September 2010 FAQs
September 2010 FAQs
Use of bladder irrigations for treatment of superficial bladder infections
Use of bladder irrigations for treatment of superficial bladder infections
Use of irrigations for treatment of bladder infections has been a practice for many years. One of the earliest reports, published in 1960, described the use of amphotericin B as a bladder irrigation for monilial cystitis.1 Since that time, a variety of antimicrobial agents have been used as bladder irrigations. There are, however, few randomized, controlled trials available to document the efficacy, as well as safety, of this practice. The following provides a brief review of antimicrobial, antifungal, and antiviral agents used topically for treatment of superficial bladder infections or cystitis.
Cidofovir is an antiviral agent indicated for treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. 2 Cidofovir is usually given by intravenous infusion, at a dose of 5 mg/kg for induction and maintenance therapy. However, several case reports have described the use of cidofovir in the treatment of BK virus-associated interstitial and hemorrhagic cystitis. Bridges and colleagues reported the outcomes of a patient treated with cidofovir bladder irrigation for treatment of hemorrhagic cystitis following allogeneic stem cell transplant.3 On day 22 after transplantation, the patient developed asymptomatic hematuria; urine cultures were positive for BK virus. Hematuria worsened by day 49 and did not respond to a reduction in immunosuppressive therapy, continuous bladder irrigation, and hyperhydration. Cidofovir 5 mg/kg in 60 mL of normal saline was instilled over 15 minutes, and the catheter clamped for 1 hour. Improvement was seen within 3 days of cidofovir. A second dose of cidofovir was given 1 week later, with further improvement seen 1 week after the second cidofovir dose.
Cidofovir was also used to treat chronic interstitial cystitis.4 A patient with a 4-year history of symptoms of cystitis and evidence of polyomavirus infection was treated unsuccessfully with ciprofloxacin and leflunomide. Intravesical cidofovir, 375 mg per week, was given for 3 doses. Improvement was seen after the first 2 doses. Decreases in viral load for both BK virus and JC virus were noted. No information was given on the method of administration.
In a third report, 6 patients who received allogeneic stem cell transplants developed symptoms of cystitis with a positive urinalysis for BK virus. 5 Cidofovir was given at a dose of 5 mg/kg in 60 mL of normal saline and instilled for 1 hour. Cidofovir was repeated daily for 2 days for patients with an indwelling catheter. Otherwise the doses were repeated weekly. All 6 patients had some degree of response, ranging from resolution of symptoms after a single dose to resolution after 2 weekly doses.
Gentamicin bladder irrigations have been used for prevention or treatment of bladder infections in children, adolescents, and adults with neuropathic bladder.6 Patients ranged in age from 4 months to 36 years, with a median age of 10 years. Gentamicin 14 mg in 30 mL of normal saline was instilled via a urinary catheter once or twice daily and allowed to remain in the bladder overnight or until the next scheduled catheterization. Gentamicin was dispensed in 30 mL unit dose syringes and stored frozen for up to 1 month. A 4-day stability was given when stored under refrigeration. Treatment was continued for a median of 90 days (range, 3 to 1095 days). Twenty-six percent of patients had breakthrough urinary tract infection during therapy. Serum gentamicin levels were low, not more than 0.4 mcg/mL in any patient.
Wood and colleagues described the use of a tobramycin continuous bladder irrigation for treatment of a urinary tract infection due to Enterobacter cloacae in a patient with acute renal failure (urine output approximately 100 mL/day).7 Tobramycin 40 mg in 1000 mL of sterile water was instilled at 42 mL/h. The serum tobramycin level was undetectable after 3 days. However, tobramycin was discontinued and the urinary catheter removed following a positive urine culture for Candida and mild bladder erosion.
Vancomycin was used as a continuous infusion to treat a urinary tract infection with methicillin-resistant Staphylococcus aureus (MRSA) in a 90-year-old nursing home resident.8 Vancomycin 1000 mg in 1000 mL of normal saline was instilled at 42 mL/h for 5 days. Urine cultures were repeated 2 days after vancomycin therapy ended and were negative for MRSA. Vancomycin serum levels were described as 'negligible'; however, the author recommended monitoring of serum levels in the event of enhanced absorption due to mucosal inflammation or increased bladder pressure.
A case report by Curtis and Biundo described the use of piperacillin as an irrigation for treatment of recurrent bladder infections.9 Previous oral therapies had failed due to intolerability by the patient. Piperacillin 500 mg in 50 mL of normal saline was given as an intermittent irrigation (instilled for 30 minutes) twice daily for 5 days. Treatment was considered successful based on resolution of symptoms.
A number of studies and reports have described the use of amphotericin as a bladder irrigation, however, there appears to be limited evidence for its efficacy.10 Tuon and colleagues conducted a meta-analysis of published trials with amphotericin B bladder irrigation. 11 Nine prospective trials were included in the analysis. The concentration of amphotericin ranged from 0.005 to 0.3 mg/mL, given as a continuous infusion (primarily as 50 mg per 1000 mL over 24 hours) or intermittently (primarily as 10 to 40 mg in 100 to 200 mL 3 times per 24 hours). For continuous infusions, rate of clearance of candiduria at 24 hours ranged from 70% to 100% for 50 mg per 1000 mL, with one report of 62% with a dose of 10 mg per 1000 mL. Longer durations were not always associated with a higher percentage of clearance. A 3-day irrigation resulted in 100% clearance of candiduria, while the rate of clearance reported with 7 days of treatment was 94%. Clearance rates were similar for intermittent therapy, ranging from 81% to 87%; one study reported a 30% clearance with 10 mg of amphotericin per100 mL.
