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I


Ibuprofen — (Advil; Alaxan; Artril; Bloom; Brofen; Dolofen; Emflam; Fenspan; Ibren; Ibugen; Ibuprohm; Ibu-Tab; Ifen; Motrin; Nobafon; Paduden; Paxofen; Profen; Prontalgin; Tarein)

International Brand Names

Actron (Paraguay, Uruguay); Adex 200 (Israel); Adex Liqui-Gels (Israel); Advil (Brazil, Colombia, Ecuador, France, Hong Kong, Mexico, Poland, Venezuela); Advil Infantil (Mexico); Advil Liqui-Gels (Israel); Afebril (Peru); Algofen (Italy); Allipen (Korea); Am-Fam 400 (India); Ampifen (Singapore); Anadvil (France); Anbifen (Thailand); Anco (Germany); Andran (Japan); Anflagen (Japan); Antarene (France); Antiflam (South Africa); Apo-Ibuprofen (Canada); Atril 300 (Brazil); Balkaprofen (South Africa); Bestafen (Mexico); Betaprofen (South Africa); Bifen (Hong Kong, Singapore); Bluton (Japan); Brufanic (Japan); Brufen (Bangladesh, Hungary, India, Indonesia, Israel, New Zealand, Pakistan, Poland, Slovenia, South Africa, Spain); Brufen 400 (Israel); Brufen Retard (New Zealand); Brufort (Italy); Brugesic (South Africa); Brumed (Thailand); Buburone (Japan); Bufect (Indonesia); Bufect Forte (Indonesia); Bupogesic (Hong Kong); Burana (Finland); Butacortelone (Mexico); Carol (Korea); Cenbufen (Thailand); Childrens Motrin (Indonesia); Combiflam (India); Cuprofen (Thailand); Dibufen (Mexico); Diffutab SR 600 (Korea); Dolan FP (Philippines); Dolgit (Germany, Taiwan); Dolocyl (Switzerland); Dolofen-F (Indonesia); Dolomax (Peru); Dolormin (Germany); Doloxene (Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama); Dolval (Mexico); Donjust B (Japan); Dorival (Spain); Drin (Greece); Druisel (Argentina); Easifon (Taiwan); Emflam-200 (India); Emodin (Argentina); Epobron (Japan); Expanfen (France); Febratic (Mexico); Febryn (Indonesia); Fenbid (England); Flamicon (Philippines); Focus (Italy); Gyno-neuralgin (Germany); H-Loniten (Colombia); IB-100 (Japan); Ibosure (Netherlands); Ibufen (Israel, Malaysia); Ibuflam (Mexico); Ibufug (Germany); Ibugesic (India); Ibuloid (Singapore); Ibumetin (Denmark, Finland, Netherlands, Norway, Sweden); Ibupen (Hong Kong); Ibupirac (Argentina); Ibuprocin (Japan); Iburon (Korea); Ibusal (Finland); Ibu-slow (Belgium); Idyl SR (Philippines); Infibu (Colombia); Ipren (Denmark, Korea, Russia, Sweden); Irfen (Switzerland); Isdol (Spain); Isodol (Spain); Lamidon (Japan); Librofem (Spain); Liptan (Japan); Lopane (Thailand); Medicol (Philippines); Mensoton (Germany); Mobilat (China); Motrin (Colombia, Ecuador, Mexico, Peru, Taiwan); Mynosedin (Japan); Nagifen-D (Japan); Napacetin (Japan); Neutropain (Hong Kong); Nobfelon (Japan); Nobgen (Japan); Norflam-T (South Africa); Norton (South Africa); Novogent (Germany); Novoprofen (Canada); Nureflex (France); Nurofen (Austria, Belgium, Czech Republic, Denmark, England, Malaysia, Netherlands, New Zealand, Philippines, Singapore, Sweden, Turkey); Nurofen for Children (Thailand); Nurofen Gel (Malaysia, New Zealand, Singapore, Thailand); Optifen (Switzerland); Opturem (Germany); Oren (Colombia); Ostarin (Indonesia); Ostofen (Thailand); Panafen (New Zealand); Pantrop (Japan); Perofen (Malaysia); Proartinal (Mexico); Profen (Hong Kong, Indonesia); Profeno (Thailand); Proris (Indonesia); Provon (Peru); Quadrax (Mexico); Ranofen (South Africa); Renidon (Philippines); Rhelafen (Indonesia); Rhelafen Forte (Indonesia); Roidenin (Japan); Rupan (Israel, Thailand); Schufen (Hong Kong); Solufen Lidose (Singapore); Spedifen (France); Spifen (France); Syntofene (France); Tabalon (Ecuador); Tabalon 400 (Mexico); Tatanal (Korea); Tofen (Thailand); Umafen (Thailand); Upfen (France); Uprofen (Taiwan); Urem (Germany); Zofen (Malaysia)

Drug Class Analgesics, non-narcotic; Antipyretics; NSAIDs
Indications Mild to moderate pain, fever, dysmenorrhea, osteoarthritis, rheumatoid arthritis
Mechanism Inhibits cyclooxygenase and lipoxygenase, leading to reduced prostaglandin synthesis
Dosage With Qualifiers Mild to moderate pain—400 mg PO q4–6 h; max 3200 mg/d
Fever—200–400 mg PO q4–6 h; max 1200 mg/d
Dysmenorrhea—400 mg PO q4–6 h; max 2400 mg/d
Osteoarthritis or rheumatoid arthritis—300–800 mg PO tid or qid; take with food, max 3200 mg/d

  • Contraindications —hypersensitivity to drug or class, ASA/NSAID-induced asthma, third-trimester pregnancy

  • Caution —hypertension, CHF, history of GI bleeding, nasal polyps

Maternal Considerations About 5% of women report prenatal use of either ibuprofen or naproxen near conception or during pregnancy. In several different trials, the addition of hydrocodone significantly enhanced the analgesic efficacy of ibuprofen. In other trials, ibuprofen significantly reduced postabortal pain and was superior to acetaminophen for the treatment of postpartum pain and episiotomy after vaginal delivery. Prophylactic ibuprofen does not decrease the discomfort associated with IUD insertion. In one prospective case-control study, prenatal ibuprofen or naproxen use increased the risk of spontaneous abortion by 80% (adjusted hazard ratio 1.8 [95% CI 1–3.2]). The association was stronger if the initial use was around conception or if it lasted more than a week. There is epidemiologic evidence linking it to PPH.
Side effects include renal failure, fluid retention, dyspepsia, GI bleeding, bronchospasm, thrombocytopenia, interstitial nephritis, hepatotoxicity, Stevens-Johnson syndrome, agranulocytosis, nausea, constipation, abdominal pain, headache, dizziness, rash, increased LFTs, tinnitus, and drowsiness.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Ibuprofen crosses the human placenta and is found in meconium. Fetal levels are dependent on maternal use, as the fetal kidney does not metabolize NSAID agents. Constriction of the fetal ductus arteriosus is reported, and it is similar in efficacy to indomethacin for closure of a neonatal PDA. There is epidemiologic evidence linking ibuprofen to gastroschisis. Similar adverse effects have been noted in rats where ibuprofen was associated with an increased prevalence of abdominal wall defects and VSD. Ibuprofen is as effective as indomethacin in closing the ductus arteriosus, but it does not affect renal function to the same extent. There is conflicting information regarding the potential impact of first trimester NSAIDs in general and ibuprofen in particular on the spontaneous abortion rate. It is probably best to avoid them in the first trimester and use acetaminophen instead.
Breastfeeding Safety Only small amounts of ibuprofen are excreted into human breast milk with a relative infant dose of < 0.75%. Less than 1 mg is excreted in the breast milk of lactating women who ingest up to 400 mg q6h. It is an analgesic of choice while breastfeeding.
Drug Interactions Increased bleeding has been reported when using ibuprofen and other NSAIDs with coumarin-type anticoagulants.
Animal studies suggest that aspirin reduces the net antiinflammatory activity of NSAIDs, including ibuprofen.
Probably reduces tubular secretion of methotrexate, and thus may increase methotrexate toxicity.
May reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
Increases lithium levels some 15% by reducing renal lithium clearance 20%. This effect has been attributed to the inhibition of renal prostaglandin synthesis.
References Alano MA, Ngougmna E, Ostrea EM, Konduri GG. Pediatrics 2001; 107:519-23.
Bednarek PH, Creinin MD, Reeves MF, et al. Contraception 2015; 91:193-7.
Burdan F, Szumilo J, Dudka J, et al. Braz J Med Biol Res 2006; 39:925-34.
Burdan F, Szumilo J, Dudka J, et al. Pharmacol Res 2006; 53:287-92.
Cuzzolin L, Dal Cere M, Fanos V. Drug Saf 2001; 24:9-18.
Elli M, Gaffuri B, Frigerio A, et al. Reproduction 2001; 121:151-4.
Hubacher D, Reyes V, Lillo S, et al. Am J Obstet Gynecol 2006; 195:1272-7.
Li DK, Liu L, Odouli R. BMJ 2003; 327:368-73.
Kamondetdacha R, Tanninandorn Y. J Med Assoc Thai 2008; 91:282-6.
Torfs CP, Katz EA, Bateson TF, et al. Teratology 1996; 54:84-92.
Townsend RJ, Benedetti TJ, Erickson SH, et al. Am J Obstet Gynecol 1984; 149:184-6.
Windle ML, Booker LA, Rayburn WF. J Reprod Med 1989; 34:891-5.
Summary Pregnancy Category: B
Lactation Category: S

  • Preconceptual ibuprofen may increase the risk of spontaneous abortion.

