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MountainPlainsAIDS EDUCATION AND TRAINING CENTER
HIV PROVIDER REFERENCE SERIESA PUBLICATION OF THE MOUNTAIN PLAINS AIDS EDUCATION AND TRAINING CENTER
A Pharmacist’s Guide to ANTIRETROVIRAL MEDICATIONS
FOR HIV INFECTED ADULTS AND ADOLESCENTS
2013
AUTHORS:
Whitney Marie Starr, FNPClinical Education Coordinator, Mountain Plains AETCInstructor, School of Medicine, Division of Infectious DiseasesUniversity of Colorado School of Medicine
Steven C. Johnson, MDMedical Director, Mountain Plains AETCProfessor, School of Medicine, Division of Infectious DiseasesUniversity of Colorado School of Medicine
Jasjit Gill, PharmDPharmacy Manager and Clinical Pharmacy Specialist, Infectious Disease Group Practice PharmacyFaculty and Clinical Instructor, Skaggs School of PharmacyUniversity of Colorado Hospital
EDiTOR:
Lucy Bradley-Springer, PhD, RN, ACRN, FAANPI & Director, Mountain Plains AETCAssociate Professor, School of Medicine, Division of Infectious DiseasesUniversity of Colorado School of Medicine
Design: Lindsay O’Connell, MS, CHESProgram Manager, Mountain-Midwest HIV Telehealth CenterMountain Plains AIDS Education and Training CenterInstructor, School of Medicine, Division of Infectious DiseasesUniversity of Colorado School of Medicine
ADDiTiONAL RESOURCES:
Mountain Plains AiDS Education and Training Center www.mpaetc.orgSchool of Medicine, Division of Infectious DiseasesUniversity of Colorado School of Medicine, Anschutz Medical CampusAurora, CO 80045 (303) 724-0867
AiDS Drug Assistance Program (ADAP) Numbers:Colorado .................................................. (303) 724-0644Kansas ..................................................... (316) 293-2682Nebraska ................................................. (402) 559-6681New Mexico ............................................. (505) 776-8032North Dakota ........................................... (701) 234-4852South Dakota ........................................... (605) 582-6246Utah .......................................................... (801) 581-5310Wyoming .................................................. (307) 265-0413
AiDS infonet http://www.aidsinfonet.org Provides one-page fact sheets on treatments, prevention, social service, and Web resources. Available in English and Spanish and appropriate for patient and clinician education.
HiV inSite http://hivinsite.ucsf.edu Contains an extensive drug database and ART side effects tables.
HiV/AiDS Treatment information Service (ATiS) www.aidsinfo.nih.gov Provides information on federally approved treatment guidelines for HIV/AIDS. Also provides updated medication and drug interaction information.
National Clinicians Consultation Center http://www.nccc.ucsf.edu/home For questions regarding:Treatment/Pharmacologic Issues – 1-800-933-3413Post-exposure Prophylaxis – 1-888-448-4911Perinatal Transmission – 1-888-448-8765Check Website for training/education tools and links to more sites with specific information regarding drug interactions and ART.
A PHARMACiST’S GUiDE TO ANTiRETROViRAL MEDiCATiONS
Introduction ...........................................................................................3
Currently Available Antiretroviral Drugs ...............................................3
ART Recommendations ........................................................................4
Starting ART ...........................................................................................4
Laboratory Tests ....................................................................................4
ART Regimens .......................................................................................6
Drug Resistance and Cross-Resistance ...............................................9
The Vital Role of Pharmacists ..............................................................9
Index by drug (Generic name) ............................................................ 41
List of Tables
Table 1. Therapy for The Chronically HIV-1 Infected Patient ..............5
Table 2. Antiretroviral Regimens Recommended for Treatment of
HIV-1 Infection in Antiretroviral Naïve Patients ...............................7
Table 3. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors ......
(NRTI) .............................................................................................. 11
Table 4. Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors
(NRTI) Metabolism and Drug Interactions .................................... 14
Table 5. Fixed Dose Combination NRTIs ............................................ 15
Table 6. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) .. 17
Table 7. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Metabolism and Drug Interactions ................................................ 20
Table 8. Entry Inhibitors ...................................................................... 23
Table 9. Entry Inhibitors Metabolism and Drug Interactions ............ 24
Table 10. Integrase Inhibitors (INSTI) ................................................ 25
Table 11. Integrase Inhibitors (INSTI) Metabolism and Drug
Interactions ...................................................................................... 26
Table 12. Protease Inhibitors (PI) ...................................................... 27
Table 13. Protease Inhibitors (PI) Metabolism and Drug
Interactions ...................................................................................... 31
Table 14. Boosting Agents .................................................................. 35
Table 15. Boosting Agents Metabolism and Drug Interactions........ 36
Table 16. Fixed-Dose Multi-Class Agents: Single Tablet
Regimens ........................................................................................ 38
Table 17. Drug Interactions Between HIV Medications and
Hepatitis C Treatments: boceprevir .............................................. 39
Table 18. Drug Interactions Between HIV Medications and
Hepatitis C Treatments: telaprevir ................................................. 40
TABLE OF CONTENTS
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Pharmacologic treatment of HIV disease has advanced rapidly since 1995. This is primarily due to the development of potent antiretroviral (ARV) agents that effectively inhibit viral replication, prevent drug resistance, and prevent or limit immune dysfunction. These advances have improved the quality of life and increased the lifespan for HIV-infected patients; they have also increased the complexity of prescribing treatment and providing care. The pharmacist plays a key role in helping patients and clinicians meet the challenges of antiretroviral treatment (ART). These challenges include:
• Frequent changes in treatment options and guidelines as new ARV medications are approved and as data from longitudinal studies provide new information about established therapeutic agents;• Known and emerging toxicities, side effects, and complications of ART as patients live longer and as ARVs are used in new combinations;• Development of resistance to ART medications requiring high levels of adherence to regimens, frequent monitoring, and complex decisions about treatment sequencing; • Drug-drug interactions with medications used to prevent or treat opportunistic infections and/or co-morbid conditions;• Psychosocial and financial barriers to treatment that patients may encounter.
Pharmacists can work with HIV-infected patients and their clinicians to promote positive health outcomes in a number of ways. Effective treatment is facilitated when pharmacists take an active role in:
• Providing drug information to clinicians and patients,• Counseling patients about treatment and side effects,• Encouraging adherence and monitoring patients for difficulties with treatment adherence, and• Screening prescriptions for appropriate dosages and potential drug-drug or drug-food interactions.
CURRENTLy AVAiLABLE ANTiRETROViRAL DRUGS
ARVs fall into five classes: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand-transfer inhibitors (INSTI), and entry inhibitors.
Nucleoside/Nucleotide Reverse Transcriptase inhibitors (NRTis) work at an early stage in viral replication. They block a viral enzyme, reverse transcriptase, by mimicking nucleosides in the growing DNA chain. Once the DNA chain is terminated, the individual virus can no longer replicate. NRTIs are the cornerstone of combination therapy. Some of these agents are combined into fixed-dose formulations to help reduce the number of capsules/tablets the patient takes daily.
Non-Nucleoside Reverse Transcriptase inhibitors (NNRTis) block reverse transcriptase through a more direct inhibition of the enzyme. Resistance develops quickly to NNRTIs when used alone, making it extremely important that they be used in maximally suppressive combination therapies. NNRTIs are often used in combination with NRTIs.
Protease inhibitors (Pis) work against HIV in a later stage of viral replication by interfering with the protease enzyme’s role in making new copies of HIV, thus producing viruses that are incapable of infecting new cells. The PIs, when used in combination with other ARVs, offer potent anti-HIV activity. PIs have a high genetic barrier to the development of resistance. These medications are often boosted with another PI, ritonavir. A newly licensed agent, cobicistat, is a pharmacokinetic booster that does not have HIV activity but will be used to boost both PIs and the integrase inhibitor, elvitegravir.
A PHARMACiST’S GUiDE TO ANTiRETROViRAL MEDiCATiONS FOR HiV-iNFECTED ADULTS AND ADOLESCENTS
Mountain Plains AIDS Education and Training Center • 2013 4
Entry inhibitors prevent entry of HIV into the target cell through a variety of mechanisms. Licensed entry inhibitors include a fusion inhibitor and a CCR5 receptor antagonist. Enfuvirtide, a fusion inhibitor, interferes with the process of viral binding (fusion) to the cell membrane by binding to the target cell. Maraviroc prevents entry by blocking CCR5, a co-receptor on the cell, necessary for viral attachment. As some viral strains may use an alternate co-receptor CXCR4 for entry, an HIV genotypic tropism assay is necessary to confirm that the patient’s virus only uses CCR5 for entry. A phenotypic tro-pism assay is also available. An HIV genotypic tropism assay is recommended due to the commercial availability over the HIV phenotypic tropism assay.
integrase Strand-Transfer inhibitors (iNSTi), also called integrase inhibitors, block viral replication by preventing the integration of viral DNA into the host genome by inhibiting the HIV integrase enzyme.
ART RECOMMENDATiONS
With the advent of combination treatment regimens, ART has become more complex. A panel of experts periodically publishes revised principles and recommendations for HIV treatment. These guidelines provide recom-mendations on when to start therapy and which medication combinations have the best evidence of efficacy in the treatment of HIV infection. Please refer to the guidelines for concerns and specific issues regarding the use of ART in patients with drug resistance or in specific populations including adolescents; intravenous drug users; patients who are co-infected with hepatitis B virus (HBV), hepatitis C virus (HCV), or Mycobacterium tuberculosis (TB); women of child-bearing age; and older adults. The guidelines can be accessed at http://aidsinfo.nih.gov/guidelines
Specific guidelines are available for ART in pregnant women and for the prevention of perinatal transmission as well as for treatment of pediatric patients. Guidelines also exist for the use of ARVs for post-exposure prophylaxis for occupational and non-occupational exposures. The most recently updated versions of each of these guidelines are available at http://aidsinfo.nih.gov/guidelines.
