece); Trandate (Austria, Belgium, Canada, Chile, Czech Republic, Denmark, England, France, Hong Kong, Hungary, Ireland, Italy, Japan, Korea, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, Taiwan, Turkey, Venezuela)

Drug Class	Adrenergic antagonists; α- and β-Blockers; Antihypertensives
Indications	Hypertension
Mechanism	Selective α ₁ - and nonselective β ₁ - and β ₂ -adrenergic receptor antagonist
Dosage With Qualifiers	Hypertension—begin 100 mg PO bid, increase 100 mg bid q2–3 w; max 2.4 g/d Acute hypertension—if diastolic BP > 105 mmHg, administer incremental dosing of 5–10 mg IV, with a cumulative dose of 40–80 mg IV over 20 min; max 300 mg IV Contraindications —hypersensitivity to drug or class, asthma, CHF, AV block, cardiogenic shock, bradycardia, hepatotoxicity, hypoglycemia Caution —MI, angina, diabetes mellitus, hepatic or renal dysfunction, cocaine, abrupt withdrawal, major surgery NOTE: Manufacturing shortages of the parenteral drug were reported in 2017 that could limit availability. NOTE: Maternal clearance of oral labetalol increased significantly during pregnancy.
Maternal Considerations	Hypertensive disorders complicate 5%–10% of pregnancies and are a leading cause of maternal and perinatal morbidity and death. Severe hypertension (systolic BP > 160 mmHg and/or diastolic BP > 110 mmHg) should be treated rapidly to reduce the risk of stroke, death, and possibly eclampsia in preeclamptic women. It is suggested that hypotensive treatment be initiated when the systolic pressure exceeds 150 mmHg because the risk of intracranial hemorrhage escalates once the systolic pressure exceeds 160 mmHg. The target systolic pressure should be in the 140s mmHg. Both IV labetalol and oral nifedipine are effective in patients with severe preeclampsia before and after delivery. However, patients on labetalol often respond better to the starting dose and have fewer side effects. Labetalol reduces BP more slowly than nifedipine, and it does not increase the maternal cardiac index like nifedipine does. There is no consensus about whether mild to moderate hypertension should be treated during pregnancy. The risks of transient severe hypertension, the likelihood of antenatal hospitalization, proteinuria at delivery, and neonatal RDS may be decreased by therapy. Labetalol has a lower risk of hypotension than parenteral hydralazine. Labetalol is better tolerated than methyldopa and provides more efficient BP control. It reduces cerebral pressure without altering cerebral perfusion. IV labetalol is equally effective as IV hydralazine for the treatment of postpartum hypertension. Labetalol may also be useful for the treatment of maternal thyrotoxicosis during labor. *Side effects* include hepatic necrosis, SLE, bronchospasm, dizziness, N/V, fatigue, dyspepsia, rhinitis, dyspnea, edema, postural hypotension, pruritus, and increased BUN/Cr.
Fetal Considerations	Labetalol crosses the human placenta, yielding an F:M ratio of 0.5 and an AF:M ratio < 0.20. Neither labetalol nor hydralazine vasodilates the perfused human cotyledon. Doppler flow studies reveal no change in umbilical, uterine, and middle cerebral resistances after treatment. IV labetalol can cause fetal bradycardia. The available data are inadequate to determine whether labetalol adversely affects the fetal or neonatal HR or the fetal HR pattern. Until such data are available, FHR changes should not be attributed to a drug effect but rather to progression of the underlying maternal or placental disease. Hypoglycemia, bradycardia, hypotension, pericardial effusion, and myocardial hypertrophy are reported after long-term oral labetalol. Fetal death may also occur after a sudden drop in the maternal BP, the risk of which can be minimized by adequate hydration. Overall, neonatal outcome is similar to that achieved with hydralazine. Labetalol may be useful for the treatment of fetal thyrotoxicosis. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically. Labetalol reduces uteroplacental blood flow selectively in guinea pigs, perhaps explaining the increased frequency of IUGR in this model.
Breastfeeding Safety	There is no consistent relation between maternal plasma and milk concentrations either within or between individuals. The risk of hypoglycemia in breastfed neonates is increased by labetalol but may be blunted with glucose-fortified formula.
Drug Interactions	May increase the risk of tremor when taken with TCAs. May blunt the bronchodilator effect of β-agonists; therefore greater than normal doses of a β-agonist may be required for the treatment of asthma. Cimetidine increases the bioavailability of labetalol. Special care should be used in establishing the dose required for BP control in such patients. Synergism with halothane has been shown. High concentrations (> 3%) should not be used because the degree of hypotension will increase and because of the possibilities of a large reduction in cardiac output and an increase in the central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol. Blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. Additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type. Patients with a history of anaphylaxis to a variety of allergens may be more reactive to repeated challenge, whether accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
References	Belfort MA, Tooke-Miller C, Allen JC Jr, et al. Hypertens Pregnancy 2002; 21:185-97. Bowman ML, Bergmann M, Smith JF. Thyroid 1998; 8:795-6. Crooks BN, Deshpande SA, Hall C, et al. Arch Dis Child Fetal Neonatal Ed 1998; 79:F150-1. el-Qarmalawi AM, Morsy AH, al-Fadly A, et al. Int J Gynaecol Obstet 1995; 49:125-30. Gilson GJ, Kramer RL, Barada C, et al. J Matern Fetal Med 1998; 7:142-7. Harper A, Murnaghan GA. Br J Obstet Gynaecol 1991; 98:453-9. Hjertberg R, Faxelius G, Belfrage P. Acta Obstet Gynecol Scand 1993; 72:611-5. Hjertberg R, Faxelius G, Lagercrantz H. J Perinat Med 1993; 21:69-75. Petersen OB, Skajaa K, Svane D, et al. Br J Obstet Gynaecol 1994; 101:871-8. Pickles CJ, Broughton Pipkin F, Symonds EM. Br J Obstet Gynaecol 1992; 99:964-8. Pirhonen JP, Erkkola RU, Makinen JI, Ekblad UU. Biol Neonate 1991; 59:204-8. Rogers RC, Sibai BM, Whybrew WD. Am J Obstet Gynecol 1990; 162:362-6. Scardo JA, Vermillion ST, Newman RB, et al. Am J Obstet Gynecol 1999; 181:862-6. Sharma KJ, Greene N, Kilpatrick SJ. Hypertens Pregnancy. 2016; 27:1-4. Shekhar S, Gupta N, Kirubakaran R, Pareek P. BJOG. 2016;123:40-7. Shi DD, Yang FZ, Zhou L, Wang N. J Clin Pharm Ther 2016; 41:657-61. Varon J, Marik PE. Chest 2000; 118:214-27. Vermillion ST, Scardo JA, Newman RB, Chauhan SP. Am J Obstet Gynecol 1999; 181:858-61. Vigil-De Gracia P, Ruiz E, López JC, et al. Hypertens Pregnancy 2007; 26:163-71.
Summary	Pregnancy Category: C Lactation Category: S Labetalol is an effective agent for the treatment of acute hypertension and thyrotoxicosis during labor. In many locales, labetalol is the preferred drug for the short-term treatment of preeclamptic hypertension. Hypoglycemia, but not IUGR, is the most common adverse neonatal effect.