In a small prospective study, Nesbit and colleagues compared 10 mg and 50 mg of amphotericin per 1000 mL of sterile water as a continuous infusion (42 mL/hr) for 72 hours.12 The study was stopped early due to a higher failure rate in the 10 mg amphotericin group. The authors reported 100% fungal eradication with 50 mg amphotericin compared with 67% in the 10 mg group.
Finally, Jacobs and colleagues compared oral fluconazole with amphotericin bladder irrigation in the treatment of fungal urinary tract infections in elderly patients.13 Amphotericin 25 mg per 500 mL of dextrose 5% was instilled continuously at 42 mL/h for 5 days; fluconazole was given orally as a 200 mg loading dose followed by 100 mg per day, or 50 mg per day for patients with reduced renal function. Rates of eradication of funguria were higher with amphotericin-96% versus 73% (p<0.05) at 2 days after treatment.
Although described in the literature, data on the efficacy of bladder irrigations for superficial bladder infections or cystitis are limited. The Infectious Diseases Society of America (IDSA) has published guidelines on the treatment of bacterial and fungal infections of the bladder, and do not recommend bladder irrigations as first-line therapy (see Table).14,15 Although local application of agents to avoid systemic exposure may be desirable, there are little data on effective concentrations, optimal duration of therapy, and best manner of administration (continuous vs. intermittent).
Table. IDSA recommendations for bladder irrigations.14,15
IDSA treatment guidelines for candidiasis
Alternatives: Intravenous Amphotericin,
Amphotericin bladder irrigation not routinely recommended (>90% response but high relapse rate), except for fluconazole-resistant Candida species (eg, C. glabrata or C. krusei) or treatment of urinary fungal mass (as adjunctive therapy).
Amphotericin 50 mg/1000 mL sterile water
IDSA treatment of catheter-associated urinary tract infections in adults
Catheter-associated infections-prevention or treatment
Data insufficient regarding bladder irrigations with antimicrobial agents in patients with indwelling catheters.
Some efficacy has been seen in preventing catheter-associated bacteriuria in patients with short-term catheterization undergoing surgical procedures.
IDSA = Infectious Diseases Society of America; NA = not available.
1. Goldman H, Littman H, Oppenheimer G, Glickman S. Monilial cystitis-effective treatment with instillations of amphotericin B. JAMA. 1960;174:359-362.
2. Vistide [package insert]. Foster City, CA: Gilead Sciences; 2000.
3. Bridges B, Donegan S, Badros A. Cidofovir bladder instillation for the treatment of BK hemorrhagic cystitis after allogeneic stem cell transplantation. Am J Hematol. 2006;81(7):535-537.
4. Eisen D, Fraser I, Sung L, Finlay M, Bowden S, OConnell H. Decreased viral load and symptoms of polyomavirus-associated chronic interstitial cystitis after intravesicular cidofovir treatment. Clin Infect Dis. 2009;48(9):e86-88.
5. Rao K, Shea T. Intravesicular cidofovir for the management of BK virus-associated cystitis. Biol Blood Marrow Transplant. 2009;15(5):391-392.
6. Defoor W, Ferguson D, Mashni S, et al. Safety of gentamicin bladder irrigations in complex urological cases. J Urol. 2006;175(5):1861-1864.
7. Wood G, Chapman J, Boucher B, et al. Tobramycin bladder irrigation for treating a urinary tract infection in a critically ill patient. Ann Pharmacother. 2004;38(7-8):1318-1319.
8. Hajjar R, Philpot C, Morley J. Continuous bladder irrigation with vancomycin for the treatment of methicillin-resistant Staphylococcus aureus. J Am Geriatr Soc. 1996;44(7):886-887.
9. Curtis L, Biundo B. Irrigation with piperacillin for the treatment of bladder infection. Int J Pharm Comp. 2001;5(3):195.
10. Drew R, Arthur R, Perfect J. Is it time to abandon the use of amphotericin B bladder irrigation? Clin Infect Dis. 2005;40(10):1465-1470.
11. Tuon F, Amato V, Filho S. Bladder irrigation with amphotericin B and fungal urinary tract infection-systematic review with meta-analysis. Int J Infect Dis. 2009;13(6):701-706.
12. Nesbit S, Katz L, McClain B, Murphy D. Comparison of two concentrations of amphotericin B bladder irrigation in the treatment of funguria in patients with indwelling urinary catheters. Am J Health-Syst Pharm. 1999;56(9):872-875.
13. Jacobs L, Skidmore E, Freeman K, Lipschultz D, Fox N. Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis. 1996;22(1):30-35.
14. Hooton T, Bradley S, Cardenas D, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663.
15. Nicolle L, Bradley S, Colgan R, et al. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40(5):643-654.
How do you safely and effectively use elastomeric pain pumps?
