o r i g i n a l c o m m u n i c a t i o n Incomplete Follow-up of Hemoglobinopathy Carriers Identified by Newborn Screening Despite Reporting in Electronic Medical Records Mara Burney, RN, MPH; kelly Schunk, MPH; Nelly J. Oundjian, MD; Richard G. Younge, MD, MPH; Mary McCord, MD, MPH; Nancy S. Green, MD funding/support: This work was supported by the Health Resources and Services Administration (H46MC09227, Dr Green) and the Irving Institute for Clinical and Translational Research (5kL2RR024157). Objective: Has the recent availability of newborn hemoglobinopathy screening results within patient electronic medical records (EMR) of birth hospitals facilitated follow-up by primary care pediatric providers? Methods: An online survey of all 137 primary care pediatric providers at a New York City academic medical center was conducted in 2008-2009 to assess practices for hemoglobinopathy trait follow-up. Physicians were resurveyed 1 year later, following educational outreach and a letter of instruction underscoring the availability of screening results in the EMR. All 62 primary care pediatricians were surveyed at a nearby city hospital for comparison. Results: Overall response rate for the initial survey at the teaching hospital was 58% for pediatricians (N = 57) and family physicians (N = 23), and 50% for pediatricians at the city hospital (N = 31). Despite high prevalence of hemoglobinopathies in the population served and screening results in EMRs, only 46.2% of providers surveyed at the academic center reported routinely checking results of their infant patients: 38.6% of pediatricians and 66.7% of family practitioners. Some respondents were unaware that results are available in the EMR. The proportion of providers checking screening results was not significantly affected by educational intervention (N = 40). Provision of recommended follow-up for a positive trait result was modestly improved, especially in referring families for genetic counseling (25% to 50%, p < .01). In contrast, most pediatricians (83%) at the city hospital routinely check and perform follow-up. Conclusion: Despite access to results in the EMR and targeted educational outreach, follow-up of hemoglobinopathy screening by primary care varies widely across clinical sites. Keywords: infant health n screening n sickle cell disease n electronic medical record J Natl Med Assoc. 2011;103:852-856 852 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION Author Affiliations: School of Nursing (Ms Burney), Department of Pediatrics (Ms Schunk and Drs Oundjian, McCord, and Green), Center for Family and Community Medicine (Dr Younge), Columbia University Medical Center, New York, New York. correspondence: Nancy S. Green, MD, Department of Pediatrics, Columbia University Medical Center, 630 w 168 St, New York, NY 10032 (nsg11@columbia.edu). inTRoDucTion T he majority of state newborn screening programs notify the birth hospital and pediatric provider of record1 of infants with positive carrier screens. Primary care providers are responsible for communicating results to families and ensuring appropriate and timely follow-up of affected children. In 2007, the American Academy of Pediatrics (AAP) released specific guidelines for NBS follow-up to emphasize the responsibilities of primary care pediatricians,2 including development of office policies and procedures to guarantee that results are communicated to affected families, along with timely confirmation testing and genetic counseling or referral. The PCP cannot assume a ‘no news is good news’ approach with regard to newborn screening…Office staff should check routinely for newborn screening results…and pursue missing results before the visit…2 Despite this consensus, several studies have demonstrated that these recommendations are frequently not followed,3-5 especially for those identified as carriers of heritable conditions such as hemoglobinopathy trait.4,5 Efficient access to newborn screening results is consistently cited by providers as a major barrier. Electronic medical records (EMRs) and integrated electronic health information systems are promoted as efficient tools to gain access to screening results, to ensure timely universal follow-up, to maintain records throughout the life course, and to integrate results from various medical testing and health care delivery systems.6 To assess the role of the EMR in compliance with these AAP recommendations regarding follow-up for VOL. 103, NOS. 9 & 10, SEPTEMBER/OCTOBER 2011 INCOMPLETE FOLLOw-UP OF SICkLE TRAIT hemoglobinopathy trait, we surveyed primary care pediatric providers in an urban academic medical center and at a nearby city hospital. Since 2007, newborn screening results have been available at both sites in the EMR within a few weeks of delivery. MATeRiAls AnD MeTHoDs survey instrument A brief, anonymous online survey was developed with Columbia’s Community Pediatrics Division to assess attitudes and practices regarding screening and follow-up for sickle cell disease and sickle trait among primary care physicians. All pediatric and family medicine practitioners caring for newborns at Columbia-New York Presbyterian Hospital (Columbia-NYP), an urban academic medical center in New York City