Lactulose — (Acilac; C-Cephulose; Cephulac; Cholac; Constilac; Constulose; Duphalac; Enulose; Evalose; Generlac; Heptalac; Laxilose)

International Brand Names

Acilac (Canada); Actilax (Australia); Alpha-Lactulose (New Zealand); Avilac (Israel); Bifinorma (Germany); Bifinorma Granulat (Germany); Bifiteral (Belgium, Germany); Danilax (Hong Kong); Dhactulose (Malaysia, Singapore); Dia-Colon (Italy); Duphalac (Austria, Belgium, Bulgaria, Chile, China, Czech Republic, Ecuador, England, Finland, France, Greece, Hong Kong, Hungary, Indonesia, Ireland, Italy, Japan, Korea, Malaysia, Netherlands, Norway, Paraguay, Philippines, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey); Farlac (Brazil); Genlac (Australia); Genocolan (Argentina); Hepalac (Thailand); Lacson (South Africa); Lactocur (Germany); Lactul (Malaysia); Lactulax (El Salvador, Honduras, Indonesia, Israel, Mexico, Panama, Peru, Uruguay); Lactulen (Colombia); Lactumed (Malaysia); Lactus (Singapore); Lactuverlan (Germany); Laevolac (Austria, Czech Republic, Hong Kong, Hungary, Israel, Italy, Portugal, Switzerland, Thailand); Laxette (South Africa); Laxilose (Canada); Laximed (Germany); Levolac (Finland, Norway); Lipebin (Peru); Livo Luk (India); Martulose (Hong Kong); Moderan (Venezuela); Monilac (Japan, Korea); Normolax (Israel); Pralax (Indonesia); Regulact (Mexico); Sirolax (Israel); Tenualax (Argentina); Tulotract (Germany)

Drug Class	Gastrointestinals; Laxatives
Indications	Constipation, hepatic encephalopathy
Mechanism	Increases stool water content, traps ammonium ions
Dosage With Qualifiers	Constipation—15–30 mL (10–20 g/d) PO qd or bid Hepatic encephalopathy—30–45 mL PO tid or qid (20–30 g tid or qid) Contraindications —hypersensitivity to drug or class, galactosemia Caution —diabetes mellitus, hypokalemia
Maternal Considerations	Constipation is common during pregnancy. Lactulose helps restore normal bowel habits. It is poorly absorbed, and women with lactose intolerance tolerate lactulose better in the third trimester because of slow transit and bacterial adaptation. Some use it to maintain a soft stool after delivery complicated by rectal extension. In one randomized controlled trial, lactulose proved safe and effective for the treatment of postpartum constipation compared with placebo. *Side effects* include acidosis, abdominal distention, belching, abdominal pain, diarrhea, anorexia, N/V, electrolyte disorders, hypernatremia, and flatulence.
Fetal Considerations	There are no adequate reports or well-controlled studies of lactulose in human fetuses. Because of poor maternal absorption, it is unlikely the maternal systemic concentration will reach a clinically relevant level. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether lactulose enters human breast milk. Because of poor maternal absorption, it is unlikely the maternal systemic concentration will reach a clinically relevant level. Breastfeeding infants require lactase to metabolize lactose, the major carbohydrate in breast milk. Lactase is located on the small intestinal brush border and is extremely vulnerable to pathogenic damage.
Drug Interactions	There are conflicting reports about use with neomycin. Theoretically, the elimination of certain colonic bacteria by neomycin and possibly other antiinfective agents may interfere with the desired breakdown of lactulose and thus prevent the acidification of colonic contents. Use with nonabsorbable antacids may inhibit the desired lactulose -induced drop in colonic pH. Other laxatives should not be used, especially during the initial phase of therapy for portal-systemic encephalopathy because the loose stools resulting from their use may falsely suggest that an adequate lactulose dosage has been achieved.
References	Baglioni A, Dubini F. Boll Chim Farm 1976; 115:596-606. Eogan M, Daly L, Behan M, et al. BJOG 2007; 114:736-40. Gattuso JM, Kamm MA. Drug Saf 1994; 10:47-65. Huang P, Gou WL, Wang XT, et al. J Biol Regul Homeost Agents 2016; 30:523-8. Mizuno O. Endocrinol Jpn 1987; 34:449-55. Northrop-Clewes CA, Lunn PG, Downes RM. J Pediatr Gastroenterol Nutr 1997; 24:257-63. Signorelli P, Croce P, Dede A. Minerva Ginecol 1996; 48:577-82. Szilagyi A, Salomon R, Martin M, et al. Clin Invest Med 1996; 19:416-26.
Summary	Pregnancy Category: B Lactation Category: S Most laxatives are relatively safe during pregnancy if used intermittently as directed.

Lamivudine — (Epivir; Epivir HBV; 3 TC)

International Brand Names

3TC (Argentina, Canada, Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Hong Kong, Indonesia, Korea, Malaysia, Mexico, New Zealand, Nicaragua, Panama, South Africa, Uruguay); 3TC-HBV (Indonesia); Epivir (Brazil, Ecuador, Paraguay, Peru, Singapore, Thailand, Venezuela); Epivir 3TC (Chile); Heptodin (China); Heptovir (Canada); Inhavir (Colombia); Ladiwin (South Africa); Lamidac (India); Zeffix (Australia, Israel, Philippines, Singapore, Taiwan, Thailand)