How do you safely and effectively use elastomeric pain pumps?
The On-Q PainBuster Pump (I-Flow) and PainPump2 (Stryker) are elastomeric pumps intended to provide post operative pain relief by delivering local anesthetic through a catheter placed directly at the surgical site. These devices are used in a variety of surgical settings and pharmacists are raising a variety of questions regarding their use.
Do these pumps provide effective pain relief?
There are a number of studies evaluating the efficacy of these pumps. Most studies compared infusion of the local anesthetic (usually ropivacaine or bupivacaine) to a saline infusion or to intravenous (IV) pain medications.1-5 A variety of drug concentrations and infusion rates have been evaluated with most studies finding both reduced pain and postoperative opioid consumption with use of these pumps. A 2006 systematic review of 44 trials found a number of benefits to delivering local anesthetic via the pumps including a decrease in pain visual analogue scores (VAS), reduced opioid consumption, as well as a decrease in post-operative nausea and vomiting.6 However, a few more recent studies have not found the pumps to improve pain control postoperatively. Coghlan and colleagues compared a subacromial ropivacaine infusion to placebo after rotator cuff surgery in 158 patients and found that the VAS pain scores between groups were not clinically different in the first 12 hours postoperatively (1.62 in the ropivacaine group versus 2.16 in the placebo group).7 Additionally, there was no difference in the amount of oral analgesia used postoperatively. In 73 patients who underwent hernia repair, Rosen and colleagues found no benefit to the use of bupivacaine wound infusion in terms of VAS pain scores or opioid use.8 Magnani and colleagues compared the On-Q PainBuster pump containing levobupivacaine to intravenous administration of ketorolac and morphine in 20 patients undergoing cesarean sections.9 They found significantly lower VAS pain scores with the use of the IV medications. Finally, in 50 patients undergoing anterior cruciate ligament reconstruction a continuous femoral nerve block was found to be more effective than ropivacaine via a continuous wound infusion with an elastomeric pain pump.10
There has been some interest in the addition of antibiotics or additional pain relievers to the anesthetic in the elastomeric pain pumps; however, efficacy data with these combinations are lacking. One abstract presented at the 2008 American Society of Anesthesiologists meeting compared the infusion of ketorolac alone or ketorolac plus ropivacaine at the surgical site in 60 patients and found ketorolac alone to be as effective as the combination for pain control.11
I-Flow, the manufacturer of the On-Q PainBuster Pump, has a clinical library on its Web site at www.iflo.com/clinical_library.php that provides a number of links to abstracts of efficacy studies for the pump.12 Readers should be cautioned that the company appears to have limited its site to those articles showing the benefit of the pump and excluded those studies that failed to show a benefit.
Are there any safety concerns with these pumps?
Both the Food and Drug Administration (FDA) and the Institute for Safe Medication Practices (ISMP) have raised concerns about the safety of the way the pumps are being used in clinical practice.13,14 The FDA issued a warning in the fall of 2009 regarding chondrolysis associated with the use of prolonged local anesthetic in the intra-articular space.13 Thirty-five cases were reported between 2006 and 2008 with most associated with prolonged infusions (48 to 72 hours) of local anesthetic. Based on this data the FDA recommended that the devices not be used for continuous intra-articular infusion in patients after orthopedic surgery.
A 2009 ISMP safety alert highlighted several concerns with these devices that are pertinent to pharmacy.14 Often the devices are filled outside of the pharmacy, typically in the operating room which raises concerns about accurate filling, labeling, and documentation of the administered medication. Another concern is the variability in infusion rates. Elastomeric pumps typically operate within 15% of the set flow rate; however, it is important to avoid over- or under-filling the reservoirs.15 The pumps are disposable and refill of the pumps is not recommended. I-Flow recommends that the On-Q pump not be used for greater than 5 days.14
A number of strategies for safe use of the pumps have been identified by ISMP.14 The following table lists ISMP's recommendations for safe dispensing of the On-Q pump.
Table 1. ISMP recommendations for safe dispensing of the On-Q Pump. 14
Establish standard concentrations for drugs used in the pumps Establish compounding procedures for any admixtures Establish order sets to facilitate screening for appropriate dose, drug interactions, allergies, and duplicate therapy Require pharmacy preparation of the reservoirs; the amount of solution should be specified based on the duration of therapy and rate of infusion (ISMP also suggests that outsourced compounding can be utilized) Require pharmacy double-check of drug, strength, and volume
What stability or compatibility information is available with commonly prescribed drugs?
There is little published information available on the stability and compatibility of anesthetics and combinations of drugs in the elastomeric pain pumps; however, the I-Flow Corporation does provide information specific to the On-Q Pump. Table 2 lists stability information with local anesthetics; however, due to sterility concerns the manufacturer recommends that the pump be connected to the patient within 24 hours if filled in the operating room or surgical suite.16 If filled in the pharmacy, the pump may be stored up to 30 hours at room temperature or 7 days under refrigeration prior to use.