with approximately 6000 births per year, and its satellite outpatient clinics were queried about the frequency with which they check newborn screening results and how to improve that rate, their practices for testing older infants or children new to the practice, actions taken for positive trait results, and suggestions for improving communication with affected families. Additional questions for family practice physicians explored obstetric screening and counseling practices for sickle trait. Survey responses were collected from December 2008 to January 2009. For comparison, the same online survey was sent to all primary care pediatricians at Harlem Hospital, a Columbia-affiliated New York City public hospital with approximately 1200 annual births. High proportions of births at both sites are to women of African and Latino descent. Prior institutional review board approvals were obtained at both centers. intervention and Resurvey Following the baseline survey, the same practitioners at Columbia-NYP received an educational intervention consisting of a lecture presentation describing the frequency of hemoglobinopathy trait in the population served, national guidelines for newborn screening follow-up for sickle trait based on the Newborn Screening ACT Sheet produced for Health Resources and Services Administration by the American College of Medical Genetics,7 recommending referral for genetic services, emphasizing the availability of results in the hospital EMR within 1 month after delivery. The lecture was followed by an e-mailed letter outlining these same points. The physician pool was subsequently resurveyed from October to December 2009 using the same online survey instrument, with a 29% response rate (N = 40). Frequencies of all responses were tabulated, and the Pearson c2 test was used to determine relationships between variables. Statistical significance was set at p < .05. ResulTs The overall response rate of Columbia-NYP primary care pediatric physicians to the initial survey was 58%: 57% of pediatricians (n = 57) and 62% of family medicine physicians (n = 23). Of pediatric and family medicine respondents, 49% and 43% were residents, respectively. checking screening Results Among pediatric providers at Columbia-NYP, 46.2% of respondents reported that they routinely check hemoglobinopathy screening results for their infant patients, defined as checking more than 80% of the time: 38.6% of pediatricians compared to 66.7% of family medicine providers (Figure 1) (p < .05). One-third of all the practitioners reported only sometimes checking results, defined as checking more than 25% of the time. One-fifth of all the providers reported hardly ever checking results. There was no statistically significant difference in these practices between physicians who were in practice for less than 5 years and those with more experience, including residents. The proportion of providers routinely figure 1. Proportion of Primary Pediatric Providers Routinely Checking Newborn Screening Hemoglobinopathy Results JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 103, NOS. 9 & 10, SEPTEMBER/OCTOBER 2011 853 INCOMPLETE FOLLOw-UP OF SICkLE TRAIT checking newborn results was not affected by the educational intervention (Figure 2). When asked about their approach to older infants or children who are new to their practice, the majority of providers reported: “I trust that the newborn screening program has screened every child” (53.4%), with 9.5% reporting that they document newborn screening results for every child. Most providers (72%) reported screening patients for hemoglobinopathy only on clinical suspicion (data not shown). The most common suggestion for increasing routine checking of results was adding a prompt to the EMR or paper progress note (59%); many providers were unaware that results already available in the EMR. Additional frequent recommendations included having parents ask about results and facilitating access to the state newborn screening program coordinator for telephone results. percentage of providers referring affected families to genetic counseling for positive trait result, from 25.3% to 50% (p < .01), and modest but not statistically significant increases in the percentage of providers confirming testing, offering testing to siblings and providing counseling to families. Actions Taken for sickle Trait Results Actions Taken for Prenatal sickle Trait Results Asked to identify the recommended actions for a positive newborn screening result for sickle trait, 18.6% of all providers replied that “no action is necessary” (Figure 3). Half (52%) reported obtaining confirmatory testing, with 28% offering testing to siblings. Sixty percent of providers reported providing counseling on sickle cell disease to families. Educational outreach resulted in a statistically significant increase in the communicating With Affected families Asked how best to improve communication with families affected by positive sickle cell disease or trait results, most providers (88.4%) supported a statewide electronic record of newborn screening results accessible by primary care practitioners. Other suggestions included access to newborn screening results by others, such as by telephone