  • First-trimester exposure should be minimized until the completion of future studies in light of the association with gastroschisis.

  • Acetaminophen (paracetamol) is the analgesic of choice in the first trimester if one must be used.

  • Ibuprofen probably poses minimal risk when taken occasionally outside the first trimester.

  • Ibuprofen is an excellent analgesic postpartum, though its efficacy is similar to that of other NSAIDs.

Ibutilide — (Corvert)

International Brand Names

None identified.

Drug Class Antiarrhythmics, class III
Indications Rapid conversion of recent atrial flutter/fibrillation
Mechanism Prolongs phase 3 of the action potential
Dosage With Qualifiers Rapid conversion of recent atrial flutter/fibrillation—0.01 mg/kg IV over 10 min, may repeat after 10 min if no response; max 1 mg/dose

  • Contraindications —hypersensitivity to drug or class, use of a class I or III antiarrhythmic within 4 h

  • Caution —renal or hepatic dysfunction, prolonged QT interval, hypokalemia, polymorphic ventricular tachycardia

Maternal Considerations There are no adequate reports or well-controlled studies of ibutilide in pregnant women. The published experience is limited to case reports and short series. Its efficacy is apparently uncompromised by pregnancy.
Side effects include bradycardia, sustained ventricular tachycardia, sustained polymorphic ventricular tachycardia, ventricular arrhythmias, tachycardia, prolonged QT interval, AV block, N/V, headache, and hypertension.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Class III antiarrhythmic drugs such as ibutilide cause a spectrum of malformations in experimental teratology studies similar to those reported for phenytoin. Class III antiarrhythmics decrease cardiac cell excitability by selectively blocking the rapid component of the I Kr , an action shared with phenytoin. Malformations associated with selective and nonselective I Kr blockers may be the dose-dependent product of embryonic bradycardia/arrhythmia resulting in (1) hypoxia, explaining embryonic death and growth restriction; (2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions; and (3) alterations in embryonic blood flow and BP, inducing CV defects.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether ibutilide enters human breast milk.
Drug Interactions Supraventricular arrhythmias may mask the cardiotoxicity associated with excess digoxin. It is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the therapeutic range.
References Burkart TA, Kron J, Miles WM, et al. Pacing Clin Electrophysiol 2007; 30:283-6.
Danielsson BR, Skold AC, Azarbayjani F. Curr Pharm Des 2001; 7:787-802.
Kockova R, Kocka V, Kiernan T, Fahy GJ. J Cardiovasc Electrophysiol 2007; 18:545-7.
Marks TA, Terry RD. Teratology 1996; 54:157-64.
Summary Pregnancy Category: C
Lactation Category: U

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

  • Other antiarrhythmic agents are available for which there is more clinical experience during pregnancy and lactation.

Idarubicin — (Idamycin)

International Brand Names

Damycin (Mexico); Idamycin (Canada, Japan, Mexico); Idaralem (Mexico); Zavedos (Argentina, Austria, Brazil, Bulgaria, Chile, China, Colombia, Costa Rica, Czech Republic, Denmark, Dominican Republic, El Salvador, England, Finland, France, Germany, Greece, Guatemala, Honduras, Hong Kong, Hungary, India, Ireland, Italy, Korea, Malaysia, Netherlands, Nicaragua, Norway, Panama, Philippines, Portugal, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Uruguay, Venezuela)

Drug Class Antineoplastics; Antibiotics
Indications AML
Mechanism Interacts with topoisomerase II and has an inhibitory effect on DNA synthesis
Dosage With Qualifiers AML—varies with protocols

  • Contraindications —hypersensitivity to drug or class, prior mediastinal radiation, prior use of either daunorubicin or doxorubicin

  • Caution —unknown

Maternal Considerations Idarubicin is an analog of daunorubicin. There are no adequate reports or well-controlled studies in pregnant women. The published experience is limited to case reports and short series. Its efficacy is apparently uncompromised by pregnancy.
Side effects include CHF, seizures, MI, ventricular arrhythmia, extravasation necrosis, myelosuppression, bleeding, enterocolitis, abdominal pain, infection, N/V, diarrhea, alopecia, mucositis, rash, pruritus, dyspnea, confusion, somnolence, cough, fever, and headache.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Idarubicin apparently crosses the human placenta, as there are multiple case reports of fetal cardiotoxicity, often in the setting of polypharmacy. However, successful pregnancies occur. In one series of 14 women with promyelocytic leukemia (APL), 5 were diagnosed and treated in the first trimester. Eleven of the 12 patients eligible for induction therapy with all-trans retinoic acid and idarubicin achieved complete remission (92%). All early pregnancies ended in abortion (only 1 spontaneous), with 4 achieving clinical remission. Eight of 9 women in late pregnancy delivered a healthy infant (6 via cesarean section). All eight babies developed normally. Idarubicin is embryotoxic and teratogenic in rodents at a fraction of the MRHD.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. It is unknown whether idarubicin enters human breast milk. However, considering its mechanism of action, it is perhaps best to avoid breastfeeding while idarubicin is administered.
Drug Interactions No formal drug interaction studies performed.
References Achtari C, Hohlfeld P. Am J Obstet Gynecol 2000; 183:511-2.
Matsuo K, Shimoya K, Ueda S, et al. Gynecol Obstet Invest 2004; 58:186-8.
Reynoso EE, Huerta F. Acta Oncol 1994; 33:709-10.
Sanz MA, Montesinos P, Casale MF, et al. Ann Hematol. 2015; 94:1357-61.
Siu BL, Alonzo MR, Vargo TA, Fenrich AL. Int J Gynecol Cancer 2002; 12:399-402.
Summary Pregnancy Category: D
Lactation Category: U

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

  • Idarubicin poses a significant risk to the fetal heart and is typically lethal to the embryo.

Idoxuridine — (Dendrid; Imavate; Presamine)

International Brand Names

Apridin Gel (Korea); Citol Idoxuridina (Paraguay); Dendrid (Bulgaria, Czech Republic, Poland); Herpidu (Hong Kong, Malaysia, Switzerland, Taiwan, Thailand); Herplex (Ecuador, Israel); Herplex-D (Canada); Idina (Mexico); IDU (Germany); Idulea (Argentina); IDU Ophthalmic Solution (Japan); Iduridin (Denmark, Norway); Iduviran (France); Isotic Ixodine (Indonesia); Oftan IDU (Hungary); Ridinox (India); Stoxil (Malaysia, New Zealand, Thailand); Synmiol (Germany); Virusan (Israel)

Drug Class Antivirals; Ophthalmics
Indications HSV keratitis
Mechanism Inhibits DNA synthesis
Dosage With Qualifiers HSV keratitis—begin 1 gtt q1h until improvement, then q2h during the day and q4h at night

  • Contraindications —hypersensitivity to drug or class

  • Caution —unknown

Maternal Considerations There is no published experience with idoxuridine during pregnancy. Idoxuridine must be administered topically, given the severity of its systemic adverse effects. The quantity of drug absorbed systemically is unknown.
Side effects include cloudy cornea, lacrimal punctual occlusions, blurred vision, and photophobia.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether idoxuridine crosses the human placenta. Rodent studies reveal evidence of teratogenicity and embryotoxicity after systemic administration.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether idoxuridine enters human breast milk.
Drug Interactions Boric acid should not be co-administered because it may form a precipitate by interacting with ingredients in idoxuridine.
References There is no published experience in pregnancy or during lactation.
Summary Pregnancy Category: C
Lactation Category: U

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

Imipenem-cilastatin — (Primaxin)

International Brand Names

Pelastin IV (Indonesia); Prepenem (Korea); Primaxin (Canada, England, Greece); Tenacid (Italy); Tienam (Austria, Brazil, Chile, Colombia, Ecuador, Egypt, England, Germany, Greece, India, Indonesia, Ireland, Israel, Japan, Mexico, Peru, Poland, Slovenia, Turkey); Tienam 500 (South Africa); Zienam (Austria, Germany)

Drug Class Antibiotics; Carbapenems
Indications Serious bacterial infection
Mechanism Bactericidal by inhibiting cell wall synthesis
Dosage With Qualifiers Serious bacterial infection—250–1000 mg IM/IV q12h; max 50 mg/kg/d or 4000 mg/d
NOTE: Renal dosing.