Table 2. Stability of preservative-free local anesthetics in the On-Q Pump. 16
Drug Concentration Room temperature storage time Bupivacaine 0.25 to 0.5% 30 days Lidocaine 1% 30 days Ropivacaine 0.2% 30 days Ropivacaine 0.2 to 0.75% 14 days
The stability of combination agents has also been studied by I-Flow and is summarized in Table 3.
Table 3. Stability of local anesthetic and combinations in the On-Q Pump. 17,18
Mixture* Infusion at room temperature Bupivacaine/Dexamethasone (0.4 mg/mL) 5 days Bupivacaine/Ketorolac (1 mg/mL) 7 days Ropivacaine/Ketorolac (1 mg/mL) 7 days
* All mixtures were 0.5% local anesthetic and infusions were initiated after 7 days of refrigerated storage. Pumps were filled to 125 mL.
In addition, the stability of bupivacaine in combination with either ceftriaxone or cefazolin has been studied by I-Flow.19 A 1 gram vial of antibiotic was combined with bupivacaine 0.5% to a final volume of 270 mL yielding a 3.7 mg/mL antibiotic solution. The bupivacaine and ceftriaxone solution contained >95% of the control at 48 hours and the bupivacaine and cefazolin solution contained >95% of the control at 72 hours.
Elastomeric pain pumps designed to deliver local anesthetic directly to the surgical site provide postoperative pain control; however, the benefit over traditional pain control methods is not entirely clear. Pharmacists should take a proactive role in the dispensing and monitoring of these pumps to ensure safe practice within their institution.
1. Yoost TR, McIntyre M, Savage SJ. Continuous infusion of local anesthetic decreases narcotic use and length of hospitalization after laparoscopic renal surgery. J Endourol. 2009;23(4):623-626.
2. Forastiere E, Sofra M, Giannarelli D, Fabrizi L, Simone G. Effectiveness of continuous wound infusion of 0.5% ropivacaine by On-Q pain relief system for postoperative pain management after open nephrectomy. Br J Anaesth. 2008;101(6):841-847.
3. Gomez-Cardero P, Ridriguez-Merchan EC. Postoperative analgesia in TKA: ropivacaine continuous intraarticular infusion. Clin Orthop Relat Res. 2010;468(5):1242-1247.
4. Schell SR. Patient outcomes after axillary lymph node dissection for breast cancer: use of postoperative continuous local anesthesia infusion. J Surg Res. 2006;134(1):124-132.
5. Ansaloni L, Agnoletti V, Bettini D, et al. The analgesic efficacy of continuous elastomeric pump ropivacaine wound instillation after appendectomy. J Clin Anesth. 2007;19(4):256-263.
6. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of continuous wound catheters delivering local anesthetic for postoperative analgesia: a quantitative and qualitative systematic review of randomized controlled trials. J Am Coll Surg. 2006;203(6):914-932.
7. Coghlan JA, Forbes A, McKenzie D, Bell SN, Buchbinder R. Efficacy of subacromial ropivacaine infusion for rotator cuff surgery: a randomized trial. J Bone Joint Surg Am. 2009;91(7):1558-1567.
8. Rosen MJ, Duperier T, Marks J, et al. Prospective randomized double-blind placebo-controlled trial of postoperative elastomeric pain pump devices used after laparoscopic ventral hernia repair. Surg Endosc. 2009;23(12):2637-2643.
9. Magnani E, Corosu R, Mancino P, Borgia ML. Postoperative analgesia after cesarean section by continued administration of levobupivacaine with the On-Q Painbuster system over the fascia vs ketorolac + morphine i.v. Clin Exp Obstet Gynecol. 2006;33(4):223-225.
10. Dauri M, Fabbi E, Mariani P, et al. Continuous femoral nerve block provides superior analgesia compared with continuous intra-articular and wound infusion after anterior cruciate ligament reconstruction. Reg Anesth Pain Med. 2009;34(2):95-99.
11. Mcniel D, Muhammad R, Manchandani R, Pagala M, Tyagaraj K. The analgesic efficacy of ketorolac and ropivacaine infusion for postoperative pain management. Anesthesiology. 2008;109:A1709.
12. ON-Q Clinical Library. www.iflo.com/clinical_library.php . Accessed July 8, 2010.
13. Food and Drug Administration. Chondrolysis reported with continuously infused local anesthetics (marketed as bupivacaine, chlorprocaine, lidocaine, mepivacaine, procaine, and ropivacaine). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders
/ucm190328.htm. Published November 13, 2009. Updated February 16, 2010. Accessed July 8, 2010.
14. Instiutute for Safe Medication Practices. Process for handling elastomeric pain relief balls (ON-Q Painbuster and others) requires safety improvements. www.ismp.org/newsletters/acutecare/articles/20090716.asp. Published July 16, 2009. Accessed July 8, 2010.
15. Skryabina EA, Dunn TS. Disposable infusion pumps. Am J Health-Syst Pharm. 2006;63(13):1260-1268.
16. Data on file. Technical bulletin: relationship between the ON-Q Pain Relief System and the USP-NF 27 <797> Pharmaceutical Compounding – Sterile Preparations. I-Flow Corporation; 2009.
17. Data on file. Technical bulletin: bupivacaine with dexamethasone – drug stability. I-Flow Corporation; 2009.
18. Data on file. Technical bulletin: bupivacaine/ropivacaine with ketorolac tromethamine stability. I-Flow Corporation; 2009.