for parents (40.6%) or by a nurse or other ancillary staff (11.6%). Among the 18 family physicians responding to this section of the survey, the majority (78%) reported offering hemoglobinopathy testing to partners of patients with positive obstetric screens for sickle trait (data not shown). Two-thirds of providers reported that they counsel these patients on sickle cell disease/trait, with 72.2% referring for formal genetic counseling. Just 50% of figure 2. Proportion of Primary Care Providers Checking Hemoglobinpathy Results, Before and After Educational Outreach (Pediatricians and Family Medicine Combined) 854 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 103, NOS. 9 & 10, SEPTEMBER/OCTOBER 2011 INCOMPLETE FOLLOw-UP OF SICkLE TRAIT prenatal providers described the possibility of a positive infant screen when the mother screened positive. Harlem Hospital Harlem Hospital providers held different attitudes and practices regarding newborn screening and followup, despite a lack of significant differences in years of practice or staff composition (ie, residents vs faculty). A majority of providers (82.7%) reported routinely checking newborn screening results. More providers at Harlem Hospital than at Columbia-NYP (74.2% vs 31.3%) reported having ever had a patient with a positive newborn screening result for sickle cell disease, p < .01). Once a positive trait result is identified, Harlem Hospital providers reported follow-up actions were similar to those of their Columbia-NYP colleagues for confirmatory testing (71.4%), offering hemoglobinopathy testing for siblings (28.6%), and providing counseling for positive trait results (53.6%). Similar to their ColumbiaNYP counterparts, one-fifth (21.4%) of providers believed that no action was necessary for a positive screen for sickle trait. Of Harlem Hospital providers, 75% reported that they routinely document the hemoglobinopathy status of their patients, as compared to 1 in 8 Columbia-NYP providers. Despite higher rates of routine checking for screening results, two-thirds of Harlem providers also requested EMR prompts and ready access to the state telephone number as ways to help improve rates of documenting results. Discussion Despite universal hemoglobinopathy screening of US newborns, high rates of affected births in New York City, national standards for newborn screening follow-up,7 AAP guidelines,2 and the availability of results in their system’s EMR for more than 1 year, fewer than half of primary care pediatric providers at a major urban academic center routinely check for hemoglobinopathy trait results. Availability of screening results in the EMR of each infant has been a much anticipated system improvement. Previously, providers expressed frustration that screening results were time consuming to obtain, often requiring telephone calls to the state screening coordinator available only during regular work hours.5,6 Nonetheless, our results indicate an underutilization of this resource. Despite generally being more accustomed to electronic medicine, residents did no better than their more senior colleagues. Even after positive trait results for a newborn were known, primary care practitioners did not routinely provide the recommended follow-up services to newborns figure 3. Proportion of Primary Pediatric Providers Performing Follow-up for Hemoglobinopathy Screening Once Hemoglobinopathy Trait Has Been Identified in a Newborn JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 103, NOS. 9 & 10, SEPTEMBER/OCTOBER 2011 855 INCOMPLETE FOLLOw-UP OF SICkLE TRAIT and their families affected by hemoglobinopathy trait. Our brief educational intervention at the academic center did not increase the proportion of providers routinely checking newborn screening results—it only modestly improved responses identifying the appropriate followup once a positive trait result was known, including performing confirmatory testing, offering testing to siblings, and providing genetic counseling. In contrast, the majority of primary practitioners at Harlem Hospital obtained results and performed followup of newborn patients from the EMR, highlighting the differing practices across sites and communities, even with comparable electronic functionality for posting and retrieving results in the EMR. Better adherence to guidelines at Harlem may be related to an increased awareness of hemoglobinopathies in communities of predominantly African descent. Providers at Columbia-NYP may be unaware that the Latino community they serve, largely of Caribbean origin, also carries sickle trait in relatively high proportion.8 Varying approaches to coordination of care between primary pediatric and genetic services may contribute to differences across sites of health care delivery. Prenatal hemoglobinopathy testing is routinely performed and documented in the EMR at both birth hospitals. Family physicians surveyed at Columbia-NYP report that three-fourths of obstetric patients with sickle trait are provided with genetic counseling. Although more routine than counseling for newborns, prenatal counseling for sickle trait still is not universal. Only half of these prenatal providers reported linking referral from prenatal and neonatal