  • Contraindications —hypersensitivity to drug or class

  • Caution —cephalosporin allergy, renal dysfunction, seizure disorder

Maternal Considerations Imipenem-cilastatin is broad-spectrum combination drug that achieves excellent pelvic tissue levels. Because of the relatively high cost, it is not considered a first-line therapy for most obstetric and gynecologic infections. There are no adequate reports or well-controlled studies in pregnant women. The clearance of imipenem-cilastatin is increased during pregnancy. Limited study reveals good clinical responses in women with chorioamnionitis or PPROM. Although imipenem-cilastatin provides effective prophylaxis for women undergoing nonelective cesarean delivery, it is no better than any other antibiotic agent used for this purpose. The selection of an agent for cesarean section prophylaxis typically is based on cost.
Side effects include pseudomembranous enterocolitis, seizures, thrombocytopenia, agranulocytosis, rash, diarrhea, oliguria, phlebitis, tachycardia, candidiasis, urine discoloration, gastroenteritis, elevated LFTs, elevated BUN/Cr, and N/V.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Imipenem-cilastatin crosses the human placenta, achieving an F:M ratio of only 0.3, whereas the AF:F ratio is 0.6. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses higher than those used clinically. Adverse outcomes in animal studies share an association with adverse maternal outcomes.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. Limited concentrations of imipenem-cilastatin are excreted into human breast milk, though the kinetics remain to be elucidated. It is generally considered compatible with breastfeeding.
Drug Interactions Probenecid produces only minimal increases in the plasma level of imipenem and should not be used.
Should not be mixed with or physically added to other antibiotics if given IV, though it may be if given IM.
Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.
References Chimura T. Jpn J Antibiot 1994; 47:1762-8.
Heikkila A, Renkonen OV, Erkkola R. Antimicrob Agents Chemother 1992; 36:2652-5.
Matsuda S, Suzuki M, Oh K, et al. Jpn J Antibiot 1988; 41:1731-41.
Ryo E, Ikeya M, Sugimoto M. J Infect Chemother 2005; 11:32-6.
Summary Pregnancy Category: C
Lactation Category: S (likely)

  • Imipenem-cilastatin 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.

Imipramine — (Imipramine Hcl; Imiprin; Janimine; Surplix; Tofnil; Tofranil; Tofranil-Pm)

International Brand Names

Antidep (India); Apo-Imipramine (Canada); Chrytemin (Japan); Daypress (Japan); Depsol (India); Depsonil (India); Ethipramine (South Africa); Fronil (Taiwan); Imidol (Japan); Imiprex (Israel); Melipramin (Czech Republic, Hungary, Poland); Melipramine (Australia); Primonil (Israel); Pryleugan (Germany); Psychoforin (Bulgaria); Sermonil (Thailand); Talpramin (Mexico); Tofranil (Argentina, Brazil, Canada, Chile, Colombia, Ecuador, Hong Kong, Indonesia, Japan, Malaysia, Mexico, Paraguay, Philippines, Taiwan, Uruguay, Venezuela); Venefon (Greece)

Drug Class Antidepressants; Tricyclics
Indications Depression, chronic pain, panic disorder
Mechanism Inhibits NE and serotonin reuptake
Dosage With Qualifiers Depression—begin 25–75 mg PO qhs; max 300 mg/d
Chronic pain—begin 0.2–0.3 mg/kg PO qhs, increase by 50% q2–3 d; max 300 mg/d
Panic disorder—begin 25 mg PO qhs

  • Contraindications —hypersensitivity to drug or class, MAOI use within 14 d, recovery from acute MI

  • Caution —history of seizure, glaucoma, CAD, thyroid disease, hepatic dysfunction, suicide risk

Maternal Considerations Depression is common during and after pregnancy but often goes unrecognized. Pregnancy is not a reason a priori to discontinue psychotropic drugs. Imipramine is the prototype TCA and is predominantly metabolized by hepatic CYP2D6. There are no adequate reports or well-controlled studies in pregnant women. It has been used extensively during pregnancy for the treatment of depression. Imipramine has also been used during pregnancy for the treatment of panic attack.
Side effects include MI, stroke, seizures, blood dyscrasias, thrombocytopenia, agranulocytosis, dry mouth, drowsiness, confusion, disorientation, blurred vision, and increased appetite.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Imipramine binds to the placental serotonin transporter and presumably crosses the human placenta. It rapidly crosses the rodent placenta and is distributed throughout the fetus. Although rodent teratogenicity studies are generally reassuring, several behavioral studies suggest prenatal exposure to imipramine alters postnatal adrenergic responses, serotonin uptake, and the response to stress.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. Imipramine and its active metabolite (desipramine) are excreted into human breast milk. The relative infant dose ranges from < 0.1%–4.4%. It is estimated that in women ingesting therapeutic doses of imipramine, the infant would ingest 0.2 mg/L, or 30 mcg/kg/d. This is similar to other tricyclic agents.
Drug Interactions CYP2D6 is reduced in a subset of whites (about 7%–10%) called “poor metabolizers.” Reliable estimates of the prevalence of reduced CYP2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of TCAs when given usual doses. Depending on the fraction of drug metabolized by CYP2D6, the increase may be small or quite large.
Certain drugs inhibit CYP2D6 and make normal metabolizers resemble poor ones. An individual who is stable on a given dose of TCA may become abruptly toxic if given one of these inhibiting drugs. CYP2D6 inhibitors include some that are not metabolized by the enzyme (e.g., cimetidine, quinidine ) and many that are substrates (many other antidepressants, phenothiazines, and the class 1C antiarrhythmics propafenone and flecainide ). All SSRIs (e.g., fluoxetine, paroxetine, sertraline ) inhibit CYP2D6 to greatly varying degrees. The extent to which SSRI-TCA interactions may pose clinical problems depends on the degree of inhibition. Caution is indicated when using TCAs with any of the SSRIs and when switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long t/2 (at least 5 w may be necessary).
May produce toxic reactions when used in combination with MAOIs.
Oral contraceptives may inhibit the metabolism of tricyclic antidepressants and may increase their plasma levels.
References Ali SF, Buelke-Sam J, Newport GD, Slikker W Jr. Neurotoxicology 1986; 7:365-80.
Balkovetz DF, Tiruppathi C, Leibach FH, et al. J Biol Chem 1989; 264:2195-8.
Berry-Bibee EN, Kim MJ, Simmons KB, et al. Contraception 2016; S0010-7824: 30165-2.
DeVane CL, Simpkins JW. Drug Metab Dispos 1985; 13:438-42.
Erickson SH, Smith GH, Heidrich F. Am J Psychiatry 1979; 136:1483.
Harmon JR, Webb PJ, Kimmel GL, Delongchamp RR. Teratog Carcinog Mutagen 1986; 6:173-84.
Sovner R, Orsulak PJ. Am J Psychiatry 1979; 136(4A):451-2.
Uguz F, Sahingoz M, Gungor B, et al. J Clin Phychopharmacol 2014; 34:513-5.
Ware MR, DeVane CL. J Clin Psychiatry 1990; 51:482-4.
Summary Pregnancy Category: D
Lactation Category: S (likely)

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

  • As for most psychotropic drugs, using monotherapy and the lowest effective quantity given in divided doses to minimize the peaks may minimize the risks.

Imiquimod — (Aldara)

International Brand Names

None identified.

Drug Class Antivirals; Dermatologics; Immunomodulators
Indications Genital warts
Mechanism TLR7 agonist; induces the expression of multiple cytokines
Dosage With Qualifiers Genital warts—apply hs 3 ×/w, wash off after 6–10 h; max 16 w

  • Contraindications —hypersensitivity to drug or class

  • Caution —unknown

Maternal Considerations The published experience with imiquimod during pregnancy is limited to case reports. There are no studies of systemic absorption.
Side effects include burning, hypopigmentation, pruritus, pain, fatigue, flulike symptoms, headache, and diarrhea.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether imiquimod crosses the human placenta. Imiquimod does not stimulate inflammatory cytokines when applied to cultured trophoblasts. Rodent studies are reassuring, revealing no evidence of teratogenicity or IUGR despite the use of doses 28 to 98 × higher than those used clinically.
Breastfeeding Safety There is no experience in nursing women. However, it is unlikely, considering the dose and route, that any significant concentration of imiquimod enters human breast milk.
Drug Interactions Imiquimod may interfere with vaccines’ responsiveness.
It may decrease the effect of BCG and nivolumab.
Echinacea may diminish the imiquimod effect.
Imiquimod may enhance the effect of fingolimod, leflunomide, natalizumab, and tofacitinib.
Pimecrolimus, roflumilast, and tacrolimus may enhance the effect of imiquimod.
References Audisio T, Roca FC, Piatti C. Int J Gynaecol Obstet 2008; 100:275-6.
Manlove-Simmons JM, Zaher FM, Tomai M, et al. Infect Dis Obstet Gynecol 2000; 8:105-11.
Summary Pregnancy Category: B
Lactation Category: S (likely)

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

  • Other treatment alternatives are available.