Drug Class	Antivirals; Nucleoside reverse transcriptase inhibitors
Indications	HIV infection, HBV infection
Mechanism	Reverse transcriptase inhibitor
Dosage With Qualifiers	HIV infection—150 mg PO bid HBV infection—100 mg PO qd Contraindications —hypersensitivity to drug or class Caution —hepatic or renal dysfunction, pancreatitis, long-term therapy, obesity
Maternal Considerations	There are no adequate reports or well-controlled studies of lamivudine in pregnant women. Lamivudine is rapidly absorbed after oral administration, reaching maximal serum concentrations after 30–90 min. Triple therapy for HIV ( zidovudine, lamivudine, nevirapine ) is a highly effective regimen, though genotypic resistance to lamivudine may occur rapidly. HIV therapy that reduces the viral load significantly reduces the risk of mother-to-child transmission. Hepatotoxicity, usually within 5 mo of beginning therapy, is a major concern during pregnancy. It is most severe when associated with HBV and HCV co-infection. There are presently two drugs for the treatment of hepatitis B during pregnancy: interferon alfa-2b and lamivudine. The initial response to lamivudine is superior to that for interferon alfa-2b. Lamivudine is reportedly safe in pregnant women with chronic HBV infection during the last weeks of pregnancy. However, reduced HBV particle number does not necessarily translate to decreased vertical transmission, and resistant HBV strains have been identified. US federal government guidelines recommend zidovudine plus lamivudine for health care personnel exposed to both HBV and HIV. Based on registry data, lamivudine -containing regimens have lower risks for spontaneous abortion, induced abortion, and preterm birth compared with non- lamivudine antiretroviral regimens. *Side effects* include acidosis, hepatic steatosis or toxicity, pancreatitis, neuropathy, neutropenia, thrombocytopenia, rhabdomyolysis, and exacerbation of hepatitis B.
Fetal Considerations	The worldwide spread of HIV-1 has resulted in an estimated 1 million children born yearly to HIV-1–infected mothers. In the absence of antiretroviral intervention, about 25% are HIV-1 infected. Maternal AZT prophylaxis reduces the rate of neonatal transmission to some 7%, with further reductions with combination therapy including lamivudine. Lamivudine readily crosses the human placenta; the AF:M ratio reportedly varies from unity to 4. This level does not necessarily prevent HBV transmission to the perinate despite undetectable maternal viral DNA. Large trials are awaited. Relative and absolute polymerase chain reaction quantification reveals a three- to fourfold mean increase in MDR1 placental transcription in HIV-infected women. Further, there is a 2.5-fold increase of immunoreactive P-glycoprotein in placentas from HIV-infected women. This overexpression of MDR1 occurs regardless of antiretroviral therapy and suggests that P-glycoprotein in placentas of HIV-infected women could modulate the maternofetal transport of antiretrovirals across the placental barrier and, as a result, decrease fetal exposure to these compounds. One randomized trial of women with HBV compared lamivudine to telbivudine to no treatment (NTx). At gestation week 28, the mothers received lamivudine or telbivudine until postpartum week 4 or no treatment. Of the 700 mothers enrolled, 648 ( telbivudine / lamivudine /NTx = 252/51/345) completed the 52-week study with 661 infants. Viral rebound occurred in 1.6% of mothers, all due to noncompliance. At delivery, significantly lower HBV DNA levels were noted in mothers who received telbivudine or lamivudine versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers ( P < 0.001). At week 52, an intention-to-treat analysis indicated 2.2% HBsAg + infants from the treated group versus 7.6% in the NTx group ( P < 0.001). There was no difference in HBsAg + rate between infants in the telbivudine and lamivudine groups (1.9% vs. 3.7%; P = 0.758).
	Neonatal prophylaxis with both zidovudine and lamivudine is initiated within 12 h of birth. Mitochondrial disorders are described in children exposed in utero to some reverse transcriptase enzyme inhibitors (e.g., zidovudine ). Although rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically, embryotoxicity occurs in rabbits. In monkeys, lamivudine becomes incorporated into the DNA of multiple fetal organs, and telomere shortening occurs. In human infants, lamivudine incorporation as well as HPRT and glycophorin A assay (GPA) mutagenesis have been documented in cord blood from infants exposed in utero to zidovudine and lamivudine. Given the risk-to-benefit ratio, these highly successful drugs will continue to be used to prevent vertical viral transmission; however, evidence of genotoxicity suggests exposed children should be followed well past adolescence for early detection of potential cancer hazard.
Breastfeeding Safety	There are no adequate reports or well-controlled studies in nursing women. Lamivudine is excreted into human breast milk, with a relative infant dose of between 4.3%–6.4%. Breastfeeding is contraindicated in HIV-infected nursing women where formula is available to reduce the risk of neonatal transmission. In women receiving zidovudine, lamivudine, and nevirapine (HAART) from 28 w of gestation until 1 mo postpartum, the median M:P ratios were 1.1, 0.6, and 1.8, respectively. HIV RNA levels in breast milk were significantly lower than in untreated women (median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at day 7; P < 0.001 for both comparisons). Almost 90% of treated women have less than 50 copies/mL compared with only one-third of untreated women. DNA loads are unaffected. Thus antiretroviral agents administered during the third trimester and after delivery reach levels similar to or higher than plasma concentrations in breast milk, can significantly reduce HIV RNA levels, and support the potential role of maternal HAART prophylaxis in reducing the risk of breastfeeding-associated transmission. Further, HIV-1 inhibitory concentrations of nevirapine are achieved in breastfeeding infants, exposing infants to the potential beneficial and adverse effects of nevirapine.
Drug Interactions	Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Their combined use is not recommended.
References	Bloom SL, Dias KM, Bawdon RE, Gilstrap LC 3rd. Am J Obstet Gynecol 1997; 176:291-3. Camus M, Deloménie C, Didier N, et al. Placenta 2006; 27:699-706. Chappuy H, Treluyer JM, Jullien V, et al. Antimicrob Agents Chemother 2004; 48:4332-6. Clarke JR, Braganza R, Mirza A, et al. J Med Virol 1999; 59:364-8. Giuliano M, Guidotti G, Andreotti M, et al. J Acquir Immune Defic Syndr 2007; 44:286-91. Hill JB, Sheffield JS, Zeeman GG, Wendel GD Jr. Obstet Gynecol 2001; 98:909-11. Johnson MA, Moore KH, Yuen GJ, et al. Clin Pharmacokinet 1999; 36:41-66. Kazim SN, Wakil SM, Khan LA, et al. Lancet 2002; 359:1488-9. Lee LM, Henderson DK. Drug Saf 2001; 24:587-97. Mandelbrot L, Landreau-Mascaro A, Rebacewic ZC, et al. JAMA 2001; 285:2083-93. Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Am J Obstet Gynecol 2001; 184:153-8. Moodley D, Pillay K, Naidoo K, et al. J Clin Pharmacol 2001; 41:732-41. Olivero OA, Fernandez JJ, Antiochos BB, et al. J Acquir Immune Defic Synd 2002; 29:323-9. Poirier MC, Olivero OA, Walker DM, Walker VE. Toxicol Appl Pharmacol 2004; 199:151-61. Shapiro RL, Holland DT, Capparelli E, et al. J Infect Dis 2005; 192:720-7. Shapiro RL, Ndung’u T, Lockman S, et al. J Infect Dis 2005; 192:713-9. Stojanov S, Wintergerst U, Belohradsky BH, Rolinski B. AIDS 2000; 14:1669. Trautwein C. Schweiz Rundsch Med Prax 2002; 91:970-6. Vannappagari V, Koram N, Albano J, Tilson H, Gee C. J Acquir Immune Defic Syndr. 2015; 68:359-64. van Nunen AB, de Man RA, Heijtink RA, et al. J Hepatol 2000; 32:1040-1. Yong S, Liu M, Wong L. Zhonghua FuChan Ke Za Zhi 2008; 43:329-31. Zhang H, Pan CQ, Pang Q, Tian R, Yan M, Liu X. Hepatology. 2014;60:468-76. Zoulim F. Drug Saf 2002; 25:497-510.
Summary	Pregnancy Category: C Lactation Category: NS A cocktail of zidovudine, lamivudine, and nevirapine significantly reduces the risk of mother-to-child transmission antenatally and postnatally, and it remains a standard for the treatment of adult HIV infection. Pregnant women should be monitored closely for hepatotoxicity after initiating therapy. Physicians are encouraged to register pregnant women under the Antiretroviral Pregnancy Registry (1-800-258-4263) for a better follow-up of the outcome while under treatment with lamivudine.