19. Data on file. Technical bulletin: bupivacaine/antibiotic stability. I-Flow Corporation; 2009.
Updated perinatal guidelines for HIV-1 infected women
Updated perinatal guidelines for HIV-1 infected women
On May 24, 2010, the Panel on Treatment of Human Immunodeficiency Virus (HIV)-Infected Pregnant Women and Prevention of Perinatal Transmission released its updated perinatal guidelines.1 These guidelines provide an update to the previous version, published online April 29, 2009. The 2010 guidelines are broken into the perinatal periods including preconception care and antepartum, intrapartum and postpartum periods. The focus of this summary is to review the recommendations specifically related to drug therapy. The reader is referred to the US Department of Health and Human Services' AIDSinfo website for the full guidelines: http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=9&ClassID=2
Overall changes to the guidelines include changes in formatting for improved readability, and addition of a rating scheme to denote the level of evidence upon which the panel's recommendations are made.1 Previously used drug name acronyms have been replaced with the full generic antiretroviral drug names. The electronic document contains references/links to other sections of the document or other guidelines that contain related information. Additionally, the updated guidelines provide a supplement on the safety and toxicity of antiretroviral agents in pregnancy.
Preconceptional counseling and care for HIV-infected women of childbearing age
Approximately 50% of pregnancies are unplanned in the United States.2 HIV-infected women of childbearing age should be counseled on safe sexual practices and appropriate contraceptive methods to reduce the risk of unplanned pregnancy, prevent HIV transmission to sexual partners, protect the woman from sexually transmitted infections, and reduce the potential to acquire more virulent or resistant HIV strains.1 Tobacco cessation counseling and avoidance of alcohol and illicit drugs should be emphasized for the health of the woman and the fetus/infant should she become pregnant. The initial evaluation of an HIV-infected woman of childbearing age should include assessment of her HIV disease status and whether antiretroviral therapy (ART) initiation is necessary for her own health. Regimens containing efavirenz or other teratogenic drugs, such as didanosine, should be avoided. Those women already on ART should have their regimen assessed for the risk of possible adverse outcomes to the mother and fetus and for teratogenicity. Suppression of maternal viral load decreases the risk of mother-to-child transmission of HIV.
Antepartum care (before delivery)
General principles regarding use of antiretroviral drugs during pregnancy
Antiretroviral drugs reduce the rate of perinatal HIV transmission via a variety of mechanisms; therefore, antiretroviral prophylaxis is recommended antepartum, intrapartum, and postnatally for prevention of perinatal HIV transmission.1 Antenatal ART therapy has been shown to reduce perinatal HIV transmission even when administered to mothers with HIV RNA levels <1000 copies/mL. Pregnant women should receive counseling on risks and benefits of initiating HIV prophylaxis/treatment. There are limited data on the consequences of long-term maternal ART use during pregnancy, including long-term consequences of in utero antiretroviral exposure to the infant. The risk of maternal disease progression, benefits of combination ART regimens, potential adverse effects to mother and fetus/infant, limited long-term outcome data, and possibility of ART resistance should the child become HIV infected should all be considered/discussed with the pregnant women when initiating therapy.
Zidovudine should be included in antenatal ART regimens; prophylaxis with zidovudine has been shown to be effective in reducing HIV transmission to the infant, regardless of the maternal HIV RNA level.1 Women who have had considerable zidovudine-related toxicity, or have well-suppressed HIV on a non-zidovudine containing regimen, indicated by a non-detectable HIV RNA level, are considered candidates for non-zidovudine containing regimens. Women with detectable levels of HIV RNA (> 500 to 1000 copies/mL) should be tested for antiretroviral resistance before initiating or changing current ART medications. Adherence to the ART treatment or prophylaxis should be emphasized.
Recommendations for use of antiretroviral drugs during pregnancy
Based on clinical trial data published in peer-reviewed journals, the Panel has developed criteria for recommending specific ART drugs based on effective viral suppression, drug toxicity, tolerability, and pharmacokinetic data in the prenatal period.1 The categories are listed below, and Table 1 contains examples of drugs falling in each category.
- "Preferred" drugs or drug combinations have demonstrated optimal efficacy with acceptable toxicity, sufficient pharmacokinetic data in pregnancy, and no evidence of teratogenicity associated with therapy.
- "Alternative" drugs or drug combinations are considered alternatives to preferred drugs due to limited or lacking data on use in pregnancy or teratogenicity, or other dosing, formulation, administration, or interaction issues are present.
- "Use in Special Circumstances" designates potential use of a drug or drug combination when the mother is intolerant or resistant to preferred or alternative agents or has a comorbdity or requires medications that interact with ART.
- "Insufficient Data to Recommend" indicates drug or drug combinations lack information pregnancy specific safety or pharmacokinetic data.
