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XIV.	Pharmacologic Considerations In HIV-Infected Pregnant Patients
	I	List Of Tables
	II	Introduction
	III	Pharmacokinetcs Of Drugs In Pregnancy
	IV	References

Chapter XIV
Pharmacologic Considerations In HIV-Infected Pregnant Patients

Paul Pham, PharmD, and
Patricia Barditch-Crovo, MD

I. List Of Tables TOP

Table 14-1:	Abbreviations
Table 14-2:	FDA Pregnancy Categories
Table 14-3:	Antiretrovirals
Table 14-4:	Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients
Table 14-5:	Safety of Commonly Used Antimicrobials
Table 14-6:	Drug Interactions of Antiretrovirals
Table 14-7:	Clinically Pertinent Food-Drug Interactions
Table 14-8:	Drugs of Special Consideration in Women
Table 14-9:	Alternative/Complimentary Medication to Avoid in Pregnancy
Table 14-10:	Dosing of Antiretroviral Agents in Renal Insufficiency and/or Hepatic Insufficiency

II. Introduction TOP

The decision to administer drugs to a pregnant woman is largely based on the therapeutic benefit to the mother and/or fetus vs. the potential risk to the mother and the developing fetus. Clinicians are often advised to avoid prescribing drugs for pregnant patients because human safety data in pregnancy are lacking for many, if not most medications. However, in some clinical situations the benefits of treatment far outweigh the risks. These are important considerations when selecting agents to treat patients with human immunodeficiency virus (HIV), to prevent mother-to-child HIV transmission, and to prevent or treat opportunistic infections.

There is limited information concerning the safety of many antiretrovirals in pregnancy. Mutagenicity, carcinogenicity, and teratogenicity studies in animals are the basis for most data on safety in pregnancy. However, generally animals are administered doses 5 to 20 times higher than those given to humans; clinical applicability to human treatment is not always clear.

It is now standard care to treat HIV-infected patients with an “antiretroviral cocktail” or a combination of antiretroviral agents, making it difficult to assess the safety of a single antiretroviral agent. More prospective clinical data are needed. Clinicians are encouraged to report all in utero exposures to the Antiretroviral Pregnancy Registry (telephone 1-800-258-4263; Fax 1-800-800-1052; Internet access www.APRegistry.com), a collaborative effort of pharmaceutical manufacturers with an advisory committee of obstetric and pediatric practitioners. Observational data on antiretroviral exposure during pregnancy are collected and are used to assess potential teratogenicity of these drugs.

The tables contained in this chapter include detailed information about pharmacologic agents commonly used in the treatment of HIV-infected women and drugs often used in pregnancy or as complementary therapies, with particular emphasis on issues related to their use in pregnancy.

III. Pharmacokinetics Of Drugs In Pregnancy TOP

Although many physiologic changes occur during pregnancy, few trials have been conducted to evaluate their clinical significance on the pharmacokinetics of commonly used drugs. Physiologic changes that may affect drug pharmacokinetics include delayed gastric emptying, decreased intestinal motility, increased volume of distribution (an average increase of 8L), increased renal blood flow (by 25–50%), and increased glomerular filtration rate (by 50%) (Davidson, 1974; Dunnihoo, 1992; Parry, 1970). Pharmacokinetics parameters of nevirapine given as a single dose of 200 mg at the onset of labor were similar but more variable than in nonpregnant adults, possibly due to incomplete absorption associated with altered gastrointestinal function during labor (Mirochnick, 1998). Recent data suggests that NVP levels may be detectable as long as 3 weeks after a single dose given at onset of labor (Jourdain, 2004). Pregnancy does not change the pharmacokinetics of ZDV, 3TC, d4T, and ddI (Moodley, 1998; Schuman, 1990; Wang, 1999). Serum concentrations of the PIs that have been studied in pregnancy (indinavir [IDV], ritonavir [RTV], and saquinavir [SQV]) appear to be lower in pregnancy when given as single PIs (without boosting) (Perinatal Guidelines Working Group, 2004). SQV achieves adequate drug levels when boosted with RTV (Acosta, 2001) and nelfinavir (NFV) achieves adequate levels when given as 1250 mg twice daily (Bryson, 2002). A recent pharmacokinetic study including 4 women on an IDV-containing regimen with or without ritonavir (RTV) found a decrease in plasma concentrations of IDV during pregnancy with spontaneous increase postpartum in two women on IDV alone, consistent with metabolic induction of cytochrome P450 activity in pregnancy; this induction was offset by the concomitant use of RTV (Kosel, 2003). The clinical significance of these differences in pregnancy is unclear.