hemoglobinopathy screening, representing missed opportunities for genetic services. As newborn screening is based on urgent notification and referral for infants affected by screened conditions such as phenylketonuria and sickle cell disease, passive availability of trait screening results may be especially resistant to educational intervention and suggests the need for active prompts in the EMR. Follow-up may be further challenged by provider attitudes about the importance of genetic services for hemoglobinopathy trait, as suggested by a survey of primary care pediatric providers reporting that a greater proportion referred for carriers of cystic fibrosis.4 Our surveys were limited by the small sample size and differing sample sizes in the survey and resurvey within the 2 clinical systems. Providers surveyed at baseline were not necessarily the same respondents as postintervention. The 2 sites do not broadly represent 856 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION primary care but rather exemplify variations in practices of newborn screening follow-up and use of the EMR in a city with a high incidence of infants with hemoglobinopathies. Larger sample sizes may have resulted in statistical significance of postintervention responses to follow-up of a positive screen. Meaningful use of electronic medical data is essential to help providers obtain, synthesize, communicate, and utilize information to enhance provision of more efficient and effective evidence-based medical services.9 Despite the optimism that EMRs would enhance communication of newborn and medical screening results in patient care,6 our results suggest that large differences remain across health care delivery sites in the practice of appropriate action on newborn screening results and that passive availability of information in EMRs is inadequate to ensure universal checking of results by primary care physicians, despite targeted information. Given the imbalance between time available and guidelines for primary care,10 an active prompt-driven electronic system for performing follow-up on screening results may provide more standardized care and satisfy meaningful use criteria of EMR for newborn screening follow-up. RefeRences 1. kavanagh PL, wang CJ, Therrell BL, Sprinz PG, Bauchner H. Communication of positive newborn screening results for sickle cell disease and sickle cell trait: variation across states. Am J Med Genet C Semin Med Genet. 2008;148C:15-22. 2. Newborn Screening Authoring Committee, AAP. Newborn Screening Expands: Recommendations for Pediatricians and Medical Homes— Implications for the System. Pediatrics. 2008;121:192-217. 3. Desposito F, Lloyd-Puryear MA, Tonniges TF, Rhein F, Mann M. Survey of Pediatrician Practices in Retrieving Statewide Authorized Newborn Screening Results. Pediatrics. 2001;108:e22. 4. kemper AR, Uren RL, Moseley kL, Clark SJ. Primary Care Physicians’ Attitudes Regarding Follow-up Care for Children with Positive Newborn Screening Results. Pediatrics. 2006;118;1836-1841. 5. Oyeku SO, Feldman HA, Ryan k, Muret-wagstaff S, Neufeld EJ. Primary Care Clinicians’ knowledge and Confidence About Newborn Screening for Sickle Cell Disease: Randomized Assessment of Educational Strategies. J Natl Med Assoc. 2010;102:676-682. 6. Mann MY, Lloyd-Puryear MA, Linzer D. Enhancing Communication in the 21st Century Pediatrics. 2006;117:S315-S319. 7. Newborn Screening ACTion Sheet—Sickle Cell Carrier. www.acmg.net/ StaticContent/ACT/ACT_sheet_Hb_carrier_trait_FAS.pdf. Accessed October 5, 2010. 8. Hassell kL. Population estimates of sickle cell disease in the US. Am J Prev Med. 2010;38:S512-S521. 9. Downing GJ, Zuckerman AE, Coon C, Lloyd-Puryear MA. Enhancing the quality and efficiency of newborn screening programs through the use of health information technology. Semin Perinatol. 2010;34:156-162. 10. Belamarich PF, Gandica R, Stein RE, Racine AD. Drowning in a sea of advice: pediatricians and American Academy of Pediatrics policy statements. Pediatrics. 2006;118:e964-e978. n VOL. 103, NOS. 9 & 10, SEPTEMBER/OCTOBER 2011 Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/ritonavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/ritonavir treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir should prompt consideration of interruption or discontinuation of treatment. Severe Skin Reactions During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (<0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis has been reported. Discontinue PREZISTA/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/ritonavir [also see Adverse Reactions]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using PREZISTA/ritonavir was 0.5%. Sulfa Allergy Darunavir contains a sulfonamide moiety. PREZISTA should be used with caution in patients with a known sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash was similar in subjects with or without a history of sulfonamide allergy. Drug Interactions See Table 1 for a listing of drugs that are contraindicated for use with PREZISTA/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to PREZISTA [see Contraindications]. Please refer to Table 6 for established and other potentially significant drug-drug interactions [see Drug Interactions]. Diabetes Mellitus / Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established. Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and treatment. Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established. Resistance/Cross-Resistance Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is unknown [see Microbiology (12.4) in full Prescribing Information]. ADVERSE REACTIONS The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions. Clinical Trials Experience: Treatment-Naïve Adults Study TMC114-C211 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing PREZISTA/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 95.0 and 91.4 weeks, respectively. The majority of the adverse drug reactions (ADRs) reported during treatment with PREZISTA/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to PREZISTA/ritonavir 800/100 mg once daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 800/100 mg once daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment naïve HIV-1-infected adult subjects are presented in Table 2 and subsequent text below the table. Table 2: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 800/100 mg Once Daily* of At Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects Randomized Study TMC114-C211 System Organ Class, PREZISTA/ritonavir lopinavir/ritonavir Preferred Term, 800/100 mg once daily 800/200 mg per day % + TDF/FTC + TDF/FTC N = 343 N = 346 Gastrointestinal Disorders Abdominal pain 5% 6% Diarrhea 8% 15% Nausea 3% 4% Vomiting 2% 3% General Disorders and Administration Site Conditions Fatigue < 1% 3% Metabolism and Nutrition Disorders Anorexia 2% < 1% Nervous System Disorders Headache 6% 5% Skin and Subcutaneous Tissue Disorders Rash 5% 6% N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine * Excluding laboratory abnormalities reported as ADRs Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving PREZISTA/ritonavir 800/100 mg once daily are listed below by body system: Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulence General Disorders and Administration Site Conditions: asthenia Hepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity) Immune System Disorders: (drug) hypersensitivity Metabolism and Nutrition Disorders: diabetes mellitus Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, StevensJohnson Syndrome, urticaria Laboratory abnormalities: Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with PREZISTA/ritonavir 800/100 mg once daily are presented in Table 3. Table 3: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects* Randomized Study TMC114-C211 Laboratory Parameter PREZISTA/ritonavir lopinavir/ritonavir Preferred Term, Limit 800/100 mg 800/200 mg % once daily per day + TDF/FTC + TDF/FTC Biochemistry Alanine Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 7% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 3% 3% Grade 4 > 10.0 X ULN < 1% 3% Aspartate Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 6% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 4% 2% Grade 4 > 10.0 X ULN 1% 2% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5.0 X ULN 2% 1% Grade 3 > 5.0 to ≤ 10.0 X ULN 0% < 1% Grade 4 > 10.0 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 4% Grade 3 > 2.5 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN 0% 0% Triglycerides Grade 2 5.65-8.48 mmol/L 3% 8% 500-750 mg/dL Grade 3 8.49-13.56 mmol/L 1% 5% 751-1200 mg/dL Grade 4 > 13.56 mmol/L < 1% < 1% > 1200 mg/dL Total Cholesterol Grade 2 6.20-7.77 mmol/L 16% 23% 240-300 mg/dL Grade 3 > 7.77 mmol/L 1% 5% > 300 mg/dL Low-Density Lipoprotein Cholesterol Grade 2 4.13-4.90 mmol/L 14% 10% 160-190 mg/dL Grade 3 ≥ 4.91 mmol/L 5% 5% ≥ 191 mg/dL Elevated Glucose Levels Grade 2 6.95-13.88 mmol/L 7% 8% 126-250 mg/dL Grade 3 13.89-27.75 mmol/L < 1% 0% 251-500 mg/dL Grade 4 > 27.75 mmol/L 0% 0% > 500 mg/dL Pancreatic Lipase Grade 2 > 1.5 to ≤ 3.0 X ULN 2% 1% Grade 3 > 3.0 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN 0% < 1% Pancreatic Amylase Grade 2 > 1.5 to ≤ 2.0 X ULN 5% 2% Grade 3 > 2.0 to ≤ 5.0 X ULN 3% 3% Grade 4 > 5.0 X ULN 0% < 1% N=total number of subjects per treatment group TDF = tenofovir disoproxil fumarate FTC = emtricitabine * Grade 4 data not applicable in Division of AIDS grading scale. Clinical Trials Experience: Treatment-Experienced Adults Study TMC114-C214 The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatmentexperienced HIV-1-infected adult subjects. The total mean exposure for subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively. The majority of the ADRs reported during treatment with PREZISTA/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to PREZISTA/ritonavir 600/100 mg twice daily (≥ 5%) of at least moderate intensity (≥ Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the PREZISTA/ritonavir arm discontinued treatment due to ADRs. ADRs to PREZISTA/ritonavir 600/100 mg twice daily of at least moderate intensity (≥ Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 4 and subsequent text below the table. Table 4: Selected Clinical Adverse Drug Reactions to PREZISTA/ritonavir 600/100 mg Twice Daily* of At Least Moderate Intensity (≥ Grade 2) Occurring in ≥ 2% of Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects Randomized Study TMC114-C214 System Organ Class, PREZISTA/ritonavir lopinavir/ritonavir Preferred Term, 600/100 mg 400/100 mg % twice daily + OBR twice daily + OBR N = 298 N = 297 Gastrointestinal Disorders Abdominal distension 2% < 1% Abdominal pain 6% 3% Diarrhea 14% 20% Dyspepsia 2% 1% Nausea 7% 6% Vomiting 5% 3% General Disorders and Administration Site Conditions Asthenia 3% 1% Fatigue 2% 1% Metabolism and Nutrition Disorders Anorexia 2% 2% Diabetes mellitus 2% < 1% Nervous System Disorders Headache 3% 3% Skin and Subcutaneous Tissue Disorders Rash 7% 3% N=total number of subjects per treatment group OBR = optimized background regimen * Excluding laboratory abnormalities reported as ADRs Less Common Adverse Reactions Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving PREZISTA/ritonavir 600/100 mg twice daily are listed below by body system: Gastrointestinal Disorders: acute pancreatitis, flatulence Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreams Skin and Subcutaneous Tissue Disorders: pruritus, urticaria Laboratory abnormalities: Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with PREZISTA/ritonavir 600/100 mg twice daily are presented in Table 5. Table 5: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects* Randomized Study TMC114-C214 Laboratory Parameter PREZISTA/ritonavir lopinavir/ritonavir Preferred Term, Limit 600/100 mg 400/100 mg % twice daily + OBR twice daily + OBR Biochemistry Alanine Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 7% 5% Grade 3 > 5.0 to ≤ 10.0 X ULN 2% 2% Grade 4 > 10.0 X ULN 1% 2% Aspartate Aminotransferase Grade 2 > 2.5 to ≤ 5.0 X ULN 6% 6% Grade 3 > 5.0 to ≤ 10.0 X ULN 2% 2% Grade 4 > 10.0 X ULN < 1% 2% Alkaline Phosphatase Grade 2 > 2.5 to ≤ 5.0 X ULN < 1% 0% Grade 3 > 5.0 to ≤ 10.0 X ULN < 1% < 1% Grade 4 > 10.0 X ULN 0% 0% Hyperbilirubinemia Grade 2 > 1.5 to ≤ 2.5 X ULN < 1% 2% Grade 3 > 2.5 to ≤ 5.0 X ULN < 1% < 1% Grade 4 > 5.0 X ULN < 1% 0% Triglycerides Grade 2 5.65-8.48 mmol/L 10% 11% 500-750 mg/dL Grade 3 8.49-13.56 mmol/L 7% 10% 751-1200 mg/dL Grade 4 > 13.56 mmol/L 3% 6% > 1200 mg/dL Table 5: Grade 2 to 4 Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjects* (continued) Randomized Study TMC114-C214 Laboratory Parameter PREZISTA/ritonavir lopinavir/ritonavir Preferred Term, Limit 600/100 mg 400/100 mg % twice daily + OBR twice daily + OBR Biochemistry Total Cholesterol Grade 2 6.20-7.77 mmol/L 25% 23% 240-300 mg/dL Grade 3 > 7.77 mmol/L 10% 14% > 300 mg/dL Low-Density Lipoprotein Cholesterol Grade 2 4.13-4.90 mmol/L 14% 14% 160-190 mg/dL Grade 3 ≥ 4.91 mmol/L 8% 9% ≥ 191 mg/dL Elevated Glucose Levels Grade 2 6.95-13.88 mmol/L 10% 11% 126-250 mg/dL Grade 3 13.89-27.75 mmol/L 1% < 1% 251-500 mg/dL Grade 4 > 27.75 mmol/L < 1% 0% > 500 mg/dL Pancreatic Lipase Grade 2 > 1.5 to ≤ 3.0 X ULN 3% 4% Grade 3 > 3.0 to ≤ 5.0 X ULN 2% < 1% Grade 4 > 5.0 X ULN < 1% 0% Pancreatic Amylase Grade 2 > 1.5 to ≤ 2.0 X ULN 6% 7% Grade 3 > 2.0 to ≤ 5.0 X ULN 7% 3% Grade 4 > 5.0 X ULN 0% 0% N=total number of subjects per treatment group OBR = optimized background regimen * Grade 4 data not applicable in Division of AIDS grading scale. Serious ADRs The following serious ADRs of at least moderate intensity (≥ Grade 2) occurred in the Phase 2b studies and Phase 3 studies with PREZISTA/ ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting. Additional ADRs to PREZISTA/ritonavir identified in adult subjects in other clinical trials The additional ADR of interest identified from other clinical trials was osteonecrosis. Patients co-infected with hepatitis B and/or hepatitis C virus In subjects co-infected with hepatitis B or C virus receiving PREZISTA/ ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/ritonavir who were not co-infected, except for increased hepatic enzymes [see Warnings and Precautions]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection. Postmarketing Experience The following events have been identified during postmarketing use of PREZISTA. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Redistribution of body fat has been reported. Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) and toxic epidermal necrolysis have been reported [see Warnings and Precautions]. DRUG INTERACTIONS See also Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information. Potential for PREZISTA/ritonavir to Affect Other Drugs PREZISTA co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 6). Potential for Other Drugs to Affect Darunavir Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 6). Established and Other Potentially Significant Drug Interactions Table 6 provides dosing recommendations as a result of drug interactions with PREZISTA/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) in full Prescribing Information for Magnitude of Interaction, Tables 10 and 11] Concomitant Effect on Clinical Comment Drug Class: Concentration Drug Name of Darunavir or Concomitant Drug HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine Didanosine should be administered ↔ darunavir one hour before or two hours after ↔ didanosine PREZISTA/ritonavir (which are administered with food). HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs) The appropriate dose of indinavir in indinavir ↑ darunavir combination with PREZISTA/ritonavir (The reference ↑ indinavir has not been established. regimen for indinavir was indinavir/ ritonavir 800/100 mg twice daily.) lopinavir/ritonavir ↓ darunavir ↔ lopinavir Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. saquinavir Appropriate doses of the combination ↓ darunavir have not been established. Hence, it ↔ saquinavir is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. HIV-1-Antiviral Agents: CCR5 co-receptor antagonists Maraviroc Maraviroc concentrations are increased ↑ maraviroc when co-administered with PREZISTA/ ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. Other Agents Antiarrhythmics: ↑ antiarrhythmics bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone digoxin ↑ digoxin Anticoagulant: warfarin ↓ warfarin ↔ darunavir Anticonvulsant: carbamazepine ↔ darunavir ↑ carbamazepine Anticonvulsant: phenobarbital, phenytoin ↔ darunavir ↓ phenytoin ↓ phenobarbital Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ ritonavir. The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. Warfarin concentrations are decreased when co-administered with PREZISTA/ ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. The dose of either darunavir/ ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ ritonavir. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) in full Prescribing Information for Magnitude of Interaction, Tables 10 and 11] (continued) Concomitant use of trazodone or Antidepressant: ↑ trazodone desipramine and PREZISTA/ritonavir trazodone, ↑ desipramine may increase plasma concentrations desipramine of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered. No dose adjustment of the combination Anti-infective: ↔ darunavir is required for patients with normal clarithromycin ↑clarithromycin renal function. For patients with renal impairment, the following dose adjustments should be considered: • For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. • For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%. Antifungals: ketoconazole, itraconazole, voriconazole Anti-gout: colchicine Antimycobacterial: rifabutin The reference regimen for rifabutin was 300 mg once daily ↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) ↑ colchicine ↑ darunavir ↑ rifabutin ↑ 25-Odesacetylrifabutin Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) in full Prescribing Information for Magnitude of Interaction, Tables 10 and 11] (continued) Caution is warranted and clinical ß-Blockers: ↑ beta-blockers monitoring of patients is recommended. metoprolol, A dose decrease may be needed for timolol these drugs when co-administered with PREZISTA/ritonavir. Benzodiazepines: parenterally administered midazolam ↑ midazolam Calcium Channel Blockers: felodipine, nifedipine, nicardipine ↑ calcium channel blockers Corticosteroid: Systemic: dexamethasone ↓ darunavir Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. Corticosteroid: Inhaled/Nasal: fluticasone ↑ fluticasone Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use. Endothelin receptor ↑ bosentan antagonists: bosentan HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin ↑ pravastatin ↑ atorvastatin ↑ rosuvastatin Immunosuppressants: ↑ immunocyclosporine, suppressants tacrolimus, sirolimus Inhaled beta agonist: salmeterol ↑ salmeterol Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are coadministered. Caution is warranted and clinical monitoring of patients is recommended. Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir. Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) in full Prescribing Information for Magnitude of Interaction, Tables 10 and 11] (continued) Narcotic Analgesic/ ↓ methadone No adjustment of methadone dosage Treatment of Opioid ↔ buprenorphine, is required when initiating coDependence: administration of PREZISTA/ritonavir. naloxone methadone, ↑ norbuprenorphine However, clinical monitoring is recombuprenorphine, mended as the dose of methadone (metabolite) buprenorphine/ during maintenance therapy may need naloxone to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/ naloxone are coadministered. A dose decrease may be needed for Neuroleptics: ↑ neuroleptics these drugs when co-administered with risperidone, PREZISTA/ritonavir. thioridazine Oral Contraceptives/ ↓ ethinyl estradiol Plasma concentrations of ethinyl estradiol are decreased due to induction estrogen: ↓ norethindrone of its metabolism by ritonavir. Alternative ethinyl estradiol, methods of nonhormonal contraception norethindrone are recommended. PDE-5 inhibitors: ↑ PDE-5 inhibitors Co-administration with PREZISTA/ ritonavir may result in an increase in sildenafil, (only the use of PDE-5 inhibitor-associated adverse vardenafil, sildenafil at events, including hypotension, syncope, tadalafil doses used for visual disturbances and priapism. treatment of erectile Use of PDE-5 inhibitors for pulmonary dysfunction has arterial hypertension (PAH): been studied with • Use of sildenafil is contraindicated PREZISTA/ritonavir) when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. • The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. Selective Serotonin ↔ darunavir If sertraline or paroxetine is Reuptake Inhibitors ↓ sertraline