Immune globulin — (Biogam; Carimune; Gamimune N 5%; Gamimune N 10%; Gammagard S/D; Gammar-P I.V.; Immune Globulin; Iveegam En; Panglobulin; Polygam S/D; Sandoglobulin; Venoglobulin-S 5%; Venoglobulin-S 10%)

International Brand Names

Allerglobuline (South Africa); Aunativ (Israel); Baygam (Canada); Beriglobin (Austria, Germany, Israel, Sweden); Beriglobina (Brazil, Ecuador, Spain); Beriglobina P (Chile); Beriglobin P (Argentina, Taiwan); Beriglobin-P (South Africa); Citax F (Mexico); Endobulin (Czech Republic, England, Finland, South Africa); Endobuline (France); Flebogamma (Israel); Gamafine (India); Gamastan Immune Globulin (Israel); Gamimune N (Canada); Gamma 16 (Israel); Gammabulin (Hong Kong); Gammagard (Denmark, France, Hungary, Italy, Netherlands, Spain, Sweden); Gammagard S D (Canada, Hong Kong, Israel); Gammagard S/D (Malaysia); Gammonativ (Denmark, Germany, Israel, Norway, Sweden); Globuman Berna (Hong Kong, Malaysia, Peru, Philippines, South Africa, Taiwan, Thailand); IG Gamma (Israel, Philippines); Intraglobin (Germany, Italy, Switzerland, Taiwan); Intraglobin F (Israel, Thailand); IV Globulin-S (Korea); Octagam (France); Pentaglobin (Austria, Germany, Thailand); Sandoglobulin (Czech Republic, Denmark, Finland, Greece, Israel, Norway, Sweden, Switzerland); Sandoglobulina (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Italy, Mexico, Nicaragua, Panama); Sandoglobuline (Belgium, France); Subcuvia (England); Venoglobulin-I (Malaysia); Venoglobulin S (Taiwan)

Drug Class Immune globulins
Indications ITP, alloimmune thrombocytopenia, primary immune deficiency diseases, B-cell chronic lymphocytic leukemia
Mechanism Unknown; inhibits natural killer cell cytotoxicity
Dosage With Qualifiers ITP—1 g/kg IV; up to 3 doses on alternating days
Alloimmune thrombocytopenia (fetal therapy)—1 – 3 g/kg IV qw from 15 w until delivery
Primary immune deficiency diseases—200 – 400 mg/kg IV × 1, then 100 – 300 mg/kg IV qmo
B-cell chronic lymphocytic leukemia—400 mg/kg IV q3 – 4 w if hypogammaglobulinemia and/or recurrent bacterial infection
NOTE: A 5% solution initially should be infused at 0.5 mL/kg/h; if well tolerated, the rate and concentration may be gradually increased to a maximum rate of 4 mL/kg/h, and then the concentration increased to 10% at 0.5 mL/kg/h up to a maximum of 8 mL/kg/h.

  • Contraindications —hypersensitivity to drug or class, acute renal failure, chronic renal failure

  • Caution —selective IgA deficiency, diabetes mellitus, age > 65 y, volume depletion, sepsis, paraproteinemia, concomitant use of known nephrotoxic drugs, CVD, prior thrombosis

Maternal Considerations IV immune globulin (human) is a solvent/detergent-treated, sterile, freeze-dried preparation of highly purified IgG derived from large pools of human plasma. The manufacturing process dramatically reduces the risk of viral transmission. The t/2 of immune globulin approximates 38 d. Epinephrine should be available for treatment of any acute anaphylactic reactions. There are few well-controlled studies in pregnant women, but several on- and off-label indications deserve specific comment. In addition to the indications listed here, immune globulin has been used with apparent success during pregnancy for dermatomyositis, Churg-Strauss vasculitis, Guillain-Barré syndrome, and acquired hemophilia A.
ITP: ITP is a common hematologic disorder in young women. Although ITP is a risk to both mother and neonate, there is no convincing evidence it poses a risk to the fetus. Cesarean delivery is not indicated for ITP.
Alloimmune thrombocytopenia: Maternal immune globulin therapy is the primary treatment for fetal alloimmune thrombocytopenia. Empiric therapy (i.e., treatment of at-risk fetuses without a definitive diagnosis) is cost effective. A high-dose weekly infusion (1 – 3 g/kg) reduces the severity of fetal alloimmune thrombocytopenia and the risk of a fetal intracranial hemorrhage. A RCT with inadequate power suggested 0.5 g/kg might be a suitable dose. The concurrent use of dexamethasone does not add value, though nonresponders to immune globulin may benefit from prednisone 60 mg PO qd. The mechanism is unknown. Maternal sera obtained after treatment with polyclonal immunoglobulin decreases constitutive and cytokine-induced ICAM-1 and VCAM-1 expression on endothelial cells. The initial fetal platelet count predicts the response to therapy, but apparently not the family history. Children with fetal alloimmune thrombocytopenia treated as fetuses have better long-term developmental-behavioral outcomes than untreated siblings, perhaps because of higher in utero platelet counts.
RBC alloimmunization: A number of pregnancies have been reported noting favorable outcomes with immune globulin (1–2 g/kg qw) treatment of women with severe Rh factor disease, though that conclusion is not unanimous. Several combine immune globulin therapy with plasmapheresis. One explanation for an improved outcome would be decreased hemolysis. In support, several groups document either a decreased need for transfusion or a reduced carboxyhemoglobin level in rH factor–immunized neonates after immune globulin therapy. Although therapy does not typically eliminate the need for fetal transfusion, it does appear to delay the gestation in which it must be started. If there is benefit, it is in those women with severe alloimmunization with a known antigen positive fetus likely to necessitate a fetal transfusion prior to 20 weeks gestation.
Recurrent abortion: The use of immune globulin in women with recurrent pregnancy loss is ineffective for the indication of primary recurrent abortion with the possible exception of antiphospholipid syndrome, but it may be associated with an increased rate of live births in women with secondary recurrent miscarriage.
Side effects include anaphylaxis, urticaria, hypotension, headache, fatigue, chills, backache, leg cramps, light-headedness, fever, flushing, slight elevation of BP, N/V, thrombosis, aseptic meningitis syndrome, increased BUN/Cr, renal dysfunction, acute renal failure, osmotic nephrosis, and death.
Fetal Considerations There are no adequate and well-controlled studies in human fetuses. Animal reproduction studies have not been conducted. IV immune globulin crosses the human placenta via the Fc′ receptors on the syncytiotrophoblast, as do endogenous immunoglobulins. However, not all commercial preparations have equal transport. Using an in vitro placental perfusion model, there was significant inhibition of placental anti-D IgG transfer with three commercial immune globulin preparations where the circulating maternal IgG concentrations were > 20 g/L. One product, which was not inhibitory, had lower circulating IgG levels (16.5 ± 0.9 g/L) and significantly reduced placental transfer of total IgG, suggesting that the reduced functional activity of IgG from immune globulin preparations may correlate with poor clinical efficacy.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. It is unknown whether immune globulin enters human breast milk, though endogenous immunoglobulins are a normal component of breast milk.
Drug Interactions Admixtures of immune globulin with other drugs and IV solutions have not been evaluated. They should be administered separately.
Antibodies in immune globulin preparations may interfere with patient responses to live vaccines, such as those for measles, mumps, and rubella.
References Bussel JB, Berkowitz RL, Lynch L, et al. Am J Obstet Gynecol 1996; 174:1414-23.
Bussel JB, Berkowitz RL, McFarland JG, et al. N Engl J Med 1988; 319:1374-8.
Chitkara U, Bussel J, Alvarez M, et al. Obstet Gynecol 1990; 76:703-8.
Devendra K, Koh LP. Ann Acad Med Singapore 2002; 31:276-80.
Ergaz Z, Gross D, Bar-Oz B, et al. Vox Sang 1995; 69:95-9.
Gaddipati S, Berkowitz RL, Lembet AA, et al. Am J Obstet Gynecol 2001; 185:976-80.
Hot A, Perard L, Coppere B, et al. Clin Rheumatol 2007; 26:2149-51.
Hutton B, Sharma R, Fergusson D, et al. BJOG 2007; 114:134-42.
Landor M, Rubinstein A, Kim A, et al. Int Arch Allergy Immunol 1998; 115:203-9.
Paridaans NP, Kamphuis MM, Taune Wikman A, et al. Fetal Diagn Ther 2015; 38:147-53.
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2006; 86(Suppl):S226-7.
Radder CM, Beekhuizen H, Kanhai HH, Brand A. Clin Exp Immunol 2004; 137:216-22.
Ruma MS, Moise KJ Jr, Kim E, et al. Am J Obstet Gynecol 2007; 196:138.e1-6.
Spencer JA, Burrows RF. Aust N Z J Obstet Gynaecol 2001; 41:45-55.
Thung SF, Grobman WA. Am J Obstet Gynecol 2005; 193:1094-9.
Urbaniak SJ, Duncan JI, Armstrong-Fisher SS, et al. Br J Haematol 1999; 107:815-7.
Voto LS, Sexer H, Ferreiro G, et al. J Perinat Med 1995; 23:443-51.
Ward MJ, Pauliny J, Lipper EG, Bussel JB. Am J Perinatol 2006; 23:487-92.
Williams L, Chang PY, Park E, et al. Obstet Gynecol 2007; 109:561-3.
Summary Pregnancy Category: C
Lactation Category: S

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

  • All infections thought to be transmitted by IV immune globulin should be reported by the health care provider to Baxter Healthcare Corporation, Hyland Immuno at 1-800-423-2862 (in the United States).