Table 1. Criteria for recommending antiretroviral agents.1
Preferred NRTI regimen, large experience with use in pregnancy
Preferred protease inhibitor regimen because of efficacy studies in humans and experience with use in pregnancy
Women with CD4+ counts of <250 cells/mL or continuation of a nevirapine-based regimen; increased risk of fatal rash and hepatic toxicity at greater CD4+ cell counts
Atazanavir + ritonavir
Saquinavir + ritonavir
Indinavir + ritonavir
Limited experience in pregnancy; saquinavir and indinavir may be less well-tolerated than atazanavir
Didanosine should be used with stavudine only in the absence of alternatives; reports of fetal lactic acidosis and hepatic failure in pregnant women
Intolerance to zidovudine or chronic hepatitis B infection due to potential fetal toxicity, theoretical decreased fetal grown, reduction in fetal bone porosity, and bone demineralization in some children
Not recommended during first trimester due to animal data showing increased risk of anencephaly, micro-opthalmia, facial clefts, and case reports of neural tube defects, a case of anophthalmia; may be considered after the first trimester if other alternate agents are not tolerated
Insufficient data to recommend
Insufficient safety or pharmacokinetic data in pregnant women
Data too limited to recommend routine use in pregnancy
Insufficient data; consult with HIV and obstetric specialists if patient has failed several other therapeutic regimens
NRTI=nucleoside reverse transcriptase inhibitor; HIV=human immunodeficiency virus.
All ART regimens during pregnancy should be individualized, taking into consideration a variety of factors including: comorbidities, patient adherence potential, regimen convenience, potential adverse drug effects on the mother, potential drug interactions with other medications, results of genotypic resistance testing, pharmacokinetic changes during pregnancy, and potential teratogenic effects on the fetus or other adverse effects on the fetus or newborn.1
There are insufficient data to determine actual teratogenic risk to the fetus due to ART exposure in the first 10 weeks of gestation; however, current data does not support major teratogenic effects with most antiretroviral drugs.1 Efavirenz is an exception as its use in early pregnancy has been associated with developmental defects; therefore, it should be avoided in the first trimester. Women already on an efavirenz-containing regimen should be placed on an alternative drug during pregnancy to avoid risk to the fetus. Pregnant women already on nevirapine should continue on nevirapine, regardless of their CD4+ cell count; there is not an increased risk for hepatic toxicity in women who have immune reconstitution while on nevirapine-based therapy. Lopinavir/ritonavir is the preferred protease inhibitor regimen during pregnancy due to the extent of experience with its use in pregnancy. Further information on use of antiretroviral drugs in pregnancy can be found online at www.APRegistry.com.3
Women who are on ART therapy but not fully suppressed (HIV RNA >500 to 1000 copies/mL) upon presentation for obstetrical care should undergo HIV resistance testing to select a fully suppressive regimen.1 Resistance testing should also be performed before the initiation of ART in HIV-infected pregnant women who have never received antiretroviral drugs.
Treatment-naïve women who meet the standard criteria for initiating ART should receive a standard potent combination using an nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) plus an non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) as soon as possible, avoiding agents with a known risk of teratogenicity.1 This regimen should be continued postpartum. Whenever possible, initiation of nevirapine should be avoided in women with CD4+ cell counts >250 cells/mL due to an increased risk of hepatotoxicity, which is often associated with a rash.
Pregnant women who have never been on ART and do not require initiation of ART for their own health may be initiated on a 3-drug ART regimen following standard guidelines after the first trimester of pregnancy.1 A triple NRTI combination of zidovudine, lamivudine, and abacavir may be considered in women who test negative for HLA-B*5701 (positive indicates risk for abacavir hypersensitivity) due to acceptable toxicities in pregnancy, despite the fact that such a regimen is no longer recommended in nonpregnant adults. Nelfinavir may also be considered due to its safe profile during pregnancy. These regimens should not be considered options in women with a high CD4+ count or high viral load (i.e., CD4+ count of >350 cells/mm 3 and HIV RNA of >100,000 copies/mL) due to inferior long-term efficacy. In such cases, a more potent regimen is suggested. The use of zidovudine as a single agent for a limited duration remains controversial. Women who wish to reduce fetal exposure to ART drugs and have HIV RNA levels <1000 copies/mL may be candidates for zidovudine monotherapy during the second and third trimesters.
Generally, when ART is initiated to prevent perinatal transmission, the drugs are discontinued postnatally with the option to reinitiate potent ART in the future.1 The drugs are typically discontinued simultaneously; however, in NNRTI-based regimens the dual NRTI backbone should be continued for at least 7 days after the NNRTI is stopped. Alternately, the NNRTI may be replaced with a PI during this time, and all the drugs may be stopped at the same time. In patients receiving an efavirenz-based NNRTI regimen, efavirenz may remain detectable in the plasma for over 3 weeks after its discontinuation. Based on expert recommendations, these patients may either continue the other 2 ART drugs in their regimen, or substitute a PI for the efavirenz, and continue this plus 2 other agents for up to 30 days.
Women who have received ART in the past, but are not on therapy upon presentation for obstetrical care should undergo HIV resistance testing. 1 The results of previous resistance testing and previous ART regimens should also be obtained and reviewed prior to initiation of a new ART regimen. In the case of complicated resistance patterns, expert consultation regarding ART regimen and teratogenicity is recommended.