The CDC has published guidance on the use of pre-exposure prophylaxis (PrEP), for the use of ART for prevention of transmission or for use in those who are uninfected but exposed, such as in serodiscordant couples; available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm?s_cid=mm6003a1_w
STARTiNG ART
Starting or changing therapy for HIV-infected adults or adolescents is based on clinical status, CD4+ T cell counts, and HIV viral load tests, as well as individ-ual patient issues. ART is recommended for all patients with confirmed HIV infection, and should be offered to all HIV-infected patients with early HIV infection. Treatment should be strongly considered, regardless of CD4+ T cell counts, in individuals with the following conditions: pregnancy, history of an AIDS-defining illness, HIV-associated nephropathy, co-infection with HBV, and to prevent transmission in serodiscordant couples. Decisions regarding the initiation of ART must be individualized to the patient after appropriate patient education regarding disease stage, drug side effects, long-term toxicities, co-morbidities, and adherence issues. ART may also be recommended during acute infection. A symptomatic illness occurs in 40%-90% of people during acute infection with HIV. It presents with fairly nonspecific symptoms including but not limited to fever, lymphadenopathy, pharyngitis, rash, myalgia, diarrhea, nausea, vomiting, and neurologic symptoms. The potential benefits to treatment at this stage of infection include a reduction in viral replication, symptoms of acute HIV infection, disease progression, and the risk of viral transmission.
LABORATORy TESTS
Pharmacists may not be responsible for monitoring these tests, but will find it helpful in patient interactions to have a general knowledge of routine labs. Of the many laboratory tests used to support diagnosis and therapy in HIV infection, several are critical and are used to determine the need to initiate or change an ART regimen: HIV viral load assays, CD4+ T cell counts, and HIV resistance testing. The combination of HIV viral load andCD4+ T cell testing provides the best information for initiating, monitoring,
Mountain Plains AIDS Education and Training Center • 2013 5
and changing ART. For patients stable on ART, the CD4+ T cell count and HIV viral load are repeated every 3-6 months.
HiV Viral Load Testing (HiV RNA Assay). HIV viral load is a quantitative measure of HIV viral RNA in the plasma. The HIV viral load indicates the current level of virus circulating in the blood and the ability of the virus to multiply. HIV viral replication in HIV infection is rapid and continuous. From the time of infection, billions of new virions are produced daily. During acute HIV infection the HIV viral load is high (105 to 106 copies/mL), then drops to a stable level or “set point,” which remains relatively constant in the absence of disease progression, therapeutic effect, or disease exacerbations. Plasma HIV RNA quantification is the best determinant of treatment efficacy. After starting ART, the viral load is expected to decrease by 1.5-2 log10 copies/mL at 4 weeks and to <50 copies/mL at 16-24 weeks. If the
viral load does not decrease by 1 log10 copies/mL at 8 weeks, drug resistance or nonadherence are the major concerns.
CD4+ T Lymphocyte Count. The CD4+ T lymphocyte count is the best marker for immunodeficiency associated with HIV infection. The CD4+ T cell count measures the ability of the immune system to protect the body. The CD4+ T lymphocyte count reflects the number of CD4+ T cells/mm3 circulating in the blood. The laboratory may report a list of several types of lymphocytes, with relative percentages, along with the absolute count. The important values are the absolute number of CD4+ T cells/mm3 and the proportion of CD4+ T cells as a subset of all lymphocytes (CD4%). Depending on the laboratory, the normal range for an adult CD4+ T count will be about 800-1200 cells/mm3. The normal range for the CD4% (of total lymphocytes) will vary depending on the lab, but >29% corresponds
TABLE 1. THERAPy FOR THE CHRONiCALLy HiV-1 iNFECTED PATiENT
This table provides general guidance rather than absolute recommendations for an individual patient. All decisions regarding initiating therapy should be made on the basis of prognosis as determined by the CD4+ T cell count, the potential benefits and risks of therapy, and the willingness of the patient to commit to daily, lifelong therapy. Before initiating therapy, patient counseling and education should be provided with a focus on the benefits and risks of therapy, potential adverse effects, and the importance of medication adherence.
Clinical Conditions and/or CD4+T cell Count Recommendations
• CD4 count <350 cells/mm3
• CD4 count 350-500 cells/mm3
• CD4 count >500 cells/mm3
ART is currently recommended for all HIV-infected individuals.
• Pregnancy• History of AIDS-defining illness*• People with HIV-associated nephropathy (HIVAN)• People co-infected with HBV when HBV treatment is indicated (treatment with fully suppressive antiviral drugs active against both HIV and HBV is recommended.)• To prevent perinatal transmission of HIV infection• To prevent or limit transmission of HIV infection within serodiscordant partners• To prevent or limit transmission of HIV infection among other risk groups (i.e. IDU)
ART is strongly recommended for individuals with these conditions.
*AIDS-defining illness per Centers for Disease Control and Prevention (CDC), 1993. **See text for details regarding clinical conditions for which ART initiation is recommended.
Table adapted from Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents; DHHS, February 2013, available at http://aidsinfo.nih.gov/guidelines
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with a CD4+ T cell count >500/mm3 and <14% corresponds with a CD4+ T cell count <200/mm3 (qualifying as an AIDS diagnosis). The absolute CD4+ T cell count can vary in the same individual depending on the time of day the blood is drawn, the laboratory used, or the presence of an acute illness. The CD4% is a more stable representation of the immune system and is used in conjunction to the absolute number to trend decline, im-provement, or stability in immune function.
HiV Resistance Testing. HIV resistance testing may be performed in a number of situations. Two different resistance tests are currently available. HIV genotyping identifies specific mutations associated with resistance in the genetic code of HIV. Phenotypes measure how well HIV replicates in the presence of specific ARV medications. Approximately 15% of treat-ment-naïve patients have baseline resistance to ARVs. As a result, an HIV genotype is recommended for every patient before initiating ART. Resis-tance testing is also done during ART if a regimen is not fully suppressive (VL >1000 copies/mL). At this point, both a genotype and phenotype may be useful in assisting the clinician in the selection of a new ART regimen. Integrase resistance testing is a separate test, useful for the recognition of resistance to integrase inhibitors only. Integrase inhibitor resistance testing is not part of the standard assessment of a treatment naïve individual unless risk factors may exist, as resistance to this class of drugs is not prevalent among individuals who are naïve to ART. INSTI-resistance testing is rec-ommended among those who have failed an INSTI-containing regimen.
Additional Tests. HLA-B*5701 genetic screening should be ordered for all patients before they start a regimen that includes abacavir, as this medication may cause a hypersensitivity reaction in some patients. Signs and symptoms of a hypersensitivity reaction include rash, fever, nausea, vomiting, malaise, fatigue, and respiratory symptoms. If the patient is negative for HLA-B*5701, the chance of a hypersensitivity reaction to abacavir is extremely low and the patient may safely start this medication. Patients who are positive for HLA-B*5701 are at risk for developing a hypersensitivity reaction and should never take abacavir; abacavir should be listed in the patient’s chart under drug allergies.
There are two HIV tropism assays currently available, a phenotypic HIV tro-pism assay and a genotypic HIV tropism assay. The genotypic HIV tropism assay incorporates a DNA sequencing if only R5 virus is detected to deter-mine susceptibility to CCR5-antagonists, such as maraviroc and enfuvir-tide. The phenotypic HIV tropism assay is also used with demonstration of virologic failure on a CCR5-inhibitor containing regimen.
ART REGiMENS
Combination therapy with at least three active ARVs from two separate drug classes is currently recommended for patients starting treatment. Treatment with less than three drugs provides only partial suppression and is not recommended. For treatment naïve patients, the 3-drug regimen should consist of 1 NNRTI and 2 NRTIs or a PI boosted with ritonavir and 2 NRTIs, or an integrase inhibitor and 2 NRTIs. Boosting PIs with low-dose ritonavir increases drug levels, prolongs the PI half-life, and can reduce pill burden. For most patients on a PI-based regimen, boosting with ritonavir is recommended. Table 2 lists the recommended combinations of ART in ART-naive patients.
Co-formulations of existing medications have improved dosing, reduced pill burdens, and allowed most patients to have once or twice daily medication regimens, with some patients taking a single pill once daily. Despite these developments, not all patients can tolerate ARVs, adhere to medication regimens, or achieve undetectable viral loads (when the virus is too low to be detectable by the available viral load assay) with combination therapy. Partial viral suppression (i.e., more than one-half log reduction in viral load), has been shown to provide clinical benefit. However, partial suppression leads to the development of drug resistance that can ultimately lead to
Patients need to be aware that multi-drug regimens function as a whole,
and that missing or stopping any of the medications can seriously jeopardize
treatment effectiveness and future options.
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TABLE 2. ANTiRETROViRAL REGiMENS RECOMMENDED FOR TREATMENT OF HiV-1 iNFECTiON iN ANTiRETROViRAL NAïVE PATiENTS
Regimens should be individualized based on the advantages and disadvantages of each combination such as the number of tablets/capsules per dose, dosing frequency, toxicities, drug-drug interactions, co-morbid conditions, and level of plasma HIV-RNA. Preferred regimens are in bold type; regimens are designated as “preferred” for use in treatment naive patients when clinical trial data suggest optimal and durable efficacy with acceptable tolerability and ease of use. Alternative regimens are those where clinical trial data show efficacy, but are considered alternative due to disadvantages compared to the preferred agent, such as antiviral activity, durability, tolerability, drug interaction potential, or ease of use. In some cases, based on individual patient characteristics, a regimen listed as alternative in this table may actually be the preferred regimen. Clinicians initiating ARV regimens in the HIV-1-infected pregnant patient should refer to Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States available at http://aidsinfo.nih.gov/guidelines/Preferred Regimens NRTi Option # of pills
NRTI-Based Option efavirenz1+ tenofovir/emtricitabine(co-formulated)2,3,4
1PI-based Options atazanavir + ritonavir (once daily)5+
ORdarunavir + ritonavir (once daily)6+
3
3
INSTI-based Option raltegravir (twice daily)+ 3Preferred regimen for pregnant women
lopinavir+ritonavir (twice daily)7+ zidovudine+lamivudine8
(co-formulated)7
Alternative Regimens
NNRTI-based regimens
efavirenz+ ORrilpivirine9+
abacavir10 + lamivudine(co-formulated)
22
rilpivirine+ tenofovir/emtricitabine(co-formulated)
1-2
treatment failure, disease progression, and the risk of transmitting resistant strains of HIV. Additional factors that contribute to resistance include inappropriate prescribing by providers, unanticipated drug interactions, drug resistance acquired during HIV transmission, previous exposure to ART agents (especially in partially suppressive regimens), late-stage disease with high viral loads and different viral strains, and patient non-adherence to treatment protocols.