  • The physician should discuss the risks and benefits of this product with the patient.

Indapamide — (Depermide; Lozol; Natralix)

International Brand Names

Agelan (Hong Kong, Ireland); Damide (Italy); Dapa (Malaysia); Dapamax (South Africa, Tanzania, Uganda, Zambia, Zimbabwe); Diflerix (Hong Kong, Taiwan); Dixamid (Greece); Extur (Spain); Fludex (Austria, Belgium, Denmark, France, Greece, Netherlands, Portugal, Switzerland, Turkey); Fludex SR (Korea); Frumeron (Thailand); Hydro-Less (South Africa); Indahexal (Australia); Indalix (Hong Kong, South Africa); Indapam (Korea); Indapress (Chile); Indicontin Continus (Hong Kong); Inpamide (Thailand); Insig (Australia); Ipamix (Italy); Lorvas (India); Lozide (Canada); Magniton-R (Greece); Millibar (China, Singapore, Taiwan); Napamide (Malaysia, New Zealand, Singapore, Thailand); Naplin (New Zealand); Natrilix (Argentina, Brazil, China, Colombia, Costa Rica, Ecuador, El Salvador, England, Finland, Germany, Guatemala, Honduras, Hong Kong, India, Indonesia, Ireland, Italy, Malaysia, New Zealand, Nicaragua, Panama, Peru, South Africa, Taiwan, Uruguay, Venezuela); Natrilix SR (Australia, Costa Rica, El Salvador, Germany, Guatemala, Honduras, India, Nicaragua, Panama, Paraguay, Philippines, Singapore, Uruguay); Natrix (Japan); Natrix SR (Korea); Pamid (Israel); Rinalix (Malaysia, Singapore); Sicco (Germany); Tandix (Portugal); Tertensif (Bulgaria, Czech Republic, Finland, Poland, Spain)

Drug Class Diuretics; Thiazides
Indications Hypertension, CHF
Mechanism Inhibits sodium and chloride reabsorption by the distal convoluted tubule; depresses smooth muscle contractility by reducing inward calcium and sodium and outward potassium currents
Dosage With Qualifiers Hypertension—begin 1.25 mg PO qam, increase if no response after 1 w; max 5 mg/d
CHF—begin 2.5 mg PO qam, increase if no response after 1 w; max 5 mg/d

  • Contraindications —hypersensitivity to drug or class, hypersensitivity to sulfonamides, hepatic or renal failure, anuria

  • Caution —unknown

Maternal Considerations There is no published experience with indapamide during pregnancy. Diuretics should not be used to treat physiologic edema of pregnancy.
Side effects include ventricular arrhythmia, hypokalemia, hyponatremia, hyperuricemia, rash, abdominal pain, orthostatic hypotension, N/V, muscle cramps, fatigue, vertigo, and pruritus.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether indapamide 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. However, other thiazide diuretics have neonatal sequelae.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether indapamide enters human breast milk. There are many other diuretic agents that have been studied during lactation.
Drug Interactions Lithium toxicity is closely related to serum lithium levels and can occur at close to therapeutic levels.
May add to or potentiate the hypotensive action of other antihypertensive drugs.
Antihypertensive effect may be enhanced in the postsympathectomized patient.
May decrease arterial responsiveness to NE, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
References There is no published experience in pregnancy or during lactation.
Summary Pregnancy Category: B
Lactation Category: U

  • Indapamide 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.

Indinavir — (Crixivan; MK-639)

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); Crixivan (Hong Kong, Israel, Korea, Malaysia, Philippines, Singapore, South Africa, Taiwan, Thailand); Elvenavir (Argentina); Indivan (Paraguay); Indivir (India)

Drug Class Antivirals; Protease inhibitors
Indications HIV infection
Mechanism Protease inhibitor
Dosage With Qualifiers HIV infection—800 mg PO q8h; drink at least 1.5 L water qd
NOTE: Reduce dose for hepatic dysfunction.

  • Contraindications —hypersensitivity to drug or class; history of nephrolithiasis; concurrent use of astemizole, cisapride, midazolam, or triazolam

  • Caution —hepatic dysfunction, diabetes mellitus

Maternal Considerations Indinavir effectively reduces the maternal HIV viral load to an undetectable level, especially when combined with other agents such as a nucleoside analog or a reverse transcriptase inhibitor. In one study of four women, clearance was increased during pregnancy as reflected in the decreased AUC. In another longitudinal study, indinavir AUC was 68% lower antepartum compared with postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.
Side effects include nephrolithiasis, diabetes mellitus, N/V, diarrhea, abdominal pain, insomnia, headache, hyperbilirubinemia, hyperlipidemia, hyperglycemia, anorexia, dry mouth, malaise, taste changes, and the lipodystrophy syndrome.
Fetal Considerations Indinavir crosses the human placenta, though the magnitude of fetal-to-maternal transfer in the isolated cotyledon is 2–3 × greater than maternal-to-fetal transfer, suggesting fetal exposure is minimal. Transport is via P-glycoprotein. In vivo, the protease inhibitors indinavir , nelfinavir , and saquinavir demonstrated unreliable placental transport, with cord blood concentrations that were frequently undetectable. That said, a teratogen review suggested indinavir and didanosine were associated with head and neck defects. Certainly, the prevention of HIV transmission remains the ultimate priority. Though most premarketing rodent teratogenicity studies are reassuring, indinavir was associated in one study with delayed growth and skeletal and ophthalmic abnormalities. Hyperbilirubinemia has occurred during treatment with indinavir.
Breastfeeding Safety There is no adequate experience in nursing women. Indinavir does enter human breast milk, and in a single case the M:P ratio was 5.4. It is excreted into rat breast milk. Regardless, breastfeeding is contraindicated in HIV-infected nursing women where formula is available to reduce the risk of neonatal transmission.
Drug Interactions Delavirdine increases the indinavir plasma concentration, and a dosage reduction may be indicated.
Efavirenz decreases the indinavir plasma concentration, and a dosage increase may be indicated.
Itraconazole and ketoconazole inhibit CYP3A4; both increase indinavir plasma concentrations, and a dosage reduction of indinavir is recommended.
There is an increase in the plasma rifabutin concentration and a decrease in the plasma indinavir concentration when both are given. The dosage of both drugs will require appropriate alteration.
Should not be co-administered with rifampin . It is a potent CYP3A4 inducer that markedly reduces indinavir plasma concentrations.
Interactions between indinavir and less potent CYP3A4 inducers such as phenobarbital, phenytoin, carbamazepine, and dexamethasone have not been studied. These agents should be used with caution.
Calcium channel blockers are metabolized by CYP3A4, which is inhibited by indinavir. Use of indinavir with calcium channel blockers may result in increased concentrations of the calcium channel blockers that can increase or prolong their therapeutic and adverse effects.
Indinavir and didanosine should be administered on an empty stomach at least 1 h apart, as a normal gastric pH is necessary for optimal absorption. In contrast, acid rapidly degrades didanosine, which is formulated with buffering agents.
References Colebunders R, Hodossy B, Burger D, et al. AIDS 2005; 19:1912-5.
Kosel BW, Beckerman KP, Hayashi S, et al. AIDS 2003; 17:1195-9.
Lorenzi P, Spicher VM, Laubereau B, et al. AIDS 1998; 12:F241-7.
McCormack SA, Best BM. Clin Pharmacokinet. 2014; 53:989-1004.
Mirochnick M, Dorenbaum A, Holland D, et al. Pediatr Infect Dis J 2002; 21:835-8.
Riecke K, Schulz TG, Shakibaei M, et al. Teratology 2000; 62:291-300.
Sibiude J, Mandelbrot L, Blanche S, et al. PLoS Med 2014; 29;11:e1001635.
Sudhakaran S, Ghabrial H, Nation RL, et al. Antimicrob Agents Chemother 2005; 49:1023-8.
Sudhakaran S, Rayner CR, Li J, et al. Br J Clin Pharmacol 2007; 63:315-21.
Unadkat JD, Wara DW, Hughes MD, et al. Antimicrob Agents Chemother 2007; 51:783-6.
Summary Pregnancy Category: C
Lactation Category: NS

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

  • Drug clearance is increased during pregnancy, suggesting that either the dose be increased or the plasma levels be monitored.