co-administered with PREZISTA/ (SSRIs): ritonavir, the recommended approach ↓ paroxetine sertraline, is a careful dose titration of the SSRI paroxetine based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. In addition to the drugs included in Table 6, the interaction between PREZISTA/ritonavir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see Clinical Pharmacology (12.3) in full Prescribing Information]: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, and tenofovir disoproxil fumarate. Other nucleoside reverse transcriptase inhibitors (NRTIs): Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and PREZISTA/ritonavir. Other PIs: The co-administration of PREZISTA/ritonavir and PIs other than lopinavir/ ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice, rats and rabbits. However, due to limited bioavailability and/or dosing limitations, animal exposures (based on AUC) were only 50% (mice and rats) and 5% (rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir. In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to PREZISTA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA. Geriatric Use Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of PREZISTA in elderly patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment No dose adjustment of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/ritonavir in subjects with severe hepatic impairment, therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration and Clinical Pharmacology (12.3) in full Prescribing Information]. Renal Impairment Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of acute overdose with PREZISTA/ritonavir is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects. No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance. PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling in full Prescribing Information] A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with PREZISTA. A Patient Package Insert for PREZISTA is available for patient information. General Patients should be informed that PREZISTA is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that therapy with PREZISTA can reduce the risk of transmitting HIV to others. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using PREZISTA. Instructions for Use General Patients should be advised to take PREZISTA and ritonavir (NORVIR®) with food every day as prescribed. Patients should be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with ritonavir (NORVIR®) in combination with other antiretroviral drugs. Patients should not alter the dose of either PREZISTA or ritonavir (NORVIR®), discontinue ritonavir (NORVIR®), or discontinue therapy with PREZISTA without consulting their physician. Patients Taking PREZISTA Once Daily If a patient misses a dose of PREZISTA or ritonavir (NORVIR®) by more than 12 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir (NORVIR®) by less than 12 hours, the patient should be told to take PREZISTA and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA or ritonavir (NORVIR®) is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA or ritonavir (NORVIR®). Patients Taking PREZISTA Twice Daily If a patient misses a dose of PREZISTA or ritonavir (NORVIR®) by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir (NORVIR®) by less than 6 hours, the patient should be told to take PREZISTA and ritonavir (NORVIR®) immediately, and then take the next dose of PREZISTA and ritonavir (NORVIR®) at the regularly scheduled time. If a dose of PREZISTA or ritonavir (NORVIR®) is skipped, the patient should not double the next dose. Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA or ritonavir (NORVIR®). Hepatotoxicity Patients should be informed that Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA co-administered with 100 mg of ritonavir. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. Post-marketing cases of liver injury, including some fatalities, have been reported. Patients should be advised about the signs and symptoms of liver problems. These may include jaundice of the skin or eyes, dark (tea colored) urine, pale colored stools, nausea, vomiting, loss of appetite, or pain, aching or sensitivity in the right upper quadrant of the abdomen. Severe Skin Reactions Patients should be informed that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported with PREZISTA co-administered with 100 mg of ritonavir. Patients should be advised to discontinue PREZISTA/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Drug Interactions PREZISTA/ritonavir may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort. Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures during therapy with PREZISTA/ritonavir because hormonal levels may decrease. Fat Redistribution Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZISTA/ ritonavir, and that the cause and long-term health effects of these conditions are not known at this time. Manufactured for Tibotec, Inc. by: JOLLC, Gurabo, Puerto Rico Distributed by: Tibotec Therapeutics Division of Centocor Ortho Biotech Products, L.P., Raritan NJ 08869 NORVIR® is a registered trademark of its respective owner. PREZISTA® is a registered trademark of Tibotec Pharmaceuticals. © Tibotec, Inc. 2006 Revised: 12/2010 10101712B