ARV medications have side effects and complications that can affect the quality of life, such as diarrhea, vomiting, vivid dreams, and peripheral
neuralgias. Certain ARVs have been shown to contribute to metaboliccomplications such as lipid abnormalities, insulin resistance, lactic acidosis, and bone abnormalities. Some side effects, such as hypersensitivity reactions or hepatotoxicity, can be very serious and even fatal. Patients should be taught about potential side effects, toxicities, and interactions, and given instructions on what to do to lessen the unfavorable symptoms, how to recognize serious symptoms, and what to do should they occur.
Drug interactions often occur between some of the ARV agents, especially the PIs and NNRTIs, as well as with other, non-ARV medications. Patients
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Alternative Regimens NRTi option # of pills
PI Based Regimens atazanavir + ritonavir+
ORdarunavir + ritonavir+
ORfosamprenavir+ritonavir (once or twice daily, dependent on tolerability of dosing)+
ORlopinavir+ritonavir (once or twice daily, dependent on tolerability of dosing)+
abacavir/lamivudine(co-formulated)
3
4
6-7
6-7
fosamprenavir + ritonavir (once or twice daily, dependent on tolerability of dosing)+
ORlopinavir + ritonavir (once or twice daily, dependent on tolerability of dosing)+
tenofovir/emtricitabine(co-formulated)
6-7
6-7
INSTI-based regimen raltegravir+ abacavir/lamivudine(co-formulated)
3
elvitegravir + cobicistat tenofovir/emtricitabine(co-formulated as a single tablet regimen)
1
Table adapted from Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents; DHHS, February 2013, available at http://aidsinfo.nih.gov/guidelines
1 Efavirenz is not recommended for use in pregnancy or in women with high pregnancy potential. Pregnancy category D. Use with caution in patients with unstable psychiatric disease. 2 Use with caution in patients with underlying renal insufficiency. Use with caution in combination with nevirapine due to early virologic failure. Strongly advise against abrupt discontinuation in patients co-infected with active hepatitis B infection. 3 Do not use tenofovir with unboosted atazanavir.4 3TC may be substituted for FTC or vice versa.5 Avoid in patients requiring high-dose (>20 mg omeprazole equivalent/day) proton pump inhibitors (PPIs). Use with caution in patients on PPIs (any dose), H2 blockers, or antacids. 6 Use with caution in patients who have a sulfonamide allergies.7 Do not use once-daily dosing in pregnant women. 8 Use with caution in the presence of pretreatment anemia and/or neutropenia. 9 Use with caution in persons with baseline HIV RNA >100,000 copies/ml. Use of PPIs with rilpivirine is contraindicated.10 Abacavir should not be used in patients who test positive for HLA-B* 5701. Use with caution in persons with baseline HIV RNA >100,000 copies/ml and in patients at high-risk for cardiovascular disease.
Mountain Plains AIDS Education and Training Center • 2013 9
should be advised to report all medications they are taking (prescription, over-the-counter, supplements, and vitamins) at each visit. Some of the most common interactions occur between drugs metabolized by CYP450 enzymes. Commonly used drugs that interact with ART include antifungals, anti-myco-bacterials, hormonal contraceptives, lipid-lowering agents (particularly statins), anticonvulsants, and erectile dysfunction agents. These drug interactions can lead to toxicities or decrease the efficacy of either drug. More information on drug interactions is available at http://aidsinfo.nih.gov/guidelines/
DRUG RESiSTANCE AND CROSS-RESiSTANCE
Reverse transcriptase, protease, and integrase are enzymes essential for the replication of HIV in an infected host. Most ARVs inhibit these enzymes and stop the formation of new viral particles. HIV drug resistance is propagated by mutations in HIV viral genes that encode the reverse transcriptase, protease, and integrase enzymes. Gene mutations can alter binding sites on these enzymes and result in an increase in the amount of drug necessary to inhibit enzyme activity. ARV drug resistance mutations arise due to the rapid turnover of HIV (up to 10 billion virions per day in an untreated person) and the high error rate of reverse transcriptase (at least 1 mutation per replication cycle). Some ARVs require only one mutation on the HIV genome to become ineffective (e.g., NNRTIs, lamivudine, nelfinavir, and emtricitabine) and others require multiple mutations in a single genome (e.g., PIs). Cross-resistance occurs when HIV strains develop resistance to one drug that confers insensitivity to other drugs in the same ARV class, including drugs the patient has never taken.
Failure to suppress viral replication leads to the selection of drug-resistant strains. This can occur due to the following factors (please see drug tables for more detailed information):
• Prescribing errors (e.g., incorrect doses; combinations that are antagonistic, such as zidovudine with stavudine; regimens with less than 3 active medications), • Drug-drug interactions between ART and other drugs used concomitantly, • Patient nonadherence to the prescribed ART regimen, and • Pre-existing drug resistance in the absence of a fully suppressive treatment regimen.
THE ViTAL ROLE OF PHARMACiSTS
What can pharmacists do to help decrease drug resistance?• Ensure that clinicians prescribe ART agents correctly.• Keep up with changes in ART medications and treatment guidelines.
Guidelines change often: refer to the guidelines on a regular basis, especially when questions arise. • Screen for drug-drug interactions. • Monitor patients for medication adherence.
How can pharmacists improve adherence to ART?
Education. Teach patients about ARV medications and their personal ART regimens.
• Create a private environment for medication counseling where the patient feels comfortable discussing HIV and HIV treatment. The patient should be able to:
• Name/recognize all medications prescribed for him/her (trade name, generic name, initials)• Explain how each medication works• Describe how and when to take each medication• Discuss what happens when doses are missed• List potential side effects • Relate how side effects can be safely managed • Quiz patients to make sure they understand this information.
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• Be prepared to repeat instructions until the patient feels secure and can answer questions about the treatment regimen, but don’t keep saying the same thing over and over. • Develop different ways to communicate with different patients.• Listen to the patient. Find out what s/he doesn’t understand and modify your teaching to meet individual needs.• Use patient education tools such as the medication chart included with this guide.
Offer support. Offer assistance and support; encourage patients who are having problems.
• Do not be judgmental.• Recommend interventions to treat side effects such as diarrhea and nausea. • Help patients develop a medication schedule. Review the patient’s medication schedule and offer advice on how to incorporate dosing schedules into daily life. • Offer adherence tools such as pillboxes and timers. Many pharmaceutical companies offer these tools at no cost.
Assure timely medication refills. Help patients refill their medications on time and maintain an adequate supply to cover needs.
• Avoid interruptions in therapy; encourage timely refills and advanced planning for trips and holidays, as well as for weekends, evenings, and other times when the pharmacy is closed. • Follow up with patients who do not order refills on all ARVs or who do not order refills on time. • Remind patients to delay starting a new regimen until they have all of the prescribed drugs. They should not begin an incomplete regimen. • Teach patients that the medication regimen works as a whole and that they need to take all medications as prescribed. Explain that partial ART (less than optimally suppressive – usually at least 3 drugs) can lead to resistance.
• If a patient decides to stop therapy, all ART meds (not just 1 or 2) should be stopped at once. There are, however, exceptions to this rule, including: • efavirenz and nevirapine, which, due to a longer half-life, should be stopped approximately 1 week prior to other ARVs in the regimen. • tenofovir and lamivudine may be concomitantly used in the treatment of hepatitis B and stopping them could cause a hepatitis B flare.
Encourage patients to discuss treatment issues with their providers.
• Remind patients that their providers need to know about all of their medications. Even something as simple as an over-the-counter treatment for diarrhea or an herbal remedy to help with sleep may be important in the overall approach to care. • Advise patients to contact their medical providers prior to stopping any portion of the ART regimen. While stopping ART can be especially risky, patients need to have in-depth discussions with their providers before stopping any medication.• Encourage patients to consult with their providers prior to starting any new medication, including over-the-counter drugs and herbal supplements.
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TABLE 3. NUCLEOSiDE/NUCLEOTiDE REVERSE TRANSCRiPTASE iNHiBiTORS (NRTi)
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
abacavir (ABC)
Ziagen®
300 mg tablets [scored]
20 mg/mL oral solution
300 mg twice daily or 600 mg once daily
Child Pugh 5-6: 200mg BID
May be taken with or without food
Alcohol increases abacavir levels by 41% - avoid alcohol
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
5-9% risk of hypersensitivity reaction that may be fatal: signs/symptoms may include rash, fever, nausea, vomit-ing, malaise, fatigue, loss of appetite, and respiratory symptoms such as sore throat, cough, or shortness of breath. Screen with a genetic test, HLA-B*5701 prior to initiation of therapy for hypersensitivity reactions
Hepatically metabolized
Dose reduction in mild hepatic impairment; Contraindicated in moderate-severe hepatic impairment
Nausea, headache, abdominal pain, malaise
If signs/symptoms of hypersensitivity reaction occur: seek medical evaluation immediately to determine need to discontinue and DO NOT restart, abacavir rechallenge has been associated with fatal hypersensitivity reaction.