  • Reduction of the maternal viral load to undetectable levels remains the prime goal.

  • 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 indinavir.

Indomethacin — (Indocin)

International Brand Names

Agilex (Argentina); Amuno (Germany); Amuno Retard (Germany); Antalgin Dialicels (Mexico); Apo-Indomethacin (Canada); Areumatin (Indonesia); Argilex (Argentina); Arthrexin (Australia, South Africa); Articulen (South Africa); Artrilona S (Uruguay); Artrinovo (Spain); Asimet (Malaysia); Benocid (Indonesia); Betacin (South Africa); Bonidon (Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Nicaragua, Panama); Catlep (Japan); Chrono-Indocid (France); Confortid (Denmark, Finland, Israel, Norway, Sweden, Switzerland); Confortid Retard (Denmark); Confortid Retardkapseln (Switzerland); Docin (Thailand); Dolazal (Netherlands); Dometin (Netherlands); Durametacin (Germany); Elmego Spray (Thailand); Elmetacin (Germany, New Zealand); Flamaret (South Africa); Grindocin (Mexico); IDC (Thailand); Idicin (India); IM-75 (Argentina); Imbrilon (England, Ireland); Imet (Italy, South Africa); Inacid (Spain); Indacin (Japan); Indalgin (Taiwan); Indo (Malaysia, Singapore); Indocap (India); Indocap S.R. (India); Indocid (Argentina, Austria, Belgium, Brazil, Canada, Denmark, England, France, Greece, Hong Kong, Israel, Malaysia, Mexico, Netherlands, Norway, Peru, Philippines, Portugal, Switzerland, Taiwan, Thailand, Venezuela); Indocid R (Hong Kong); Indocid-R (New Zealand); Indocolir (Germany); Indocollyre (France, Hong Kong, Israel, Korea); Indogesic (Hong Kong, Israel); Indolag (Israel, Puerto Rico, South Africa); Indolar SR (England); Indomecin (Colombia); Indomed (Israel); Indomed F (Thailand); Indomee (Sweden); Indomelan (Austria); Indometicina McKesson (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama); Indometin (Finland); Indomin (Israel); Indono (Thailand); Indo-Phlogont (Germany); Indorem (Puerto Rico); Indosima (Paraguay); Indo-Tablinen (Germany); Indotard (Israel); Indovis (Israel); Indoy (Taiwan); Indrenin (Czech Republic); Indylon (South Africa); Inflazon (Japan); Lauzit (Japan); Malival (Mexico); Malival AP (Mexico); Metacen (Italy); Methacin (Malaysia); Methocaps (South Africa); Metindol (Bulgaria, Czech Republic, Poland, Thailand); Novomethacin (Canada); Reumacid (Israel); Reusin (Spain); Rheumacid (South Africa); Rheumacin (New Zealand); Rheumacin SR (New Zealand); Salinac (Japan); Sidocin (Taiwan); Vi-Gel (Philippines); Vonum (Germany)

Drug Class Analgesics, non-narcotic; Antiarthritics; NSAIDs; Antiinflammatories
Indications Dysmenorrhea, mild to moderate pain, osteoarthritis or rheumatoid arthritis, tocolysis
Mechanism Inhibits cyclooxygenase and lipoxygenase, leading to reduced prostaglandin synthesis
Dosage With Qualifiers Dysmenorrhea—25 mg PO tid or qid
Mild to moderate pain—25–50 mg PO tid prn
Osteoarthritis or rheumatoid arthritis—begin 25 mg PO bid or tid, or 50 mg prn qid, increase by 25–50 mg q7d; max 200 mg/d
Tocolysis—50 mg PR or PO load, then 25 mg PO/PR q6h × 2 d
NOTE: Available in liquid, tablet, and suppository.

  • Contraindications —hypersensitivity to drug or class, ASA/NSAID-induced asthma, third-trimester pregnancy

  • Caution —hypertension, CHF, history of GI bleeding, nasal polyps

Maternal Considerations PBPK/PD modeling suggests a higher dose of indomethacin during pregnancy is required to achieve levels similar to those in the nonpregnant patient. Indomethacin is used off-label for the treatment of presumed preterm labor. However, the most recent Cochrane review concludes that the evidence for indomethacin as a tocolytic is weak at best. Indomethacin is no better and likely inferior to calcium channel blockers such as nifedipine, which has a stronger safety profile. Continuing indomethacin after the successful treatment of presumed preterm labor does not further delay delivery or enhance outcome and should not be condoned. Similarly, indomethacin is advocated for the treatment of the sonographically detected short cervix. Here, too, there is little quality evidence to support the practice. It does not appear to delay preterm delivery of women with a dilated cervix independent of cerclage. Indomethacin has multiple non–prostaglandin-related actions, including the inhibition of MMPs 2 and 9 in amnion, chorion, and decidua. Such actions may contribute to its antiinflammatory effect. Indomethacin reduces renal free water clearance and can cause abrupt maternal weight gain and edema when first initiated. Indomethacin should probably be avoided in women at risk for delivery within 24 h, as a 50-mg dose reproducibly prolongs the maternal bleeding time, which will reach abnormal levels in half of these cases.
Side effects include renal failure, fluid retention, dyspepsia, GI bleeding, bronchospasm, thrombocytopenia, interstitial nephritis, hepatotoxicity, Stevens-Johnson syndrome, agranulocytosis, nausea, constipation, abdominal pain, headache, dizziness, rash, increased LFTs, tinnitus, and drowsiness.
Fetal Considerations Indomethacin crosses the placenta, and fetal sequelae are common. Fetal levels are dependent on the maternal, as NSAIDs are not metabolized by the fetal kidney. A third of fetuses exposed to indomethacin for 1 w or more develop oligohydramnios or evidence of ductal constriction. These adverse effects are completely avoidable, as there are no demonstrable benefits over the long term for the indication of preterm labor or incompetent cervix. Other prostaglandin synthase inhibitors reputedly have a lower incidence of fetal sequelae when used as a tocolytic agent, though the quantity of clinical experience is much smaller than that for indomethacin. These differences are clear in the neonate when comparing ibuprofen to indomethacin for the closure of a PDA. Because of its effect on fetal urine output, indomethacin is used to treat idiopathic polyhydramnios. It should not, however, be used in twin gestations complicated by the so-called stuck twin, or the “oligo-polyhydramnios sequence.” In this scenario, there is no evidence that indomethacin prolongs gestation, and it can lead to fetal renal shutdown. The effects of indomethacin on the fetal kidneys are dose and duration dependent. Stopping it typically results in reversal of the abnormal sonographic findings. Indomethacin is used postnatally for the pharmacologic closure of a PDA. Constriction of the fetal ductus is common when indomethacin is used to treat preterm labor. It, too, reverses with cessation, and the long-term impact of in utero ductal constriction on the otherwise healthy fetus is currently unknown. A short course (< 48 h) of indomethacin for the treatment of preterm labor does not alter the newborn’s responsiveness to indomethacin postnatally. In uncontrolled trials, indomethacin tocolysis was associated with an increased risk of IVH and NEC in the neonate. These reports remain to be confirmed. In other uncontrolled studies, neurodevelopment was unaffected by antenatal exposure.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. The quantity of indomethacin excreted into human breast milk is low, with a relative infant dose of approximately 1.2%. Neonatal plasma levels are typically below detection. In one case report, seizures in a nursing infant were observed.
Drug Interactions Diflunisal should not be used. It decreases the renal clearance and significantly increases the plasma concentration of indomethacin. Combined use has been associated with fatal GI hemorrhage.
Should not be used with other NSAIDs. Chronic concurrent administration of aspirin decreases indomethacin concentration some 20%.
Patients receiving oral anticoagulants should be observed for a change in their PT if indomethacin is added.
Probenecid increases the indomethacin plasma level. Therefore a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect.
Decreases the tubular secretion of methotrexate and may potentiate its toxicity.
NSAIDs increase cyclosporine -induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
A clinically relevant increase in the plasma lithium level results from a decrease in renal lithium clearance. This effect is attributed to inhibition of prostaglandin synthesis.
May increase the serum concentration and prolong the t/2 of digoxin. Serum digoxin levels should be closely monitored when indomethacin and digoxin are used together.
In some patients, indomethacin reduces the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. The patient should be observed closely to determine if the desired diuretic effect is obtained.
Reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide or by salt or volume depletion.
Should not be administered with triamterene, as it may cause reversible acute renal failure.
May cause hyperkalemia in patients on potassium-sparing diuretics.
NSAIDs may blunt the antihypertensive effect of β-adrenoceptor blockers. Patients should be observed carefully to confirm the desired therapeutic effect.
May reduce the antihypertensive effect of captopril.
May cause a false-negative dexamethasone suppression test.
Food may delay indomethacin absorption.
References Alqahtani S, Kaddoumi A. PLoS One. 2015;10:e0139762.
Amin SB, Kamaluddeen M, Sangem M. Am J Obstet Gynecol 2008; 199:41.e1-8.
Berghella N, Prasentcharo-Ensuk W, Cotter A, et al. Am J Perinatal 2008 Nov 19 (Epub ahead of print).
Besinger RE, Niebyl JR, Keyes WG, Johnson TR. Am J Obstet Gynecol 1991; 164:981-6.
Bivins HA Jr, Newman RB, Fyfe DA, et al. Am J Obstet Gynecol 1993; 169:1065-70.
Carlan SJ, O’Brien WF, O’Leary TD, Mastrogiannis D. Obstet Gynecol 1992; 79:223-8.
Cordero L, Nankervis CA, Gardner D, Giannone PJ. J Perinatol 2007; 27:22-7.
Eeg-Olofsson O, Malmros I, Elwin CE, et al. Lancet 1978; 2:215.
Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Obstet Gynecol 1999; 94:869-77.
Iannucci TA, Besinger RE, Fisher SG, et al. Am J Obstet Gynecol 1996; 175:1043-6.
King JF, Flenady VJ, Papatsonis DN, et al. Cochrane Database Syst Rev 2002; (2):CD002255.
Lebedevs TH, Wojnar-Horton RE, Yapp P, et al. Br J Clin Pharmacol 1991; 32:751-4.
Lunt CC, Satin AJ, Barth WH Jr, Hankins GD. Obstet Gynecol 1994; 84:820-2.
Newton ER, Shields L, Ridgway LE 3rd, et al. Am J Obstet Gynecol 1991; 165:1753-9.
Reinebrant HE, Pileggi-Castro C, Romero CL, et al. Cochrane Database Syst Rev 2015; 5:CD001992.
Restaino I, Kaplan BS, Kaplan P, et al. Am J Med Genet 1991; 39:252-7.
Robin YM, Reynaud P, Orliaguet T, et al. Pathol Res Pract 2000; 196:791-4.
Suarez RD, Grobman WA, Parilla BV. Obstet Gynecol 2001; 97:921-5.
Ulug U, Goldman S, Ben-Shlomo I, Shalev E. Mol Hum Reprod 2001; 7:1187-93.
Weintraub Z, Solovechick M, Reichman B, et al. Arch Dis Child Fetal Neonatal Ed 2001; 85:F13-7.
Summary Pregnancy Category: C (< 30 w gestation); D (≥ 30 w gestation)
Lactation Category: S (probably)