Lamotrigine — (Lamictal)

International Brand Names

Lamepil (India); Lamictin (South Africa); Lamodex (Israel); Lamogine (Israel); Lamotrix (Malaysia); Neurium (Brazil)

Drug Class	Anticonvulsants
Indications	Seizures (partial)
Mechanism	Unknown
Dosage With Qualifiers	Seizures—begin 50 mg/d, then increase up to 50–250 mg PO bid; max 500 mg/d NOTE: Avoid abrupt withdrawal. Contraindications —hypersensitivity to drug or class, abrupt withdrawal Caution —hepatic or renal dysfunction, allergy to valproate
Maternal Considerations	Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. There are no adequate reports or well-controlled studies of lamotrigine during pregnancy. Concerns over teratogenicity of AEDs must be weighed against the risks of seizures to the mother and fetus. Lamotrigine is by far the most extensively studied of the newer AEDs. Lamotrigine clearance increases during pregnancy, and many women require a higher dose to maintain therapeutic levels. Pronounced alterations have been reported, with an increase of > 300% from baseline in late pregnancy in some patients on monotherapy. Seizure deterioration during pregnancy may be prevented or reduced by closely monitoring the serum levels. Lamotrigine is an inhibitor of dihydrofolate reductase. Adequate folate supplementation beginning at preconception is wise. The impact of pregnancy on clearance reverses quickly postpartum. The most frequent adverse maternal effect is skin rash, typically in the first month of treatment. Planned pregnancy and counseling before conception is crucial. Counseling should cover folate supplementation, the importance of medication compliance, the risk of teratogenicity, and the importance of prenatal care. Lamotrigine increases the metabolism of ethinyl estradiol and progestogens; a preparation containing at least 50 mcg of ethinyl estradiol is recommended. *Side effects* include rash (0.3% and may be life threatening), dysmenorrhea, dizziness, ataxia, somnolence, diplopia, headache, blurred vision, N/V, dyspepsia, rhinitis, anxiety, insomnia, pain, weight decrease, chest pain, infection, aplastic anemia, hemolytic anemia, thrombocytopenia, hepatic failure, aphasia, confusion, and nystagmus.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. Lamotrigine crosses the human placenta, achieving an F:M ratio near unity. Lamotrigine was measured in six mother-infant pairs at the time of delivery. Maternal daily doses (200 and 650 mg) correlated with maternal and umbilical cord serum concentrations, and the serum levels correlated with amniotic fluid levels. Lamotrigine inhibits dihydrofolate reductase, an enzyme necessary for the biosynthesis of nucleic acids and proteins. Women taking anticonvulsant medication of any type have a 4%–8% risk of delivering a child with a birth defect compared with 2%–4% in the general population. A Cochrane review of the literature concluded that levetiracetam and lamotrigine exposure carried the lowest overall risk of malformation compared to untreated women with epilepsy or women treated with other antiepileptic agents. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR at doses analogous to humans. The highest doses cause maternal and fetal toxicity characterized by IUGR and ventricular dilation. Though some data are conflicting, registry data do not reveal a significant increase in the risk of major malformation (2.8% for first-trimester exposure with monotherapy, but 4.3% with polytherapy). Use of monotherapy at the lowest effective quantity given in divided doses to minimize the peaks can minimize the risks. Pregnancy databases suggest valproate is significantly more teratogenic than carbamazepine, and the combination of valproate and lamotrigine is particularly teratogenic.
Breastfeeding Safety	The median M:P ratio ranges from 0.5–0.8, 2–3 w postpartum. The relative infant dose ranges from 9.2%–18.3%, and nursed infants achieve plasma concentrations approximating 30% of the mother’s plasma level. Breastfed infants should be monitored for side effects. Adverse symptoms are rarely reported in breastfed infants of mothers taking lamotrigine or any other AEDs, and prospective studies have failed to demonstrate any negative developmental effects in children who have been exposed to antiepileptic agents via breast milk.
Drug Interactions	Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with co-administration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone. The addition of valproate may increase lamotrigine steady-state concentrations by slightly more than twofold. The addition of carbamazepine, phenobarbital, phenytoin, or primidone can decrease lamotrigine steady-state concentrations by approximately 40%. The AUC and C _max of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine (15 mg qd) to lamotrigine (200 mg qd) in healthy male volunteers (n = 16) compared with healthy male volunteers receiving lamotrigine alone (n = 12). This reduction in lamotrigine concentration is not expected to be clinically relevant. In a study in 10 male volunteers, rifampin (600 mg/d for 5 d) increased the apparent clearance of a single 25-mg dose of lamotrigine by twofold (AUC decreased by approximately 40%). An inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism. In a study of an oral contraceptive preparation containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel, the apparent clearance of lamotrigine (300 mg/d) increased some twofold with a mean decrease in AUC of 52% and in C _max of 39%. Trough serum lamotrigine concentrations gradually increased and were twofold higher at the end of the week of the inactive preparation. Gradual but transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week) for women not also taking a drug that increases the clearance of lamotrigine (e.g., carbamazepine, phenobarbital, phenytoin, primidone, rifampin ). The increase in lamotrigine levels will be greater if the dose of lamotrigine is increased in the few days before or during the pill-free week. Dosage adjustments may be necessary for women receiving oral contraceptive preparations.
	Did not affect the pharmacokinetics of the ethinyl estradiol component of an oral contraceptive preparation containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel. However, there was a decrease in the AUC and C _max of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis. The effects of doses of lamotrigine other than 300 mg/d have not been studied. The possibility of decreased contraceptive efficacy in some patients cannot be excluded, and women should be instructed to promptly report changes in their menstrual pattern (e.g., breakthrough bleeding).
References	Bar-Oz B, Nulman I, Koren G, Ito S. Paediatr Drugs 2000; 2:113-26. Crawford P. CNS Drugs 2002; 16:263-72. Crawford P. Epilepsia 2005; 46(Suppl 9):117-24. Cunnington M, Ferber S, Quartey G; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Epilepsia 2007; 48:1207-10. Dolk H, Jentink J, Loane M, et al. Neurology 2008; 71:714-22. Greenhalgh J, Hounsome J, McKay AJ, et al. Cochrane Database Syst Rev 2016; 11:CD010224. Marchi NS, Azoubel R, Tognola WA. Arq Neuropsiquiatr 2001; 59:362-4. Ohman I, Vitols S, Tomson T. Epilepsia 2000; 41:709-13. Paulzen M, Lammertz SE, Veselinovic T, Goecke TW, Hiemke C, Gründer G. Int Clin Psychopharmacol. 2015;30:249-54. Sabers A, Gram L. Drugs 2000; 60:23-33. Tennis P, Eldridge RR; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Epilepsia 2002; 43:1161-7. Tran TA, Leppik IE, Blesi K, et al. Neurology 2002; 59:251-5. Veiby G, Bjørk M, Engelsen BA, Gilhus NE. Seizure. 2015;28:57-65. Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Williams J, Myson V, Steward S, et al. Epilepsia 2002; 43:824-31.
Summary	Pregnancy Category: C Lactation Category: S (likely) Lamotrigine is well tolerated and drug interaction problems are modest with the possible exception of oral contraceptive failure. Lamotrigine should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Lansoprazole — (Lopral; Ogastro; Prevacid; Zoton)