Hepatitis B and C testing is recommended for all HIV-infected pregnant women.1 Women who test negative for hepatitis B virus (HBV) should receive the HBV vaccine series. Women who test positive for HBV should also be tested for hepatitis A virus (HAV), and should receive the HAV vaccine series if negative. The reader is referred to the guideline for recommendations on management of HBV or hepatitis C coninfection.
Generally, ART should be continued throughout the antepartum period.1 Discontinuation of ART during pregnancy may be necessary in some situations including drug-related toxicities, hyperemesis secondary to pregnancy, inability to take oral medications due to acute illness or planned surgery, inability to acquire medications, or by patient request. When short-term drug discontinuation is indicated, all ART medications should generally be discontinued at the same time and restarted at the same time. Drugs with a longer half-life may prove problematic when acute discontinuation is warranted. Nevirapine and efavirenz (NNRTIs) have very long half-lives, and may be detected in the blood for 3 weeks or longer following drug discontinuation. When drugs with shorter half-lives are discontinued earlier, the persistent subtherapeutic drug levels pose the risk for development of resistance. Certain ethnicities, such as African-American and Hispanic, may possess genetic polymorphisms that result in an even slower rate of drug clearance from the body. Some experts recommend stopping the NNRTI first and continuing the other ART medications for a certain period of time; however, an ideal timeframe for continuation of the other 2 drugs has not been established, but have been continued for up to 30 days after discontinuation of efavirenz.
In the case of failure of viral suppression after adequate treatment duration, the patient should be assessed for treatment adherence, incorrect dosing, or potential issues with drug absorption.1 Resistance testing should be conducted in these patients if a change in the drug regimen is necessary. HIV RNA levels should be assessed every 2 to 6 weeks following initiation or change to an ART regimen. Patients are expected to have a drop in HIV RNA levels of at least 1 log10 copies/mL by 1 to 4 weeks after initiation of therapy. Maternal antenatal viral load correlates with the risk of transmission during birth; HIV-infected women who have HIV RNA levels >1000 copies/mL near the time of delivery should he scheduled for a cesarean delivery to minimize this risk.
Intrapartum (childbirth) antiretroviral therapy/prophylaxis
Intrapartum intravenous zidovudine is recommended for all HIV-infected women to reduce perinatal transmission of HIV.1 Those on a stavudine-containing regimen should stop stavudine during administration of intravenous zidovudine, but should continue the rest of their antiretroviral regimen. Similarly, women on fixed-dose regimens that contain zidovudine should take the other components orally while the zidovudine is administered intravenously. Single-dose nevirapine at the time of delivery has been associated with development of nevirapine resistance. This resistance may be reduced by using a nevirapine "tail" in the mother and infant such as 7 or more days of zidovudine and lamivudine.
Regardless of cause, all women with HIV RNA levels >1000 copies/mL near the time of delivery should be offered a scheduled cesarean delivery at 38 weeks gestation to reduce the risk of transmission. It is unclear whether cesarean delivery reduces the risks of transmission in women with lower HIV RNA levels, and vaginal birth may be considered. All HIV-infected women delivering via cesarean section should be treated with prophylactic antibiotics.
Postpartum and neonatal postnatal care
Neonates whose mothers did not receive antenatal ART prophylaxis should be treated postnatally with zidovudine.1 A multi-national study of patients born without antenatal therapy and examining the effectiveness of zidovudine alone or with 1 or 2 other agents is ongoing. Currently, a 6-week course of zidovudine monotherapy is recommended for neonates in the United States whose mothers did not receive antenatal or intrapartum therapy.
With further supporting evidence, the panel reaffirms that breastfeeding should be avoided whenever socially and economically feasible. 1 Maternal triple drug prophylaxis and infant prophylaxis using nevirapine may decrease postnatal transmission via breast milk; however, these treatments may be associated with an increased risk of drug resistance in infants despite prophylaxis and should be avoided.
National Perinatal HIV Hotline
The National Perinatal HIV Hotline (1-888-448-8765) is run by the National HIV/AIDS Clinicians' Consultation Center, a free consultation line for healthcare providers caring for HIV-infected women and their infants ( http://www.nccc.ucsf.edu/about_nccc/perinatal_hotline/).4
- AIDSinfo Web site: http://AIDSinfo.nih.gov
- Information on teratogenic effects of most antiretroviral drugs: www.APRegistry.com
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. May 24, 2010; pp 1-117. http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed July 10, 2010 .
- Centers for Disease Control and Prevention. Unintended pregnancy prevention: home. http://www.cdc.gov/reproductivehealth/unintendedpregnancy/index.htm . Accessed August 30, 2010.
- The antiretroviral pregnancy registry. http://www.nccc.ucsf.edu/about_nccc/perinatal_hotline/. Accessed August 30, 2010.
- University of California, San Francisco. National HIV/AIDS Clinicians' Consultation Center. http://www.nccc.ucsf.edu/about_nccc/perinatal_hotline/. Accessed August 30, 2010.
By Sheri VanOsdol, PharmD
Should quinine be used for treatment of nocturnal leg cramps?
Should quinine be used for treatment of nocturnal leg cramps?