  • Indomethacin is popular as a tocolytic agent allowing for the administration of corticosteroids; calcium channel blockers are the preferred agent from the standpoint of both safety and efficacy.

  • Indomethacin has a significant impact on the fetal and at times maternal renal and CV systems.

  • Chronic therapy with indomethacin for short/dilated cervix or prior preterm labor does not delay delivery and is discouraged outside of a research setting.

  • Indomethacin should be used during pregnancy only if the benefit justifies the potential perinatal risk.

Infliximab — (Remicade)

International Brand Names

Remicade (Argentina, Brazil, Canada, Chile, Colombia, Hong Kong, Israel, Korea, Malaysia, Mexico, Peru, Philippines, Singapore, Thailand, Venezuela); Revellex (South Africa)

Drug Class Antiinflammatories; Antirheumatics; Inflammatory bowel disease agents; Monoclonal antibodies; Tumor necrosis factor modulators
Indications Crohn’s disease, rheumatoid arthritis
Mechanism A chimeric monoclonal antibody that binds and inhibits TNF-α
Dosage With Qualifiers Crohn’s disease, moderate to severe—5 mg/kg IV × 1
Crohn’s disease, fistulizing—5 mg/kg IV × 1 for weeks 0, 2, 6
Rheumatoid arthritis—begin 3 mg/kg IV × 1 for weeks 0, 2, 6; may increase dose up to 10 mg/kg

  • Contraindications —hypersensitivity to drug or class, hypersensitivity to mouse proteins, active infection

  • Caution —pregnancy, MS, chronic or recurrent infections, latent TB, demyelinating disease

Maternal Considerations There are no adequate reports or well-controlled studies of infliximab use during pregnancy. The current experience is limited to case reports and small series.
Side effects include sepsis, opportunistic infections, worsening of CHF, chest pain, serum sickness–like reaction, lupus-like syndrome, fever, chills, myalgias, backache, arthralgias, dizziness, N/V, dyspepsia, pruritus, rash, URI, UTI, hypertension, hypotension, facial or hand edema, and elevated LFTs.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. Anti-TNF agents such as infliximab are transported across the placenta by the second trimester. Although infliximab during pregnancy in IBD patients seems to be safe in the short term, there are concerns about the consequences of the early exposure on the development of the newborn immune system. In response, some suggested that anti-TNF drugs should be stopped during the second trimester when the mother is in remission; this approach seems to be safe for the mother and minimizes fetal exposure. Rodent teratogenicity studies have not been performed because this drug does not cross-react with TNF-α in other species.
Breastfeeding Safety There are no adequate reports or well-controlled studies in nursing women. Infliximab is a high-MW antibody. No drug was detected in two women studied over multiple time points. In three postpartum women, infliximab (5 mg/kg) was detected within 12 h after the administration of a 5 mg/kg dose. The highest milk concentrations were 0.09 to 0.105 mcg/mL 2 to 3 d after the dose, resulting in a relative infant dose of < 1%.
Drug Interactions Use with etanercept (another TNF-α–blocking agent) and anakinra (an IL-1 antagonist) increases the risks of serious infection and neutropenia without providing any additional benefit compared with these drugs alone.
References Ben-Horin S, Yavzori M, Kopylov U, et al. J Crohns Colitis 2011; 5:555-8.
Hale TW. Medications and Mother’s Milk, 10th ed. Amarillo, TX: Pharmasoft Publishing, 2002:374.
Khan N, Asim H, Lichtenstein GR. Expert Opin Drug Saf 2014; 13:1699-708.
Kiely CJ, Subramaniam K, Platten J, et al. Intern Med J 2016; 46:616-9.
Mahadevan U, Kane S, Sandborn WJ, et al. Aliment Pharmacol Ther 2005; 21:733-8.
Roux CH, Brocq O, Breuil V, et al. Rheumatology (Oxford) 2007; 46:695-8.
Srinivasan R. Am J Gastroenterol 2001; 96:2274-5.
Vasiliauskas EA, Church JA, Silverman N, et al. Clin Gastroenterol Hepatol 2006; 4:1255-8.
Summary Pregnancy Category: B
Lactation Category: S (likely)

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

  • Early experience in women with medically significant diseases is reassuring.

Influenza vaccine — (Fluimmune; Fluogen; Flu Shield; Flushield; Fluvirin; Fluzone)

International Brand Names

Agrippal (England, Ireland, Italy, Philippines, South Africa); Agrippal S1 (Hong Kong); Alorbat (Germany); Begrivac (Austria, Germany); Begrivac F (Israel); Fluad (Hong Kong); Fluarix (Argentina, Australia, Brazil, Chile, Hong Kong, Mexico, New Zealand); Fluviral S/F (Canada); Fluvirin (England, Ireland); Fluvirine (France); Fluzone (Canada, England, Ireland); Hiberix (Australia, Costa Rica, El Salvador, Guatemala, Honduras, India, Nicaragua, Panama, Peru, Taiwan, Thailand); Inflexal (Austria, Italy, Spain); Inflexal Berna (Philippines, South Africa); Inflexal Berna Polyvalent Vaccine (Malaysia); Inflexal V (England, Ireland); Influvac (Australia, South Africa); Mastaflu (England, Ireland); Mutagrip (Belgium, France, Germany, Netherlands, Spain); Sandovac (Austria); Vaxigrip (Austria, Belgium, Bulgaria, Denmark, France, Greece, Hong Kong, India, Israel, Korea, Netherlands, New Zealand, Norway, Philippines, South Africa); X-Flu (South Africa)

Drug Class Vaccines
Indications Nonimmune status
Mechanism Active immunity
Dosage With Qualifiers Nonimmune status—0.5 mL IM × 1

  • Contraindications —hypersensitivity to drug or class, hypersensitivity to eggs, past history of Guillain-Barré syndrome, active febrile illness