International Brand Names

Agopton (Austria, Germany, Switzerland); Betalans (Indonesia); Compraz (Indonesia); Daxar (Belgium); Digest (Indonesia); Ilsatec (Mexico); Inhipraz (Indonesia); Keval (Mexico); Lancid (Korea); Lancopen (Colombia); Langaton (Korea); Lanpra (Korea); Lanpraz (Colombia); Lanprol (Israel); Lanproton (Colombia); Lansazol (Israel); Lansone (Hungary); Lansop (Korea); Lansopep (Colombia); Lansozole (Korea); Lanster (Korea); Lanston (Korea); Lanvell (Indonesia); Lanximed (Colombia); Lanz (Philippines); Lanzol-30 (India); Lanzopral (Argentina, Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama, Paraguay, Peru, Uruguay, Venezuela); Lanzor (France, Germany, South Africa); Lanzul (Poland); Lapraz (Indonesia); Laproton (Indonesia); Lasgan (Indonesia); Laz (Indonesia); Lopral (Colombia, Peru); Neutron (Colombia); Ogast (France); Ogastro (Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru); Praton (Korea); Prevacid (Canada, Malaysia, Philippines, Singapore, Thailand); Prezal (Netherlands); Prolanz (Indonesia); Prosogan (Indonesia); Pysolan (Indonesia); Sopralan-30 (Indonesia); Suprecid (Philippines); Takepron (China, Hong Kong, Japan, South Africa, Taiwan); Takepron OD (Hong Kong); Ulpax (Mexico); Zoton (England, Ireland, Israel, Italy); Zoton Fastab (England, Ireland)

Drug Class	Gastrointestinals; Proton pump inhibitors
Indications	GERD, esophagitis, gastric or duodenal ulcer, H. pylori infection, hypersecretory conditions, stress ulcer, ulcer prophylaxis
Mechanism	Hydrogen-potassium ATPase inhibitor
Dosage With Qualifiers	GERD—15–30 mg PO qd or bid × 8 w Esophagitis—30 mg PO qd or bid × 8 w Gastric ulcer—30 mg PO qd or bid × 8 w Duodenal ulcer—15 mg PO qd or bid × 8 w H. pylori infection—30 mg PO bid × 10–14 d Hypersecretory conditions—60 mg PO qd; max 90 mg PO bid Stress ulcer—15–30 mg PO, through feeding tube Ulcer prophylaxis—15–30 mg PO qd Contraindications —hypersensitivity to drug or class Caution —long-term use, hepatic dysfunction
Maternal Considerations	The effect of estrogen and progesterone on lower esophageal sphincter tone is a recognized factor. GERD or heartburn occurs in 45%–85% of women during pregnancy, and its treatment consists of reducing gastric acidity following a step-up algorithm beginning with lifestyle modifications and dietary changes. Antacids or sucralfate are first-line medical therapy, followed by histamine receptor antagonists. Ranitidine is probably preferred because of its documented efficacy and safety profile in pregnancy, even in the first trimester. Proton pump inhibitors should be reserved for the woman with intractable symptoms or complicated reflux disease. Proton pump inhibitors like lansoprazole are generally considered effective treatment for GERD in pregnant women. Adverse effects have not been reported. Further, proton pump inhibitors are first-line agents for the prevention of “aspiration syndrome” during general anesthesia. Lansoprazole has also been used with apparent success to treat a woman with Zollinger-Ellison syndrome during pregnancy. *Side effects* include hepatic failure, blood dyscrasias, Stevens-Johnson syndrome, erythema multiforme, pancreatitis, toxic epidermal necrolysis, headache, diarrhea, asthenia, candidiasis, chest pain, CVA, hypertension/hypotension, hypomagnesemia, MI, and palpitations.
Fetal Considerations	There are no well-controlled studies in human fetuses. It is unknown whether lansoprazole crosses the human placenta. Epidemiologic and postmarketing surveillance studies are reassuring, reporting no evidence of teratogenicity. Rodent studies too are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether lansoprazole enters human breast milk. It is excreted into rodent milk.
Drug Interactions	Metabolized through the CYP3A and CYP2C19 isozymes. When given with theophylline (metabolized by CYP1A2, CYP3A), a minor increase (10%) in theophylline clearance occurs. Thus some women may require titration of their theophylline dosage when lansoprazole is started or stopped. There have been reports of increased INR and PT in patients receiving proton pump inhibitors such as lansoprazole with warfarin. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored more closely. In a single-dose crossover study examining lansoprazole 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 g, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively. Therefore proton pump inhibitors should be taken at least 30 min prior to sucralfate. May interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ampicillin, digoxin, iron, ketoconazole ).
References	Broussard CN, Richter JE. Drug Saf 1998; 19:325-37. Diav-Citrin O, Arnon J, Shechtman S, et al. Aliment Pharmacol Ther 2005; 21:269-75. Ramakrishnan A, Katz PO. Curr Treat Options Gastroenterol 2002; 5:301-10. Richter JE. Gastroenterol Clin North Am 2003; 32:235-61.
Summary	Pregnancy Category: B Lactation Category: U Lansoprazole should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Latanoprost — (Xalatan)