Since 1969, the Food and Drug Administration (FDA) has received numerous adverse event reports associated with the use of quinine.1 These reports included events such as cardiac arrhythmias, thrombocytopenia, severe hypersensitivity reactions, and death. The FDA noted that these events were occurring primarily in patients using the drug for treatment of nocturnal leg cramps. In addition, the FDA cited that there is a lack of evidence supporting the efficacy of quinine for this condition. This prompted the FDA to rescind its approval of quinine for the treatment of nocturnal leg cramps in 1995.2 Unfortunately, many clinicians continued to prescribe quinine off-label for the management of this condition because of their familiarity with the drug and the lack of other agents for management of leg cramps. By 2006, the FDA increased its efforts to stop the use of quinine for nocturnal leg cramps by ordering unapproved quinine drugs to be removed from the market.1 This resulted in the availability of only one approved quinine product, known as Qualaquin, for the treatment of uncomplicated malaria. The FDA stressed that quinine was appropriate for the management of malaria, but should not be used for nocturnal leg cramps because the risks of the drug exceed the benefits for this condition.
New REMS for Qualaquin
On July 8, 2010, the FDA announced that a new Risk Evaluation and Mitigation Strategy (REMS) was going to be implemented for Qualaquin because of the continued off-label use of the drug for nocturnal leg cramps.3,4 A total of 38 cases of serious adverse events associated with quinine were submitted to the FDA from April 2005 to October 1, 2008, with the majority of cases occurring in patients (n=25) taking the drug for the treatment or prevention of nocturnal leg cramps. Only 1 patient was taking the drug for treatment of malaria. Hematological events were the most common (24 events), followed by 10 miscellaneous events (i.e., gastrointestinal symptoms, hearing loss, rash, electrolyte imbalance, and drug interaction), and 4 cardiovascular events. Of the 24 hematological events, 21 patients had thrombocytopenia that required hospitalization and 4 cases were further classified as thrombotic thrombocytopenic purpura (TTP, n=2) and idiopathic thrombocytopenic purpura (n=2). The median time to onset of the thrombocytopenia was 13.5 days and median platelet count was 4500 cells/µL (range, 1000 to 83,000 cells/ µL; data from 18 patients). In addition, 2 deaths were reported, 1 as a result of TTP and 1 from hemolysis. The thrombocytopenia resolved in the majority of patients once the quinine was discontinued and other interventions were started.
Based on the continued reports of quinine-associated adverse events, a REMS program is now in place for Qualaquin, which includes prescriber and patient education.4 For prescribers, a "Dear HealthCare Provider" letter was issued describing the risk of serious and life-threatening hematologic adverse events with quinine and how the drug should not be used off-label for the management of nocturnal leg cramps.5 The REMS requires that the manufacturer distributes the letter to providers expected to prescribe the drug and to the executive directors/professional relations departments of 11 professional organizations, which include the American Academy of Family Physicians, American Academy of Neurology, American Academy of Sleep Medicine, American Association of Orthopedic Surgeons, American College of Cardiology, American College of Physicians, American College of Rheumatology, American Geriatrics Society, American Osteopathic Association, American Society of Nephrology, and Infectious Disease Society of America. 4 All of the members of these societies will also receive a copy of the letter.
For patients, a "Medication Guide" is now required to be given with every Qualaquin prescription.4 This guide discusses how the drug should not be used off-label for leg cramps and describes numerous symptoms patients should be aware of to indicate that they may be having a serious reaction to the drug.6 The FDA has also developed a consumer handout titled "Using Malaria Medication for Leg Cramps is Risky", which can be accessed at www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM218269.pdf.7
Clinicians need to be aware of the serious adverse events associated with the use of quinine and should only prescribe the drug for malaria. Based on a 50-year history of adverse events associated with quinine and the lack of solid efficacy data for the management of nocturnal leg cramps, it should never be used for this condition. When verifying an order for quinine, check the diagnosis to ensure the patient has malaria. If the patient does not have malaria, contact the prescriber and educate him/her that use of quinine for conditions other than malaria is not appropriate. If quinine is being used for malaria, educate patients to look for signs of potentially serious adverse events such as bruising, severe nose bleeds, blood in the urine or stool, purple, brown, or red spots on the skin, chest pain, and rash; patients should be encouraged to report any of these symptoms to their health care provider immediately.
1. Food and Drug Administration. FDA advances effort against marketed unapproved drugs. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108799.htm. Accessed August 23, 2010.
2. Crum NF, Gable P. Quinine-induced hemolytic-uremic syndrome. South Med J. 2000;93(7):726-728.
3. Food and Drug Administration. FDA drug safety communication: new risk management plan and patient medication guide for Qualaquin (quinine sulfate). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
ucm218202.htm. Accessed August 23, 2010.
4. Food and Drug Administration. Qualaquin: Risk Evaluation and Mitigation Strategy (REMS). www.fda.gov/downloads/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/UCM217721.pdf. Accessed August 23, 2010.
5. AR Scientific. Dear healthcare provider letter. www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/UCM221259.pdf. Accessed August 23, 2010.
6. AR Scientific. Medication guide: Qualaquin. www.qualaquin.com/MEDICATION_GUIDE_Qualaquin.pdf. Accessed August 23, 2010.
7. Food and Drug Administration. Using malaria medication for leg cramps is risky. www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM218269.pdf. Accessed August 23, 2010.