Lactic acidosis
didanosine (ddl)
Videx®
Videx EC®
Videx EC®
125, 200, 250, or 400 mg capsules
Videx® 100, 167 or 150 mg packet/powder for solution
Videx® Powders 2 g/bottle and 4 g/bottle
Body weight ≥60 kg: 400 mg once daily EC capsule With TDF: 250 mg daily
Body weight <60kg: 250 mg daily EC capsule With TDF: 200 mg daily
Take on an empty stomach 30 min before, or 2h after a meal
Avoid alcohol – increases risk of pancreatitis
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
With tenofovir, dose may be reduced to 250 mg per day
Monitor for ddl toxicity
Concomitant use with d4T not recommended
May reduce dose if there is renal dysfunction
Capsules are enteric coated; take capsules whole
Nausea, vomiting, diarrhea, peripheral neuropathy, headaches, rash
Pancreatitis, hepatitis, lactic acidosis with hepatic steatosis, cardiovascular events
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Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
emtricitabine (FTC)
Emtriva®
200 mg capsule
10 mg/mL oral suspension
200 mg daily [capsule]
240 mg daily [suspension]
May be taken with or without food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Must reduce dose if there is renal dysfunction
Solution: Expires after 3 months if stored at room temperature
Headache, diarrhea, nausea, rash, skin discoloration
Lactic acidosis with hepatic steatosis
lamivudine (3TC)
Epivir®
150 mg tablets [scored] and 300 mg tablets
10 mg/mL suspension
>50 kg: 300 mg daily or 150 mg twice daily
<50 kg: 4 mg/kg twice daily
May be taken with or without food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Must reduce dose if there is renal dysfunction
May contain sucrose
Nausea, headache, diarrhea, abdominal pain, and alopecia
Lactic acidosis with hepatic steatosis
stavudine (d4T)
Zerit®
15, 20, 30, and 40 mg capsules
1 mg/mL oral solution
>60 kg: 40 mg twice daily
<60 kg: 30 mg twice daily
May be taken with or without food
Avoid alcohol
May contain sucrose
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Dosage reduction may be ef-fective for peripheral neuropa-thy and is necessary if there is renal dysfunction
Concomitant use with ddl not recommended
Do not open capsules.
Solution: refrigerate after reconstitution & use within 30 days
Peripheral neuropathy, nausea, vomiting, diarrhea, headache, rash, body fat changes
Pancreatitis, lactic acidosis with hepatic steatosis (higher incidence than with other NRTIs), hyperlipidemia
Mountain Plains AIDS Education and Training Center • 2013 13
tenofovir(TDF)
Viread®
150, 200, 250, and 300 mg tablets
40 mg/g powder
300 mg tablet daily May be taken with or without food
Fatty meals may increase bioavailability
Supplementation with calcium and vitamin D in patients with a history of osteopenia or bone fracture can be considered
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Must reduce dose if renal dysfunction
Powder: Mix with 2-4 ounces of soft food (applesauce, baby food, yogurt) & swallow imme-diately. DO NOT mix in liquid
Tablet: May be crushed and dissolved in liquid
Nausea, diarrhea, vomiting, flatulence, asthenia, renal insufficiency
Lactic acidosis with hepatic steatosis, Fanconi syndrome, decreased bone mineral density
zidovudine (AZT)
Retrovir®
100 mg capsules, 300 mg tablets
10 mg/mL IV solution, 10 mg/mL oral solution
300 mg twice daily or 200 mg 3 times a day
May be taken with or without food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Must reduce dose if there is renal dysfunction
IV: DO NOT give, rapid infusion, or bolus
May alter taste
May cause fingernail discoloration
Nausea, vomiting, anorexia, headaches, malaise, insomnia, asthenia
Anemia, neutropenia, pan-creatitis, lactic acidosis with hepatic steatosis, body fat changes, myopathy
Note: CrCL = creatine clearance *Usual doses are provided. Doses may vary based on weight, the presence of renal or hepatic failure or when using combinations that have pharmacokinetic interactions. Dosage reduction may be required. The association of NRTIs with body fat changes varies from agent to agent. Treatment naïve patients should be on 2 NRTIs if no contraindications. +This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 14
TABLE 4. NUCLEOSiDE/NUCLEOTiDE REVERSE TRANSCRiPTASE iNHiBiTORS (NRTi) METABOLiSM AND DRUG iNTERACTiONS
Metabolism of NRTis Medications That Should NOT be Administered With NRTis
Medications That Have Clinically Significant Drug Interactions With NRTIs+
abacavir (ABC) Ziagen®
Hepatically metabolized None Narcotics: methadoneOther: ganciclovir, protease imhibitors, ribavarin , valganciclovir
didanosine (ddl) Videx® Videx EC®
Renal elimination
No CYP450 effects
Intracellular metabolism by cellular enzymes (MMDx)
Antiretrovirals: stavudineOthers: allopurinol, febuxostat, hydroxyurea, ribavirin
Antiretrovirals: abacavir, tenofovir, tipranivirAcid Reducers: H2RAAntibiotics: ciprofloxacinNarcotics: methadoneOther: hydroxyurea, ganciclovir, valganciclovir
emtricitabine (FTC) Emtriva®
Renal elimination
No CYP450 effects
Antiretrovirals: lamivudine Other: ganciclovir, ribavirin, valganciclovir
lamivudine (3TC) Epivir®
Renal elimination
No CYP450 effects
None Other: sulfamethoxazole/trimethoprim, ribavirin, ganciclovir, valganciclovir
stavudine (d4T)Zerit®
Renal elimination
No CYP450 effects
Antiretrovirals: didanosine, zidovudine
Narcotics: methadoneOther: doxorubicin, hydroxyurea, ribavirin
tenofovir (TDF)Viread®
Renal elimination
P-gp Inducer
None Antiretrovirals: adefovir, atazanavir, cidofovir, didanosineHepatitis: adefovir, telaprevirOther: ganciclovir, probenecid, valganciclovir
Zdovudine (AZT) Retrovir®
Renal elimination
Minor CYP450 effects
Antiretrovirals: stavudineOthers: clozapine
Antibiotics: clarithromycinNarcotics: methadoneOther: ganciclovir, valganciclovir, ribavirin
Metabolism of NRTIs - AZT-hepatic via glucuronidation; renal excretion of metabolites; ddl - 55% renally eliminated as unchanged drug; ddC - renally eliminated; d4T - renal excretion 50%; 3TC - renally eliminated; abacavir - hepatic via alcohol dehydrogenase and glucuronyl transferase; metabolites excreted renally 85%; FTC - renally eliminated; tenofovir - renally eliminated
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 15
TABLE 5. FixED DOSE COMBiNATiON NRTiS
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
lamivudine/zidovudine(AZT/3TC)
Combivir®
3TC 150 mg + AZT 300 mg [scored]
1 tablet every 12 hours
May be taken with or without food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
DO NOT USE if CrCl <50 mL/min
May contain sucrose
See individual components
abacavir/lamivudine(ABC/3TC)
Epzicom®
3TC 300 mg + ABC 600 mg
1 tablet once daily May be taken with or without food
Alcohol increase abacavir levels by 41% - avoid alcohol
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Not recommended for CrCl <50 mL/min
Risk of hypersensitivity reaction
See individual components
emtricitabine/tenofovir(FTC/TDF)
Truvada®
FTC 200 mg + TDF 300 mg
1 tablet once daily May be taken with or without food; fatty meals may increase the bio-availability; supplementation with calcium and vitamin D in patients with a history of osteopenia or bone fracture can be considered
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
CrCl 30-49 mL/min: increase dosing interval to every 48h
CrCl <30 mL/min or hemo- dialysis: not recommended
See individual components
Mountain Plains AIDS Education and Training Center • 2013 16
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
abacavir/ lamivudine/ zidovudine (ABC/3TC/AZT)
Trizivir®
ABC 300 mg + AZT 300 mg + 3TC 150 mg
1 tablet twice daily May be taken with or without food
Alcohol increase abacavir levels by 41% - avoid alcohol
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose
Not recommended for CrCl <50 mL/min
Risk of hypersensitivity reaction
See individual components
Note. CrCL = creatine clearance +This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 17
TABLE 6. NON-NUCLEOSiDE REVERSE TRANSCRiPTASE iNHiBiTORS (NNRTi)
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
delavirdine (DLV)
Rescriptor®
100, 200 mg tablets 400 mg 3 times a day
May be taken with or without meals
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Space doses 1 hour apart from antacids and ddI chewable tablets, suspension and oral solutionVery susceptible to resistance
100 mg tablets can be dissolved in 3 ounces of water. 200 mg tablets should be taken whole (Do not readily disperse in water)Major CYP3A4 inhibitor;Many drug interactions.
Rash, elevated liver enzymes, headaches, fatigue, GI upset, neutropenia
Stevens-Johnson Syndrome, Erythema multiforme, hepatitis
efavirenz (EFV)
Sustiva®
50, 200 mg capsules, or 600 mg tablets
600 mg once daily preferably at bedtime
Take on an empty stomach
Avoid high-fat meals, or take at or before bedtime
High-fat meals increase absorption of efavirenz leading to CNS effects
Alcohol increases risk of hepa-totoxicity with efavirenz and in-creased CNS depression – avoid/limit alcohol
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Should not be administered during pregnancy or in women with pregnancy potential, unless negative pregnancy test prior to initiation and patient is using 2 effective contraceptive meth-ods, including 1 barrier method (Pregnancy Category D)Tablets should be taken whole
Capsules can be opened, mixed in applesauce, grape jelly, or plain yogurt (Capsule mixtures should be given within 30 min)Major CYP3A4 Inducer; many drug interactions
Potential false positive canna-binoid urine test
Rash, drowsiness, diarrhea, dizziness, anxiety, depres-sion, trouble concentrating, unusual dreams (effects usually transient lasting 2-4 weeks), elevated liver enzymes, hyperlipidemia
Erythema multiforme
Mountain Plains AIDS Education and Training Center • 2013 18
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
etravirine(ETV)intelence®
100, 200 mg tablets 200 mg twice daily Take after a meal
Maintain adequate hydration un-less advised otherwise
If a dose is missed and it has been <6h, take the missed dose. If it has been >6h, skip missed dose and take next scheduled dose. Never double dose.