International Brand Names

Louten (Colombia)

Drug Class	Ophthalmics; Prostaglandins
Indications	Elevated intraocular pressure
Mechanism	Increases aqueous humor outflow
Dosage With Qualifiers	Elevated intraocular pressure—1 gt (1.5 mcg) OS/OD qd Contraindications —hypersensitivity to drug or class Caution —asthma
Maternal Considerations	The published experience with latanoprost during pregnancy is limited to case reports. *Side effects* include epithelial keratitis, blurred vision, eyelid skin darkening, intraocular inflammation, iris pigmentation changes, macular edema, burning, hyperemia, foreign body sensation, itching, dry eyes, tearing, photophobia, ocular pain, discharge, rash, lid crusting, and asthma/exacerbation of asthma.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether latanoprost crosses the human placenta. Considering the dose and route, it is unlikely the maternal systemic concentration will reach a clinically relevant level. Embryotoxicity was observed in rodents treated with a dosage more than 15 × the MRHD.
Breastfeeding Safety	There is no published experience in pregnancy. It is unknown whether latanoprost enters human breast milk. However, considering the dose and route, it is unlikely the breastfed neonate would ingest clinically relevant amounts.
Drug Interactions	A precipitate occurs when eyedrops containing thimerosal are mixed with latanoprost. Such drugs should be administered at least 5 min apart.
References	DeSantis M, Lucchese A, Carducci B, et al. Am J Ophthalmol 2004; 138:305-6.
Summary	Pregnancy Category: C Lactation Category: S (likely) Latanoprost should be used during pregnancy and lactation only if the benefit justifies the potential risk.

Leflunomide — (Arava)

International Brand Names

Arabloc (Australia); Arava (Israel)

Drug Class	Antirheumatics; Immunomodulators
Indications	Rheumatoid arthritis
Mechanism	Pyrimidine synthesis inhibitor with antiproliferative activity
Dosage With Qualifiers	Rheumatoid arthritis—begin 100 mg PO qd × 3 d, then 10–20 mg PO qd NOTE: Check level q14d (normal above 0.02 mcg/mL). Contraindications —hypersensitivity to drug or class, pregnancy Caution —immunodeficiency, blood dyscrasias, bone marrow suppression, infections, HBV or HCV infection
Maternal Considerations	The published literature during pregnancy is limited to case reports of first-/second-trimester exposures. Based on animal study (see Fetal Considerations), leflunomide is contraindicated during pregnancy, and effective contraception is a must. Women desiring pregnancy must discontinue leflunomide before conceiving, preferably at least 4 mo before. Further, the manufacturer recommends preconception treatment with cholestyramine to increase drug elimination with subsequent verification that plasma levels are less than 0.02 mg/L. *Side effects* include hepatotoxicity, immunosuppression, leukopenia, pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, diarrhea, alopecia, N/V, headache, RDS, dyspepsia, rash, back pain, pruritus, asthenia, allergic reactions, dizziness, weight loss, and paresthesias.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. Leflunomide likely crosses the human placenta. No pattern of malformations has been reported in infants exposed to leflunomide, but the number of reported pregnancy outcomes is small. In an ongoing prospective controlled study of rheumatoid arthritis (RA) medications in pregnancy being conducted by OTIS, data on pregnancy exposures and outcomes were collected from 45 pregnant women between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women preconception. All 16 exposed pregnancies and 27 (93%) of the pregnancies with exposure prior to conception yielded liveborn infants. There were 2 infants with major malformations in mothers exposed during pregnancy, but none in the preconception exposure group. There was a potential known alternative etiology for at least some of the defects observed. These findings provide some reassurance that leflunomide is unlikely to be a major human teratogen. The incidences of anophthalmia and microphthalmia are increased in rats treated with only 0.1 × the concentration recommended in humans. In rabbits, a dose analogous to the human is associated with embryotoxicity and bony abnormalities.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether leflunomide enters human breast milk. In light of the animal studies, it is best to avoid breastfeeding if leflunomide must be prescribed.
Drug Interactions	Cholestyramine or activated charcoal produces a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide ). The prevalence of side effects increases when leflunomide is given with hepatotoxic substances. This is also a risk when leflunomide is followed by such drugs. In one small study with methotrexate, one-third of patients experienced a twofold or greater increase in hepatic enzymes. All elevations resolved, four despite continuation of both drugs and six after discontinuation of leflunomide. Three patients met “ACR criteria” for liver biopsy (1: Roenigk Grade I, 2: Roenigk Grade IIIa). No pharmacokinetic interaction was identified. M1 was shown in in vitro studies to cause increases ranging from 13% to 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. Although the clinical significance of this finding is unknown, there was extensive use of NSAIDs in clinical studies and no differential effect was observed. M1 was shown in in vitro studies to increase the free fraction of tolbutamide 13%–50% at concentrations in the clinical range. The clinical significance of this finding is unknown. M1 peak levels were increased (∼ 40%) after concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin. Increased INR has been rarely reported when leflunomide and warfarin are co-administered.
References	Brent RL. Teratology 2001; 63:106-12. Cassina M, Johnson DL, Robinson LK, et al. Arthritis Rheum 2012; 64:2085-94. Chambers C, Koren G, Tutuncu ZN, et al. Can Fam Physician 2007; 53:409-12. DeSantis M, Shaface G, Cavaliere A, et al. Ann Rheum Dis 2005; 64:1096-7. Elefant E, Chambers C, da Silva J, et al. Ann Rheum Dis 2016; 75:795-810. Götestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Kraemer B, Abele H, Hahn M, et al. Hypertens Pregnancy 2008; 27:247-52. Neville CE, McNally J. Rheumatology 2007; 46:1506. Prakash A, Jarvis B. Drugs 1999; 58:1137-64.
Summary	Pregnancy Category: X Lactation Category: U Leflunomide is a potent teratogen in some rodents; however, human data are far less ominous. Until more conclusive data is available, women receiving leflunomide should use effective contraception and avoid pregnancy. Health care providers are encouraged to register patients by calling 1-877-311-8972 to improve knowledge of fetal outcomes of pregnant women exposed to leflunomide. There are alternative agents for which there is more experience during pregnancy and lactation.