  • Caution —unknown

Maternal Considerations All women who intend to become pregnant or are pregnant should receive an influenza vaccine. Pregnant women have increased susceptibility to viral respiratory diseases. Influenza-associated excess mortality during pregnancy has been documented during the pandemics. The increased risk may result from (1) increased HR, stroke volume, and oxygen consumption; (2) decreased lung capacity; and (3) changes in immunologic function. A study during 17 interpandemic influenza seasons revealed that the relative risk for hospitalization for cardiorespiratory conditions during pregnancy increased from 1.4 between 14 and 20 w gestation to 4.7 between 37 and 42 w gestation, compared with women 1–6 mo postpartum. Researchers estimate that an average of 1–2 hospitalizations can be prevented for every 1000 pregnant women vaccinated. Vaccination can be performed in any trimester. If a pregnant woman develops influenza, she should be treated with supportive care. The nasal spray vaccine is not recommended for use in pregnant women. Antiviral medications should be reserved for infected women who either were not vaccinated or became infected with an uncovered strain.
Side effects include sepsis, opportunistic infections, worsening of CHF, chest pain, serum sickness–like reaction, lupus-like syndrome, fever, chills, myalgias, backache, arthralgias, dizziness, N/V, dyspepsia, pruritus, rash, URI, UTI, hypertension, hypotension, facial or hand edema, and elevated LFTs.
Fetal Considerations One study of influenza vaccination of > 2000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine. The risk of preterm birth increases when pregnant women get influenza, and there is a greater chance their babies will have birth defects. Vaccine-stimulated IgG crosses the placenta, perhaps conveying some degree of passive immunity, and B- and T-cell immune responses occur in the fetus after maternal influenza vaccination. Maternal influenza vaccination reduces respiratory illness rates in their infants by almost two-thirds up to 6 m of age. There is no evidence of teratogenicity with heat-inactivated virus if given in the first trimester. Rodent studies are also reassuring.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether influenza vaccine enters human breast milk. It is likely the stimulated maternal IgG is excreted into the breast milk.
Drug Interactions There are conflicting reports on the effects of influenza vaccine on the elimination of some drugs metabolized by the hepatic CYP system.
Hypoprothrombinemia in patients receiving warfarin and elevated serum theophylline concentrations have occurred.
Patients with impaired immune responsiveness, whether due to immunosuppressive therapy (including irradiation, large amounts of corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents), a genetic defect, HIV infection, leukemia, lymphoma, generalized malignancy, or other causes, may have a reduced antibody response to active immunization procedures. If feasible, specific serum antibody titers or other immunologic responses may be determined after immunization to assess immunity. Chemoprophylaxis may be indicated for high-risk persons who are expected to have a poor antibody response to influenza vaccine. Short-term (< 2 w) corticosteroid therapy or intraarticular, bursal, or tendon injections with corticosteroids should not be immunosuppressive. Inactivated vaccines are not a risk to immunocompromised individuals, although their efficacy may be substantially reduced.
References Goldman RD, Koren G. Can Fam Physician 2002; 48:1768-9.
Heinonen OP, Shapiro S, Monson RR, et al. Int J Epidemiol 1973; 2:229-35.
Irving WL, James DK, Stephenson T, et al. BJOG 2000; 107:1282-9.
Louik C, Kerr S, Van Bennekom CM, et al. Vaccine 2016; 34:4450-9.
Neuzil KM, Reed GW, Mitchel EF, et al. Am J Epidemiol 1998; 148:1094-102.
Nunes MC, Aqil AR, Omer SB et al. Am J Perinatol 2016; 33:1104-14.
Rastogi D, Wang C, Mao X, et al. J Clin Invest 2007; 117:1637-46.
Ressel GW. Am Fam Physician 2002; 66:894-9.
Sumaya CV, Gibbs RS. J Infect Dis 1979; 140:141-6.
Zaman K, Roy E, Arifeen SE, et al. N Engl J Med 2008; 359:1555-64.
Summary Pregnancy Category: C
Lactation Category: S (likely)

  • All pregnant women should be vaccinated in preparation for influenza seasons regardless of trimester.

Insulin aspart — (NovoLog)

International Brand Names

NovoMix 30 (Australia, Israel); Novorapid (Israel)

Drug Class Antidiabetic agents; Hypoglycemics
Indications Diabetes mellitus
Mechanism Stimulates peripheral glucose uptake, inhibits hepatic glucose production, inhibits adipocyte lipolysis, inhibits proteolysis, and enhances protein synthesis
Dosage With Qualifiers Diabetes mellitus—individualized; should include an intermediate- or long-acting insulin
NOTE: Give SC < 15 min qac, onset < 0.5 h, peak 0.1–3 h, max duration 3–5 h.
DKA—begin 0.1 U/kg IV bolus, then 0.1 U/kg/h infusion; decrease infusion rate when glucose < 275 mg/dL

  • Contraindications —hypersensitivity to drug or class, hypoglycemia

  • Caution —hypokalemia, renal or hepatic dysfunction

Maternal Considerations Insulin aspart is a rapid-acting human insulin analog whose onset is roughly twice as fast as regular human insulin. It is similar to insulin lispro, which is similar to regular human insulin in controlling postprandial hyperglycemia without increasing the risk of hypoglycemia. Insulin aspart has an added advantage over regular human insulin in that it can be taken immediately before the meal, rather than 30–60 min before. One well-powered RCT concluded that insulin aspart is at least as safe and effective as regular human insulin when used in basal-bolus therapy with neutral protamine Hagedorn (NPH) insulin in pregnant women with type 1 diabetes, and it may potentially offer some benefits in terms of postprandial glucose control and preventing severe hypoglycemia. Careful monitoring of glucose levels coupled with active regulation of the insulin dose is crucial for an optimal outcome.
Side effects are similar to regular human insulin and include hypoglycemia, hypokalemia, lipodystrophy, pruritus, rash, and injection site reaction.
Fetal Considerations Insulin does not cross the placenta. Hyperglycemia is associated with both embryopathy and fetopathy. Women with insulin-requiring diabetes prepregnancy are at increased risk of bearing a child with a structural malformation. The magnitude of the risk correlates directly with the overall degree of hyperglycemia. Normalization of glucose prior to conception lowers the risk below that of control populations. Euglycemia after the embryonic stage prevents the diabetic fetopathy. A review of the literature indicates no statistically significant difference in the congenital anomaly rate among fetuses exposed to insulin analogs compared with those exposed to human insulin or neutral protamine Hagedorn insulin . Although rodent teratogenicity studies show increased early pregnancy losses, these are likely the product of severe hypoglycemia. Children of women whose diabetes was poorly controlled during the pregnancy are at increased risk for obesity, type 2 diabetes, hypertension, and cardiovascular disease. These epigenetic mediated risks are transferred to subsequent generations.
Breastfeeding Safety There is no published experience in nursing women. Biosynthetic insulins are large proteins, and only trace amounts are excreted into breast milk. Human insulin is a normal component of breast milk. A wide body of clinical experience with similar insulin preparations suggests it is compatible with breastfeeding. Lactating women may require dose or meal adjustments or both.
Drug Interactions Many drugs affect glucose metabolism and may necessitate an insulin dose adjustment. Drugs that can increase the hypoglycemic effect include ACEIs, disopyramide, fibrates, fluoxetine, MAOIs, oral hypoglycemic agents, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide ), and sulfonamide antibiotics.
Drugs that can decrease the hypoglycemic effect include corticosteroids, danazol, diuretics, estrogens and progestogens (e.g., in oral contraceptives), isoniazid, niacin, phenothiazine derivatives, somatropin, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline ), and thyroid hormones.
β-Blockers, clonidine, lithium, and alcohol may either potentiate or weaken the hypoglycemic effect of insulin. Pentamidine may sometimes cause hypoglycemia, which is sometimes followed by hyperglycemia.
Signs and symptoms of hypoglycemia may be reduced or absent under the influence of sympatholytic medicinal products such as β-blockers, clonidine, guanethidine, and reserpine.
References de Jong J, Garne E, Wender-Ozegowska E, et al. Diabetes Metab Res Rev 2016; 32:366-75.
Mathiesen ER, Kinsley B, Amiel SA, et al; Insulin Aspart Pregnancy Study Group. Diabetes Care 2007; 30:771-6.
Simmons D. Curr Diab Rep 2002; 2:331-6.
Whitmore TJ, Trengove NJ, Graham DF, et al. Int J Endocrinol 2012; 2012:296368.
Summary Pregnancy Category: B
Lactation Category: S

  • Euglycemia for the duration of pregnancy is the goal of diabetes mellitus therapy during pregnancy.

  • Insulin aspart is a clinically attractive insulin for the control of postprandial glucose levels at least as effectively as regular human insulin.

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

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