May disperse in glass of water if unable to swallow tablets (DO NOT mix with grapefruit juice, carbonated beverages, or warm water)
May produce false positives on some cannabinoid and benzodiazepine screening tests
CYP3A4 inducer; CYP2C9/2C19 inhibitor; many drug interactions
Rash, nausea, hyperlipidemia, peripheral neuropathy
Hepatomegaly, atrial fibrillation, renal failure, hepatic failure, Stevens-Johnson Syndrome, erythema multiforme, toxic epidermal necrolysis
nevirapine (NVP)
ViramuneTM
200 mg tablets [scored]
400 mg ER tablet 50 mg/5 mL oral suspension
initial200 mg daily for 14 days
Maintenance Immediate Release: 200 mg two times daily
Extended Release: 400 mg once daily
Not recommended for use if baseline CD4+ T cell count >250 cells/ mm3 in females or >400 cells/ mm3 in males
May be taken with or without food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose
Baseline LFTs and monitor at 2 weeks, 4 weeks, and frequently until 18 weeks of therapy LFTs should continue to be monitored every 3-6 months after the initial 18-week period Maximum induction takes place in 14 to 28 days
Lead-in dosing should be repeated if drug is interrupted for any reason for more than 7 days
If switching from efavirenz, start immediately at maintenance dose (400 mg/day)
ER Tablet: Take whole; Do not crush, chew, or divide.
Contraindicated in moderate to severe hepatic impairment.
Rash, GI upset, headaches, elevated liver enzymes
Erythema multiforme, hepa-toxicity (>risk if baseline CD4+ T cell count >250 cells/mm3 in females or >400 cells/mm3 in males)
Stevens-Johnson Syndrome, erythema multiforme, toxic epidermal necrolysis
Mountain Plains AIDS Education and Training Center • 2013 19
rilpivirine(RPV)
EdurantTM
25 mg tablet 25 mg once daily Take with a normal/high-calorie meal
Protein supplement drink is not recommended
If a dose is missed within 12h, take it with a meal as soon as pos-sible. If a dose is missed by >12h, wait until the next scheduled dose and skip the missed dose. Never double dose.
If warranted take rilpivirine at least 4h before or 12h after H2RA
T\If warranted take rilpivirine at least 4h before or 2h after antacids
Contraindicated with PPIs
Resistance patterns are very similar to ETV
Rash, insomnia, headache, depression, hyperlipidemia; increases hepatic enzymes, increases creatinine, body fat changes
Glomerulonephritis. QTc prolongation
*Usual doses are provided. Doses may vary based on weight, the presence of renal or hepatic failure, or when using combinations that have pharmacokinetic interactions.
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 20
TABLE 7. NON-NUCLEOSiDE REVERSE TRANSCRiPTASE iNHiBiTORS (NNRTi) METABOLiSM AND DRUG iNTERACTiONS
Metabolism of NNRTis Medications That Should NOT be Administered With NNRTis
Medications That Have Clinically Significant Drug Interactions With NNRTIs+
delavirdine (DLV)
Rescriptor®
Strong Inhibitor of CYP3A4, CYP2C19, CYP2C9, CYP2D6
CYP3A4 Substrate
Antihistamine: astemizole, terfenadineBenzodiazepines: alprazolam, midazolam, triazolamErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Gi Agents: cisaprideNeuroleptics: pimozide
Acid Reducers: antacids, H2RA, PPIAnticoagulants: warfarinAntidepressants: trazodoneAntimycobacterials: clarithromycinCardiac: bepridil, amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone, DHP-CCBCorticosteroids: dexamethasone, fluticasoneHerbs: St. John’s Wortimmunosuppressants: cyclosporine, tacrolimusNarcotics: methadoneStatins: atorvastatin, fluvastatinOther: amphetamines, sildenafil, hormonal contraceptives
efavirenz (EFV)
Sustiva®
Strong Inducer of CYP3A4
Moderate Inhibitor of CYP2C19, CYP2C9, & CYP3A4
CYP2B6 & CYP3A4 Substrate
Antimycobacterials: rifapentineBenzodiazepine: midazolam, triazolamErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Gi Agents: cisaprideHerbs: St John’s WortNeuroleptics: pimozide
Anticoagulants: warfarinAntibiotics: clarithromycinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: buproprion, paroxetine, sertralineAntifungals: fluconazole, itraconazole, posaconazole, voriconazoleAntimycobacterials: rifabutin, rifampinBenzodiazepines: alprazolam, lorazepam, midazolam, triazolamCardiac: DHP-CCB, diltiazem, verapamilCorticosteroids: dexamethasone, fluticasoneHepatitis Medications: boceprevir, telaprevirNarcotics: buprenorphine, methadoneStatins: atorvastatin, lovastatin, simvastatin, pitavastatin, pravastatin, rosuvastatinOther: hormonal contraceptives, atovaquone/proguanil
Mountain Plains AIDS Education and Training Center • 2013 21
etravirine(ETV)
intelence®
Moderate inhibitor of CYP2C19 & CYP2C9
Strong Inducer of CYP3A4
CYP2C19, CYP2C9, & CYP3A4 Substrate
Antimycobacterials: rifampin, rifapentineAnticonvulsants: carbamazepine, phenobarbital, phenytoinHepatitis Medications: boceprevir, telaprevirHerbs: St John’s WortOthers: clopidogrel
Antibiotics: clarithromycinAnticoagulants: warfarin, clopidogrelAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: paroxetineAntifungals: fluconazole, itraconazole, posaconazole, voriconazoleAntimycobacterials: clarithromycin, rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam, diazepamCardiac: amiodirone, flecanide, propafenone, quinidineCorticosteroids: dexamethasoneHerbs: St. John’s WortNarcotics: buprenorphine, methadoneStatins: atorvastatin, fluvastatin, lovastatin, simvastatin, pitavastatin, pravastatin, rosuvastatinOther: hormonal contraceptives, PDE5 inhibitors
nevirapine(NVP)
ViramuneTM
Strong inducer of CYP2B6 & CYP3A4
CYP3A4 Substrate
Antiretrovirals: atazanavirAntifungals: ketoconazoleAntimycobacterials: rifampin, rifapentineHepatitis Medications: boceprevir, telaprevirHerbs: St John’s Wort
Antibiotics: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntifungals: fluconazole, itraconazole, voriconazoleAntimycobacterials: rifabutinBenzodiazepines: alprazolam, diazepamCardiac: DHP-CCB, diltiazem, verapamilCorticosteroids: dexamethasoneHerbs: St. John’s WortNarcotics: buprenorphine, methadoneStatins: lovastatin, simvastatin, pitavastatinOther: hormonal contraceptives
Mountain Plains AIDS Education and Training Center • 2013 22
Metabolism of NNRTis Medications That Should NOT be Administered With NNRTis
Medications That Have Clinically Significant Drug Interactions With NNRTIs+
rilpivirine(RPV)
EdurantTM
CYP3A4 Substrate Acid Reducers: PPIAntiretrovirals: EfavirenzAntimycobacterials: rifabutin, rifampin, rifapentineAnticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoinHepatitis Medications: boceprevir, telaprevirHerbs: St John’s Wort
Antiretrovirals: NNRTIAcid Reducers: antacids, H2RAAntibiotics: clarithromycin, erythromycinAntifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazoleAntimycobacterials: rifabutin,rifampin, rifapentineBenzodiazepines: alprazolamCorticosteroids: dexamethasoneHerbs: St. John’s WortNarcotics: methadoneStatins: atorvastatin, pitavastatinOther: hormonal contraceptives, sildenafil
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 23
TABLE 8. ENTRy iNHiBiTORS
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
enfuvirtide (T-20) Fuzeon®
108 mg vials
reconstitute with 1.1 mL sterile water (90 mg/mL)
90 mg SQ every 12h No dietary restrictions
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Patients must be willing and capable of preparing and administering injections
Requires thorough education about storage, preparation, SQ injection and prevention of injection site reactions
Reconstituted drug may be refrigerated up to 12h prior to use
Ensure proper syringe disposal
Local injection site reactions, diarrhea, nausea, fatigue, ab-dominal pain, pneumonia
Hypersensitivity reaction, bacterial pneumonia
maraviroc(MVC)
Selzentry®
150, 300 mg tablets 300 mg twice daily
150 mg twice daily if given with strong CYP3A inhibitors
600 mg twice daily if given with a strong CYP3A inducer
May be taken with or without meals
If a dose is missed, take it as soon as possible; if is <6h until the next dose, wait and take that dose and skip the missed dose. Never double dose.
Patients must receive tropism test to ensure they have CCR5-tropic virus only
Dose adjustment required in renal impairment
Concomitant use of St. John’s Wort not recommended
Must adjust dose for renal impairment
CYP3A4 substrate
Dizziness, rash, cough, fever, respiratory infections, diarrhea, nausea, headache, orthostatic hypotension, lipodystotrophy
Hepatotoxic, cardiac events related to coronary artery disease
*Usual doses are provided. Doses may vary based on weight, the presence of renal or hepatic failure, or when using combinations that have pharmacokinetic interactions+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 24
TABLE 9. ENTRy iNHiBiTORS - METABOLiSM AND DRUG iNTERACTiONS
Metabolism of Entry inhibitors Medications That Should NOT be Administered With Entry inhibitors
Medications That Have Clinically Significant Drug Interactions With Entry Inhibitors+
enfuvirtide(T-20)
Fuzeon®
Peptide catabolism None Antiretrovirals: protease inhibitors
maraviroc(MVC)
Selzentry®
CYP3A and P-gp substrate
Herbals: St. John’s Wort Strong inhibitors or inducers of CyP3A and P-gp
Antibiotics: clarithromycin, erythromycinAntiepileptics: carbamazepine, phenobarbital, phenytoin Antidepressants: fluvoxamineAntifungals: ketoconazole, itraconazole, clarithromycin Antineoplastics: dasatinibAntiretrovirals: protease inhibitors (except tipranavir/ritonavir), NNRTIsAntimycobacterials: rifampinCardiac: amiodarone, diltiazem, verapamilOther: potent CYP3A inhibitors or P-gp (e.g., nefazodone, telithromycin, etc.)