Lepirudin — (Refludan)

International Brand Names

Refludin (South Africa)

Drug Class	Anticoagulants; Thrombin inhibitors
Indications	Thrombocytopenia, heparin-induced
Mechanism	Direct inhibitor of thrombin independent of ATIII
Dosage With Qualifiers	Heparin-induced thrombocytopenia/thrombosis—begin 0.4 mg/kg, then 0.15 mg/kg/h IV; max 44 mg Contraindications —hypersensitivity to drug or class Caution —bleeding; renal dysfunction; increased risk of bleeding, including AV malformations; hypertension; recent surgery
Maternal Considerations	Heparin-induced thrombocytopenia is a rare but potentially life-threatening reaction to both heparin and LMWH. It is the most common drug-induced immune-mediated thrombocytopenia. Lepirudin effectively treats the thrombocytopenia by inhibiting thrombin. Many patients develop antibodies (40%), and the aPTT should be monitored during long-term therapy. The published experience during pregnancy is limited to 13 cases, including first-trimester treatment. *Side effects* include bleeding, anemia, hematuria, intracranial hemorrhage, fever, GI bleeding, increased LFTs, and epistaxis.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether lepirudin crosses the human placenta; it does cross the rat placenta. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether lepirudin enters human breast milk.
Drug Interactions	Use with thrombolytics (e.g., rt-PA, streptokinase ) may increase the risk of bleeding complications and considerably enhance the effect of lepirudin on aPTT prolongation. Use with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding.
References	Dager WE, White RH. Ann Pharmacother 2002; 36:489-503. Furlan A, Vianello F, Clementi M, Prandoni P. Haematologica 2006; 91(8 Suppl):ECR40. McCrae KR, Bussel JB, Mannucci PM, et al. Hematology (Am Soc Hematol Educ Program) 2001; 282-305. Young SK, Al-Mondhiry HA, Vaida SJ, et al. Pharmacotherapy 2008; 28:1531-6.
Summary	Pregnancy Category: B Lactation Category: S (likely) Heparin-induced thrombocytopenia is the most frequently encountered drug-induced, immune-mediated adverse thrombocytopenia. Therapeutic options are limited.

Letrozole — (Femara)

International Brand Names

None identified.

Drug Class	Antineoplastics, aromatase inhibitor
Indications	Breast cancer
Mechanism	Inhibits aromatase
Dosage With Qualifiers	Breast cancer—2.5 mg PO qd Contraindications —hypersensitivity to drug or class Caution —renal dysfunction
Maternal Considerations	Letrozole is a nonsteroidal aromatase inhibitor that significantly lowers estradiol and estrone. It is used mostly for adjuvant therapy. Letrozole has also been used to treat infertility associated with poor response to FSH stimulation. There is no published experience during pregnancy, though limited reports suggest it is at least as effective as clomiphene . *Side effects* include thromboembolism, muscular pain, N/V, fatigue, arthralgia, cough, chest pain, hot flashes, diarrhea, abdominal pain, viral infection, edema, hypertension, and anorexia.
Fetal Considerations	There are no well-controlled studies in human fetuses. It is unknown whether letrozole crosses the human placenta. There is no difference in the overall rates of major and minor congenital malformations among newborns of women who conceived after letrozole or clomiphene treatments. However, it appears that congenital cardiac anomalies were less frequent in the letrozole group. Letrozole is embryotoxic, fetotoxic, and teratogenic in rodents even at low doses. Because in the primate estrogen modulates placental vascular endothelial growth/permeability factor expression and angiogenesis, letrozole could conceptually impact placentation.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether letrozole enters human breast milk.
Drug Interactions	Use with tamoxifen (20 mg daily) reduced letrozole plasma levels by 38%. There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.
References	Albrecht ED, Robb VA, Pepe GJ. J Clin Endocrinol Metab 2004; 89:5803-9. Forman R, Gill S, Moretti M, et al. J Obstet Gynaecol Can 2007; 29:668-71. Mitwally MF, Casper RF. Fertil Steril 2002; 77:776-80. Roque M, Tostes AC, Valle M, Sampaio M, Geber S. Gynecol Endocrinol 2015; 31:917-21.
Summary	Pregnancy Category: D Lactation Category: U Letrozole is an adjuvant agent for the treatment of breast cancer. Letrozole should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Leucovorin — (Calcium folinate; Citrovorum factor; Lerderfoline; Ledervorin-Calcium; Wellcovorin)

International Brand Names

Antrex (Finland); Asovorin (Argentina); Calciumfolinat-Ebewe (Taiwan); Calcium Leucovorin (Australia); Citrec (Sweden); Folina 15 (Thailand); Folinoxan (Philippines); Lederfolin (England, Italy, Spain); Lederfoline (France); Lederle Leucovorin (Canada); Ledervorin Calcium (Belgium, Netherlands); Leucocalcin (Paraguay); Leucovorin (Austria, Bulgaria, Czech Republic, Denmark, England, Finland, Germany, Greece, Hungary, Ireland, New Zealand, Norway, Sweden, Switzerland, Thailand, Uruguay); Leucovorina Calcica (Peru); Leucovorine Abic (Netherlands); Litacor (Philippines); Lovorin (Philippines); Medsavorin (Mexico); Nyrin (Korea, Malaysia); Oncofolic (Germany); Refolinon (England); Rescufolin (Norway); Rescuvolin (Belgium, Denmark, Germany, Greece, Indonesia, Israel, Korea, Philippines, Sweden, Switzerland, Thailand); Robin (Korea); Rontafur (Argentina); Tecnovorin (Brazil, Ecuador)