**Table 14-1: Abbreviations** **TOP**
Drug Abbreviations
ABC: Abacavir (Ziagen)	INV: Invirase (saquinavir, HGC)
APV: Amprenavir (Agenerase)	IVIG: Intravenous immune globulin
ATV: Atazanavir (Reyataz)	LPV/r: Lopinavir/Ritonavir (Kaletra)
AZT: Zidovudine (Retrovir)	NFV: Nelfinavir (Viracept)
CBV: Combivir (AZT+3TC)	NNRTI: Non-nucleoside Reverse Transcriptase Inhibitor
ddI: Didanosine (Videx)	NRTI: Nucleoside Reverse Transcriptase Inhibitor
d4T: Stavudine (Zerit)	NVP: Nevirapine (Viramune)
ddC: Zalcitabine (Hivid)	PI: Protease Inhibitor
DLV: Delavirdine (Rescriptor)	RBT: Rifabutin (Mycobutin)
EFV: Efavirenz (Sustiva)	RTV: Ritonavir (Norvir)
FTC: Emtricitabine (Emtriva)	SQV: Saquinavir (Invirase, Fortovase)
ENF: Enfuvirtide (Fuzeon, T-20)	3TC: Lamivudine (Epivir)
FTV: Fortovase (saquinavir, SGC)	TDF: Tenofovir (Viread)
fAPV: Fosamprenavir (Lexiva)	TMP-SMX: Trimethoprim sulfamethoxazole (Bactrim, etc.)
HU: Hydroxyurea	TZV: Trizivir (ABC+AZT+3TC)
IDV: Indinavir (Crixivan)	VZIG: Varicella zoster immune globulin
INH: Isoniazid	ZDV: Zidovudine (Retrovir)
Miscellaneous Abbreviations
ART: Antiretroviral Therapy	pk: pharmacokinetcs
ARV: antiretroviral	po: by mouth
AUC: area under the concentration time curve (i.e. total drug exposure)	qd: daily
Cmax: peak serum concentration	qid: four times per day
Cmin: trough serum concentration	qm: monthly
EC: Enteric Coated	qod: every other day
HAART: Highly Active Antiretroviral Therapy	qw: every week
IV: Intravenous	soln: solution
IM: Intramuscular	tid: three times per day
VL: Viral Load	tiw: three times per week
bid: twice per day	TAM: thymidine analogue mutation
biw: twice per week	TDM: Therapeutic drug monitoring
hs: bedtime (hour of sleep)	ULN: upper limit of normal
mo: month

**Table 14-2: FDA Pregnancy Categories** **TOP**
A	Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later trimesters).
B	Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted.
C	Safety in human pregnancy has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus.
D	Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
X	Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.

Table 14-3: Antiretrovirals

Table 14-4: Commonly Used Antimicrobials for the Treatment and
Prevention of Opportunistic Infections in HIV-Infected Patients

Table 14-5: Safety of Commonly Used Antimicrobials

Table 14-6: Drug Interactions of Antiretrovirals

**Table 14-7: Clinically Pertinent Food-Drug Interactions** **TOP**
Valganciclovir / Itraconazole Capsule / Ritonavir / Atazanavir: Should be taken with food or within 2 hr of eating. AZT: Can be taken with food to decrease GI side effects. Saquinavir[1] (Fortovase® and Invirase®) / Atovaquone / Nelfinavir: Should be administered with a high-fat meal. Efavirenz / Amprenavir: High-fat meal should be avoided. Didanosine[2] / Indinavir[3] / Itraconazole Solution / EFV: Should be taken on an empty stomach (1 hr before or 2 hr after meals). Grapefruit Juice: Increases saquinavir levels 40–100% but decreases indinavir AUC by 26%.

[1] No food restriction when saquinavir is co-administered with RTV.
[2] No food restriction when ddI is co-administered with TDF.
[3] No food restriction when IDV is co-administered with RTV.

**Table 14-8: Drugs of Special Consideration in Pregnant Women** **TOP**
Drug Name	FDA Class	Comments
Terbutaline	B	Terbutaline has produced significant increases in birth weights (Briggs et al, 1998). Follow-up studies did not show increased adverse fetal outcomes (Svenningsen,1982).
Ritodrine	B	The manufacturer reports that ritodrine administration after the 20th wk of gestation has not been associated with an increase in fetal abnormalities.
Methergine	C	Indicated for postpartum uterine bleeding due to atony. According to the manufacturer, oral methylergonovine .2 mg 3–4 times daily may be administered to nursing mothers for a MAXIMUM of 1 wk postpartum to control uterine bleeding. Should not be given during antenatal period. Should not be used in women with hypertension (including pre-eclampsia) or heart disease.
Pain Medication
Acetaminophen	B	Acetaminophen is considered safe for shortterm use in all stages of pregnancy.
Aspirin	C	Use of aspirin, especially of chronic or intermittent high doses, should be avoided in pregnancy. May increase risk for maternal or newborn hemorrhage. Full dose aspirin in 3rd trimester may result in premature closure of ductus arteriosus and may prolong gestation and labor. Acetaminophen is preferred analgesic/antipyretic during pregnancy.
Nonsteroidal anti-inflammatory drugs (NSAIDs)	C	Avoid in pregnancy. Due to prostaglandin synthesis inhibition, constriction of ductus arteriosus has been reported. Persistent pulmonary hypertension in the newborn has occurred when NSAIDs were used in 3rd trimester or near term. NSAIDs have been shown to inhibit labor and prolong pregnancy and have been associated with decreases in amniotic fluid volume.
Narcotic analgesic	B	Narcotic analgesics can be used short term in pregnancy. Avoid the use of high doses for prolonged periods near term as neonatal withdrawal can occur.

Table 14-9: Alternative/Complimentary Medication to Avoid in Pregnancy

Table 14-10: Dosing of Antiretroviral Agents in Renal Insufficiency
and/or Hepatic Insufficiency

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