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 25
TABLE 10. iNTEGRASE iNHiBiTORS ( iNSTi)
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
raltegravir(RAL)
isentress®
Film Coated Tablet: 400 mg
Chewable Tablet: 100mg & 25mg
400 mg twice daily May be taken with or without food
Chewable tablet contains phenylalanine
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose
Dose adjust with rifampin
No renal or hepatic adjustments
UGT1A1 Substrate
Separate dose from antacids due to binding effect
Film tablet: Swallow whole
Film and chewable tablet are NOT bioequivalent, do not substitute.
Caution in Gilbert’s Syndrome – Increased drug levels & side effects
Nausea, headache, insomnia, fatigue, CK elevations, lipid changes
Stevens-Johnson Syndrome, toxic epidermal necrolysis, myopathy/ rhabdomyolysis, renal failure
elvitegravir(EVG)
(available in a combination single tablet regimen with tenofovir, emtricitabine, and cobicistat)
StribildTM
150 mg in a fixed-dose combination with 150 mg COBI + 200 mg FTC + 300 mg TDF
150 mg EVG + 150 mg COBI once daily
Fixed-dose combination should be taken with food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose
Mostly metabolized by CYP3A4, some minor glucuronidation (UGT1A1 & UGT1A3)
May not be used in some renally compromised patients
DO NOT use in Child Pugh class C (Severe)
Headache, unusual dreams, fatigue, dizziness, diarrhea, drowsiness, anxiety, nausea, abdominal swelling, rash, pneumonia, muscle spasms
Elevated liver enzymes, elevated lipase
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 26
TABLE 11 . iNTEGRASE iNHiBiTORS ( iNSTi) - METABOLiSM AND DRUG iNTERACTiONS
Metabolism of integrase inhibitors Medications That Should NOT be Administered With integrase inhibitors
Medications That Have Clinically Significant Drug Interactions With Integrase Inhibitors+
raltegravir (RAL)
isentress®
Undergoes phase 2 hepatic metabolism by UGT1A1
Herbs: St. John’s Wort Antiretrovirals: atazanavir, efavirenz, etravirine, ritonavir, rifampin, fosamprenavir, tipranavirAcid reducers: omeprazoleOthers: Drugs that are strong inhibitors or inducers (especially) of UGT1A1
elvitegravir (EVG)
(Currently available in a combination single tablet regimen with tenofovir, emtricitabine, and cobicistat)
StribildTM
CYP3A4 substrate Not established with elvitegravir aloneContraindications to StribildTM due to elvitegravir component:
Antimycobacterials: rifabutin, rifampin, rifapentineAntiretrovirals: atazanavir, efavirenz, etravirine, fosamprenavir, nevirapine, tipranavirBenzodiazepines: midazolam, trazolamHepatitis Medications: boceprevir, telaprevirStatins: lovastatin, simvastatinOthers: sildenafil
Antifungals: intraconazole, posaconazole, voriconazoleAntibiotics: clarithromycin Antidepressants: SSRIs, TCAsAntiepileptics: carbamazepine, phenobarbital, phenytoin Antiretrovirals: rilpivirine, ritonovir, saquinavirBenzodiazepines: clonazepam, diazepamCardiac: amiodarone, digoxin, flecanide, propafenoneStatins: atorvastatin, rosuvastinOthers: hormonal contraceptives, drugs that are strong inhibitors or inducers of CYP3A4
Note: Currently only available in combination product Stribild®. Spe-cific data on drug interactions with elvitegravir alone is limited.
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 27
TABLE 12. PROTEASE iNHiBiTORS (Pi)
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
darunavir (DRV)
Prezista®
75, 150, 400, 600, 800 mg tablets
With no DRV muta-tions: 800 mg DRV + 100 mg RTV once daily
With at least one DRV mutation: 600 mg DRV + 100 mg RTV twice daily
Take with food
For once a day administration: if a dose is missed, and is >12h since the last scheduled dose, wait and take the next dose. If a dose is missed and is <12h since the last scheduled dose, take it as soon as possible. Never double dose.
For twice a day dosing: if a dose is missed, and is >6h hours since the last scheduled dose, wait and take the next dose. If a dose is missed and it is <6h since the last scheduled dose, take it as soon as possible. Never double dose.
No dose adjustment in renal or hepatic impairment
Unboosted DRV is not recommended
Use caution in patients with sulfa allergies
Not recommended in severe he-patic dysfunction (Child Pugh C)
Rash, diarrhea, hypertriglyidemia, abdominal pain, vomiting, nausea
Hepatitis, SJS, TEN, diabetes mellitus
atazanavir (ATV)
Reyataz®
100, 150, 200, 300 mg capsules
If used with tenofovir use ATV 300 mg + RTV 100 mg (RTV booster) once daily
If RTV not tolerated, use ATV 400mg once daily
If used with EFV, use ATV 400 mg + RTV 100 mg once daily
Take with food
If a dose is missed, take it as soon as possible. If it is <6h until the next dose, wait until then and skip the missed dose.
Use caution with any acid-re-ducing agents; Dose ATV 12h apart from H2 blocker dosing
Use caution in patients on medications that may cause PR interval prolongation or if there is underlying conduction defect
UGT1A1 Inhibitor
Caution in Gilbert’s Syndrome
Take 2h before or 1h after antacids
Administer 300/100 mg ATV/RTV 12h after PPI’s
Hyperglycemia, body fat changes†, hyperbilirubinemia, possible increased bleeding in patients with hemophilia, GI distress Prolonged PR interval, hepatitis, SJS, TEN, erythema multiforme
Mountain Plains AIDS Education and Training Center • 2013 28
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
fosamprenavir (FPV)
Lexiva®
700 mg tablet
50 mg/mL oral suspension
1,400 mg + RTV 200 mg daily or 700 mg + RTV 100 mg twice daily
If previous PI use, once daily regimen not recommended, use: 700 mg + RTV 100 mg twice daily
If co-administration with EFV 600mg: 700 mg + RTV 100 mg twice daily or 1,400 mg + RTV 300 mg daily
Tablets may be taken with or without food if taken alone.
Take with food if taken concurrently with RTV. Suspension should be taken with-out food in adults and with food in children.
If a dose is missed and it has been <4h since the last dose, take it as soon possible. If it is almost time for the next dose, or >4h, wait until the next scheduled dose and skip the missed dose.
Never double dose.
If vomiting occurs within 30 min after the first dose, take a second dose right away.
Oral birth control may not work as effectively on this medication
Suspension: Readminister dose of suspension if emesis occurs within 30 min after dose
Caution in patients with sulfa allergies (Contains sulfa moiety)
Dose adjustment in hepatic impairment may be required
Rash, diarrhea, nausea, vomiting, headache, circumoral parasthesias
Stevens-Johnson Syndrome, DM, neutropenia, nephrolithiasis
indinavir (iDV)
Crixivan®
200, 400 mg capsules
800 mg every 8 hours unboosted
With RTV: 800 mg + RTV 100 or 200 mg every 12 hours
Should be taken on an empty stom-ach 1h before or 2h after a meal
Avoid garlicAvoid St. John’s WortCan be taken with a light meal (e.g., dry toast, skim milk, or corn flakes). May be taken with food if given with RTV
Drink 1.5 liters of water each day
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Dose adjustment in hepatic impairment may be required
Nausea, diarrhea, increased indirect bilirubin, headaches, blurred vision, dizziness, rash, hyperglycemia, alopecia, dry skin, dry mouth, dry eyes
Body fat changes† hyper-lipidemia, nephrolithiasis, thrombocytopenia, hemolytic anemia, possible increased bleeding in patients with hemophilia dizziness
Mountain Plains AIDS Education and Training Center • 2013 29
lopinavir + ritonavir (LPV/RTV)
Kaletra®
LPV 100 mg + RTV 25 mg
LPV 200 mg + RTV 50 mg
LPV 80 mg + RTV 20 mg/1.0 mL oral solution
Treatment experi-enced: 400/100 mg twice daily or 800/200 mg once daily
With EFV or NVP: 500/125 mg twice daily
Tablet may be taken with or without food
Solution should be taken with food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Solution must be refrigerated
Tablet exposure to high humidi-ty outside original container for >2 weeks not recommended
Liquid has a strong taste
DO NOT use once daily dosing in pregnancy
Nausea, diarrhea, taste perversion, perioral dermatits, circumoral paresthesia
Elevated transaminases, hyperglycemia, hyperlipidemia, body fat changes†, possible increased bleeding in patients with hemophilia
nelfinavir (NFV)
Viracept®
250, 625 mg tablets
50mg/g oral powder
1,250 mg twice daily or 750 mg 3 times daily
Should be taken with a meal
Do not administer with acidic food or juice, which can lead to a bitter taste
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Do not use 3 times daily dosing in pregnant women
Oral powder contains phenylalanine
Boosting is NOT effective due to non-CYP3A4 routes of metabolism
Tablet & powder may be mixed in a small amount of water
Diarrhea (can be severe), flatulence, nausea, rash Hyperglycemia, hyperlipid-emia, body fat changes†, elevated transaminases, possible increased bleeding in patients with hemophilia
saquinavir (SQV)
invirase®
500 mg tablet
200 mg capsules
Unboosted not recommended
1,000 mg + RTV 100 mg twice daily
Take within 2h of a meal
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Store at room temperature
Avoid grapefruit juice
Avoid starting if baseline QT exceeds 450 milliseconds
Nausea, diarrhea, headaches, increased transaminases, increased triglycerides, hyperlipidemia Hyperglycemia, body fat changes†, possible increased bleeding in patients with hemophilia, QT prolongation
Mountain Plains AIDS Education and Training Center • 2013 30
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
tipranavir (TPV)
Aptivus®
250 mg capsules
100 mg/mL oral solution
500 mg + RTV 200 mg twice daily
Risk-benefit not yet established in treat-ment naïve patients
Oral solution formulation contains vitamin E – avoid extra vitamin E supplementation
Should be taken with food.