Drug Class	Antidotes; Toxicology; Vitamins/minerals
Indications	Leucovorin rescue after folate inhibition
Mechanism	Counteracts folate antagonists
Dosage With Qualifiers	Leucovorin rescue—15 mg IV/IM/PO q6h 24 h after last methotrexate dose Contraindications —hypersensitivity to drug or class, vitamin B ₁₂ deficiency, pernicious anemia, megaloblastic anemia Caution —seizure disorder
Maternal Considerations	Gestational trophoblastic disease is a spectrum of disorders ranging from the benign complete or partial hydatidiform mole to malignant choriocarcinoma. Although the preponderance of women are cured by surgery, the occasional patient requires chemotherapy. Methotrexate, an inhibitor of dihydrofolate reductase, is the first-line agent. It can persist in human tissue for long periods. Leucovorin is a derivative of tetrahydrofolate and as such circumvents the metabolic block. Supplementation minimizes toxicity and can counteract inadvertent overdose. Methotrexate may be given as a single dose IM, which usually does not require leucovorin, or in a multiple-dose regimen, which does require leucovorin rescue. Methotrexate with leucovorin rescue is a highly effective, well-tolerated, nonsurgical treatment for patients with ectopic pregnancy. *Side effects* include anaphylactic reaction, seizures, syncope, urticaria, and N/V.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses (see folic acid ). Folate is quickly transferred across the placenta. Rodent teratogenicity studies have not been conducted. Periconceptional folate supplementation increases fertility (higher cumulative rates of multiple births). A deficiency of folic acid increases the incidence of NTDs, and randomized studies reveal that 4 mg/d of folic acid prior to conception prevents their recurrence. It is not known whether leucovorin supplementation would have the same effect.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether leucovorin enters human breast milk.
Drug Interactions	Large amounts of folic acid may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone, and they may increase the frequency of seizures in susceptible patients. May enhance the toxicity of 5-fluorouracil. Preliminary animal and human studies reveal that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain one to three orders of magnitude lower than the usual methotrexate concentration following intrathecal administration. High doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.
References	Barnhart K, Coutifaris C, Esposito M. Expert Opin Pharmacother 2001; 2:409-17. Bruno MK, Harden CL. Curr Treat Options Neurol 2002; 4:31-40. Czeizel AE, Dudas I, Metneki J. Arch Gynecol Obstet 1994; 255:131-9. Elit L, Covens A, Osborne R, et al. Gynecol Oncol 1994; 54:282-7. Gillespie AM, Kumar S, Hancock BW. Br J Cancer 2000; 82:1393-5. Homesley HD. J Reprod Med 1994; 39:185-92. Kendall A, Gillmore R, Newlands E. Curr Opin Obstet Gynecol 2002; 14:33-8. Kwon JS, Elit L, Mazurka J, et al. Gynecol Oncol 2001; 82:367-70. Larson DM, Tipping SJ, Mulligan GM, et al. Wis Med J 1995; 94:664-7. McNeish IA, Strickland S, Holden L, et al. J Clin Oncol 2002; 20:1838-44. Newlands ES, Bower M, Holden L, et al. J Reprod Med 1998; 43:111-8. Wegner C, Nau H. Neurology 1992; 42:17-24.
Summary	Pregnancy Category: C Lactation Category: U Leucovorin should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

Leuprolide — (Lupron; Procren)

International Brand Names

Carcinil (Germany); Enanton Depot (Denmark, Finland, Norway, Sweden); Enantone (Austria, France, Germany); Enantone Depot (Italy); Enantone LP (Thailand); Enantone SR (China, Hong Kong); Leuplin (Korea); Leuplin Depot (Taiwan); Lorelin Depot (Hong Kong, Korea); Lucrin (France, Hong Kong, Korea, Malaysia, Mexico, Portugal, Singapore); Lucrin Depot (Belgium, Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Hungary, Israel, Korea, Mexico, Netherlands, Nicaragua, Panama, Singapore, Switzerland, Turkey); Lupride (India); Lupride Depot (India); Luprolex (Philippines); Luprolex Depot (Philippines); Lupron (Argentina, Brazil, Canada, Chile, Colombia, Ecuador, Paraguay, Uruguay, Venezuela); Lupron Depot (Argentina, Brazil, Canada, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, Venezuela); Procren Depot (Denmark, Finland, Norway, Sweden); Procrin (Spain); Prostap (England, Ireland); Reliser (Mexico); Tapros (Indonesia)

Drug Class	Antineoplastics, hormone modifier
Indications	Endometriosis, uterine fibroids
Mechanism	Inhibits the release of the gonadotropins by suppressing ovarian steroidogenesis
Dosage With Qualifiers	Endometriosis—3.75 mg IM qmo Uterine fibroids—3.75 mg IM qmo NOTE: Administer iron and check the bone mineral density if treatment extends longer than 3 mo. Contraindications —hypersensitivity to drug or class, undiagnosed vaginal bleeding Caution —bone metastases, osteoporosis, psychiatric disorder, depression
Maternal Considerations	Gonadotropin-releasing agonists are important for the treatment of infertility and are often used with IVF. There are no adequate reports or well-controlled studies of leuprolide during pregnancy, nor is there an indication for its use. *Side effects* include angina, cardiac arrhythmias, MI, pulmonary emboli, spinal cord compression, paralysis, bone density loss, erythema multiforme, libido decrease, thyroid enlargement, anxiety, blurred vision, lethargy, memory disorder, mood swings, itching, nervousness, numbness, paresthesias, cough, pleural rub, pneumonia, dry skin, ecchymosis, hair loss, local skin reactions, pigmentation, skin lesions, pulmonary fibrosis, dysuria, incontinence, leukopenia, hemoptysis, pelvic fibrosis, hair growth, and hypoproteinemia.
Fetal Considerations	There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether leuprolide crosses the human placenta. No malformations are reported in women inadvertently exposed to leuprolide during pregnancy. However, early exposure of a male fetus may lead to micropenis. Rodent studies reveal a dose-dependent increase in the incidence of major malformations and IUGR.
Breastfeeding Safety	There is no published experience in nursing women. It is unknown whether leuprolide enters human breast milk.
Drug Interactions	No clinically relevant interactions identified.
References	McMahon DR, Kramer SA, Husmann DA. J Urol 1995; 154:825-9. Tan HH, Yeong CT, Loh KE. Aust N Z J Obstet Gynaecol 2006; 46:336-40. Tay CC. Hum Fertil 2002; 5:G35-7.
Summary	Pregnancy Category: X Lactation Category: U Leuprolide is currently contraindicated during ongoing pregnancy. Barrier contraception is recommended if therapy is initiated for indications other than infertility. No malformations are described in women inadvertently exposed to leuprolide.