Boost w/Ritonavir is required
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Use with caution if known sulfa allergy
Administer 2h apart from ddl-EC and liquid antacids
Use with caution with hepatic impairment
Refrigerate capsules, may be stored at controlled room temperature (77°F or below) for 60 days.
Major Pg-p Inducer
Capsules contain dehydrated alcohol 7% w/w (0.1g per capsule)
Nausea, vomiting, diarrhea
Clinical hepatitis, hepatic decompensation, elevated transaminases, symptoms of sulfa allergy, rash, photosensitivity, hyper- glycemia, hyperlipidemia, body fat changes, possible increased bleeding in patients with hemophilia, increased risk of rash with estrogen use
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 31
TABLE 13. PROTEASE iNHiBiTORS (Pi) - METABOLiSM AND DRUG iNTERACTiONS
Metabolism of Protease inhibitors Medications That Should NOT Be Administered With Protease inhibitors
Medications That Have Clinically Significant Drug Interactions With Protease Inhibitors+
darunavir (DRV)
Prezista®
Strong inhibitor of CYP3A4 & P-gp
CYP3A4 Substrate
Antimycobacterials: rifampin, rifapentineBenzodiazepines: midazolam, triazolamErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, salmeterol, sildenafil for PAH
Antibiotics: clarithromycinAcid Reducers: H2RA, PPIAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: paroxetine, sertraline, TCAsAntifungals: itraconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam, diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, digoxin, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasoneHepatitis Medications: boceprevir, telaprevirHerbals: St. John’s WortNarcotics: buprenorphine, methadoneStatins: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol
atazanavir (ATV)
Reyataz®
Strong Inhibitor of CYP3A4 & UGT1A1
CYP3A4 Substrate
Antimycobacterials: rifampin, rifapentineAntiretrovirals: etravirine, nevirapineBenzodiazepines: midazolam, triazolamErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, irinotecan, salmeterol, sildenafil for PAH
Antibiotics: clarithromycinAcid Reducers: Antacids, H2RA, PPIAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: trazodone, TCAsAntifungals: fluconazole, itraconazole, posaconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam,diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, digoxin, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasoneHepatitis Medications: boceprevir, telaprevirHerbals: St. John’s WortNarcotics: buprenorphine methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol, atovaquone/proguanil
Mountain Plains AIDS Education and Training Center • 2013 32
Metabolism of Protease inhibitors Medications That Should NOT Be Administered With Protease inhibitors
Medications That Have Clinically Significant Drug Interactions With Protease Inhibitors+
fosamprenavir (FPV)
Lexiva®
Strong Inhibitor of CYP3A4
CYP3A4 & P-gp Substrate
Antimycobacterials: rifampin, rifapentineAntiretrovirals: etravirineBenzodiazepines: midazolam, triazolamCardiac: amiodoirone flecainide, propafenoneErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, salmeterol, sildenafil for PAH
Antibiotics: clarithromycinAcid Reducers: Antacids, H2RA, PPICardiac: bosentan, digoxin, DHP-CCB, diltiazemAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: paroxetine, trazodone, TCAsAntifungals: itraconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam,diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, digoxin, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasoneHepatitis Medications: boceprevir, telaprevirHerbals: St. John’s WortNarcotics: buprenorphine, methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol
indinavir (iDV)
Crixivan®
CYP3A4 & P-gp Substrate
Strong Inhibitor of CYP3A4
Benzodiazepines: midazolam, triazolam, alprazolamCardiac: amiodaroneErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortStatins: simvastatin, lovastatinNeuroleptics: pimozideOthers: alfuzosin, sildenafil for PAH
Acid Reducers: Antacids, H2RA, PPIAntibiotics: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: paroxetine, venlafaxine, trazodone, TCAsAntifungals: itraconazole, ketoconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam, diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, DHP-CCB, quinidine, lidocaine Corticosteroids: dexamethasone, fluticasoneHepatitis medications: boceprevir, telaprevirHerbals: St. John’s Wortimmunosuppressants: cyclosporine, tacrolimus, sirolimusNarcotics: buprenorphine, methadoneStatins: atorvastatin, rosuvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol, midazolam
Mountain Plains AIDS Education and Training Center • 2013 33
lopinavir + ritonavir (LPV/RTV)
Kaletra®
Strong Inhibitor of CYP3A4
CYP3A4 Substrate
Antimycobacterials: rifampin, rifapentineBenzodiazepines: midazolam, triazolamCardiac: amiodarone, quinidineErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Gi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, salmeterol, sildenafil for PAH
Acid Reducers: H2RA, PPIAntibiotics: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, lamotrigine, phenobarbital, phenytoin, valproic AcidAntidepressants: bupropion, trazodone, TCAsAntifungals: itraconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam,diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasone, prednisoneStatins: simvastatin, lovastatinHepatitis medications: boceprevir, telaprevirHerbals: St. John’s WortNarcotics: buprenorphine methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol, atovaquone/proguanil
nelfinavir (NFV)
Viracept®
Strong Inhibitor of CYP3A4
CYP3A4, CYP2C19, & P-gp Substrate
Antimycobacterials: rifampinBenzodiazepines: midazolam, triazolamCardiac: amiodarone, quinidineErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin
Anticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressant: trazodoneAntigout: colchicineAntimycobacterial: rifabutinCardiac: bosentanCorticosteroid: fluticasoneHepatitis medications: boceprevir, telaprevirimmunosuppressant: cyclosporine, tacrolimus, sirolimusNarcotics: methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: salmeterol, azithromycin, hormonal contraceptives, PDE5 Inhibitors
Mountain Plains AIDS Education and Training Center • 2013 34
Metabolism of Protease inhibitors Medications That Should NOT Be Administered With Protease inhibitors
Medications That Have Clinically Significant Drug Interactions With Protease Inhibitors+
saquinavir (SQV)
invirase®
Strong Inhibitor of CYP3A4 & P-gp
CYP3A4 & P-gp Substrate
Antimycobacterials: rifampin, rifapentineBenzodiazepines: midazolam, triazolamCardiac: amiodarone, dofetilide, flecainide, lidocaine, propafenone, quinidineErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Gi motility agents: cisaprideHerbals: St. John’s Wort, garlic supplementsNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, salmeterol, sildenafil for PAHSedatives/Hipnotics: trazodone
Acid Reducers: PPIAntibiotics: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: trazodone, TCAsAntifungals: fluconazole, itraconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam, diazepam, lorazepam, oxazepam, midazolam, triazolamCardiac: bosentan, digoxin, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasoneHepatitis medications: boceprevir, telaprevirHerbals: St. John’s WortNarcotics: methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol
tipranavir (TPV)
Apitvus®
CYP3A4 Substrate
Strong Inhibitor of CYP3A4 & CYP2D6
Inducer of P-gp
Antimycobacterials: rifampin, rifapentineAntiretrovirals: etravirineBenzodiazepines: midazolam, triazolamCardiac: amiodarone, flecainide, propafenone, quinidineErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Gi motility agents: CisaprideHerbals: St. John’s WortNeuroleptics: pimozideStatins: simvastatin, lovastatinOthers: alfuzosin, salmeterol, sildenafil for PAH
Acid Reducers: Antacids, PPIAntibiotics: clarithromycinAnticoagulants: warfarinAnticonvulsants: carbamazepine, phenobarbital, phenytoinAntidepressants: bupropion, trazodone, TCAsAntifungals: fluconazole, itraconazole, voriconazoleAntimycobacterials: rifabutin, rifampin, rifapentineBenzodiazepines: alprazolam,diazepam, lorazepam, oxazepam, midazolam, tiazolamCardiac: bosentan, digoxin, DHP-CCB, diltiazemCorticosteroids: dexamethasone, fluticasoneHerbals: St. John’s WortHepatitis medications: boceprevir, telaprevirNarcotics: buprenorphine, methadoneStatins: atorvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatinOther: PDE5 Inhibitors, hormonal contraceptives, colchicine, salmeterol
Note. TCAs = tricyclic antidepressants +This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 35
TABLE 14. BOOSTiNG AGENTS
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
cobicistat (COBi)
(Currently available in a combination sin-gle tablet regimen with tenofovir, emtricitabine, and elvitegravir) StribildTM
Currently only available in a single tablet regimen with TDF, ETC, and EVG
150 mg in fixed dose tablet
Take with food
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose.
Never double dose.
Inhibitor of CYP3A enzymes with no antiretroviral activity
Store at room temperature
Closely monitor patients w/ >0.4 mg/dL increase in Scr from baseline
Pneumonia, skin rash, loss of coordination, anogenital warts, vomiting, laboratory abnormalities, abnormal dreams/nightmares, fatigue, dizziness, diarrhea, drowsiness, headache, anxiety, nausea, abdominal distention, rash, flatulence
Lactic acidosis, pancreatitis, Hepatitis B, hepatomegaly with steatosis, hepatotoxic-ity, immune reconstitution syndrome, rhabdomyolysis, Fanconi syndrome, renal impairment
ritonavir (RTV)
Norvir®
100 mg tablets and capsules
80 mg/mL solution
Used primarily as a booster for other PIs – see specific PI
Should be taken with food
Maintain adequate hydration
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose.
Never double dose.
Tablets do not require refrigeration
Tablets: If stored outside of original container discard after 2 weeks
Do not refrigerate oral solution.
Solution contains 43% ethanol by volume
Potent CYP3A4 Inhibitor; Many drug interactions
Capsules must be refrigerated, but may be stored at controlled room temperature for 30 days
Nausea, vomiting, diarrhea, taste perversion, extremity and circumoral paresthesia
Elevated transaminases,hyperglycemia, hyperlip-idemia, body fat changes, possible increased bleeding in patients with hemophilia. QTc elongation, and PR interval
+This list is not all-inclusive
Mountain Plains AIDS Education and Training Center • 2013 36
TABLE 15. BOOSTiNG AGENTS - METABOLiSM AND DRUG iNTERACTiONS
Metabolism of Boosting Agents Medications That Should NOT Be Administered With Boosting Agents
Medications That Have Clinically Significant Drug Interactions With Boosting Agents
ritonavir (RTV) Norvir®
Major inhibitor of CYP3ACYP3A (major) and CYP2D6 (minor) substrate
Alpha Adrenergic Antagonists: alfuzosinCardiac: amiodarone, flecainide, propafenone, quinidineAntifungals: voriconazoleBenzodiazepines: midazolam, triazolamCardiac: amiodarone, flecainide, propafenone, quinidineErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozidePDE5 inhibitors: sildenafil (when used for pulmonary hypertension)Statins: lovastatin, simvistatin
Drugs metabolized by CyP3A
Analgesics: tramadol, propoxyphene, methadone, fentanylAnesthetics: meperidineAnticoagulants: warfarinAnticonvulsants: carbamazepine, clonazepam, ethosuximide, divalproex, lamotrigine, phenytoinAntidepressants: SSRIs, TCA s, nefazadone, bupropion, desipramine, trazodoneAntiemetics: dronabinolAntifungals: ketoconazole, itraconazole, voriconazoleAnti-gout: colchicineAntibiotics: clarithromycin, metronidazole, rifabutin, rifampinAntineoplastics: dasatinib, nilotinib, vincristine, vinblastineAntiretrovirals: protease inhibitors (all except nelfinavir), NNRTIs (delavirdine), entry inhibitors maravirocAntiparasitic: atovaquone, quinidineBronchodilators: theophyllineBenzodiazepines: midazalomCardiac: disopyramide, lidocaine, mexiletine, metoprolol, timolol, diltiazem, nifedipine, verapamilimmunosuppressants: cyclosporine, tacrolimus, sirolimusinhaled Steroids: fluticasoneLong-acting beta adrenoceptor agonists: salmeterolNeuroleptics: perphenazine, risperidone, thioridazoneOral contraceptives: ethinyl estradiolPDE5 inhibitors: sildenafil, tadalafil, vardenafil Statins: atorvastatin, rosuvastatinSteroids: dexamethasone, fluticasone, prednisoneStimulants: methamphetamineOthers: disulfram
Mountain Plains AIDS Education and Training Center • 2013 37
cobicistat(COBi) (Currently available in a combination single tablet regi-men with tenofovir, emtricitabine, and cobicistat)
StribildTM
Not established with cobicistat aloneDrugs metabolized by CyP3A4Note: Specific data on drug interactions is limited due to investigational drug status.
Contraindications to StribildTM due to cobicistat component:
Alpha Adrenergic Antagonists: alfuzosinBenzodiazepines: midazolam, triazolamErgot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovineGi motility agents: cisaprideHerbals: St. John’s WortNeuroleptics: pimozidePDE5 inhibitors: sildenafil (when used for pulmonary hypertension)Statins: lovastatin, simvistatin
Drugs metabolized by CyP3A4Note: Specific data on drug interactions is limited due to investigational drug status.*Similar to ritonavir drug interaction profile*
Antifungals: intraconazole, posaconazole, voriconazoleAntibiotics: clarithromycin Antidepressants: SSRIs, TCAsAntiepileptics: carbamazepine, phenobarbital, phenytoin Antiretrovirals: rilpivirine, ritonovir, saquinavirBenzodiazepines: clonazepam, diazepamCardiac: amiodarone, digoxin, flecanide, propafenoneStatins: atorvastatin, rosuvastinOthers: hormonal contraceptives, drugs that are strong inhibitors or inducers of CYP3A4
Note: Currently available in combination product Stribild®. Specific data on drug interactions with cobicistat
Mountain Plains AIDS Education and Training Center • 2013 38
TABLE 16. FixED-DOSE MULTi-CLASS AGENTS: SiNGLE TABLET REGiMENS
Generic Name (abbreviation) Trade Name®
Available Dosage Forms
Usual Dose* Dietary Consideration
Missed Dose
Special Dosing Considerations
Common Adverse Effects+
Serious Adverse Effects+
tenofovir/emtricitabine/ efavirenz (TDF/FTC/EFV)
Atripla®
TDF 300 mg/ FTC 200 mg/ EFV 600 mg
1 tablet once daily preferably at bedtime
Take on an empty stomach; supplementation with calcium and vitamin D in patients with a history of osteopenia or bone fracture can be considered
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose.
Do not use if CrCl <50 mL/min
Pregnancy Category D
May produce false-positives on some cannabinoid and benzodiazepine screening tests
See individual agents
emtricitabine/rilpivirine/ tenofovir (FTC/RPV/TDF)
CompleraTM
FTC 200 mg/ RPV 25 mg/ TDF 300 mg
1 tablet once daily Take with a high-fat meal; sup-plementation with calcium and vitamin D in patients with a history of osteopenia or bone fracture can be considered
If a dose is missed within 12h, take it with a meal as soon as possible. If the next regular dose is <12h away, wait until then to use the medicine and skip the missed dose. Never double dose.
Should not be taken with dexamethasone, St. John’s Wort, rifabutin, rifampin, rifapentine, carbamazepine, phenobarbital, phenytoin
Contraindicated with PPIs
See individual agents
emtricitabine/tenofovir/ elvitegravir/ cobicistat (FTC/TDF/EVG/COBi)
StribildTM
FTC 200 mg/ TDF 300 mg/ EVG 150 mg/ COBI 150 mg
1 tablet once daily Take with a meal
If a dose is missed, take it as soon as possible; if it is close to the scheduled dose, wait and take that dose. Never double dose
Do not initiate if CrCl <70 mL/min
Continued use not recommended if CrCl falls to <50 mL/min
Reduce dose of miravaroc to 150 mg with coadministration
Store at room temperature
See individual agents
Mountain Plains AIDS Education and Training Center • 2013 39
TABLE 17. DRUG iNTERACTiONS BET WEEN HiV MEDiCATiONS AND HEPATiTiS C TREATMENTS
boceprevir (Victrelis®) Drug interactions with HiV Medications
Concurrent Medication Effect Recommendation
atazanavir/ritonavir (ATV/RTV)
Reyataz®/Norvir®
atazanavir AUC decreased 35%atazanavir Cmin decreased 49%ritonavir AUC decreased 36%boceprevir AUC unchanged
Co-administration not recommended
darunavir/ritonavir (DRV/RTV)
Prezista®/Norvir®
darunavir AUC decreased 44%darunavir Cmin decreased 59%ritonavir AUC decreased 26%bocepravir AUC decreased 29%boceprevir Cmin decreased 35%
Co-administration not recommended
lopinavir/ritonavir (LPV/RTV) Kaletra®
lopinavir AUC decreased 34%lopinavir Cmin decreased 43%ritonavir AUC decreased 23%boceprevir AUC decreased 44%boceprevir Cmin decreased 35%
Co-administration not recommended
efarivenz (EFV)
Sustiva®
efavirenz AUC increased 20%boceprevir AUC decreased 19%boceprevir Cmin decreased 44%
Co-administration not recommended
tenofovir (TDF)
Viread®
No significant changes reported No dose adjustment necessary
raltegravir (RAL)
isentress®
No significant changes reported No dose adjustment necessary
Note: AUC =Area under the curve, used as a measure of overall drug exposure; Cmin = Minimum concentration, often referred to as the trough concentration
Mountain Plains AIDS Education and Training Center • 2013 40
TABLE 18. DRUG iNTERACTiONS BET WEEN HiV MEDiCATiONS AND HEPATiTiS C TREATMENTS
telaprevir (incivek®) Drug interactions with HiV Medications
Concurrent Medication Effect Recommendation
atazanavir/ritonavir (ATV/RTV)
Reyataz®/Norvir®
telaprevir AUC decreased 20%atazanavir AUC increased 17%atazanavir AUC increased 85%
No dose adjustment necessary
darunavir/ritonavir (DRV/RTV)
Prezista®/Norvir®
darunavir AUC decreased 40%telaprevir AUC decreased 35%
Co-administration not recommended
fosamprenavir/ritonavir (FPV/RTV)
Lexiva®/Norvir®
amprenavir AUC decreased 47%telaprevir AUC decreased 32%
Co-administration not recommended
lopinavir/ritonavir (LPV/RTV)
Kaletra®
lopinavir levels unchangedtelaprevir AUC decreased 54%
Co-administration not recommended
efavirenz (EFV)
Sustiva®
efavirenz AUC unchangedtelaprevir AUC decreased 26%telaprevir Cmin decreased 47%When used with tenofovir: efavirenze AUD decreased 15-18%, telaprevir AUC decreased 18-20%
Increase telaprevir dose to 1125 mg Q8H
tenofovir (TDF)
Viread®
tenofovir AUC increased 30%tenofovir Cmin increased 6-41%
Monitor for tenofovir associated toxicity
raltegravir (RAL)
isentress®
raltegravir AUC increased 31%telaprevir levels unchanged
No dose adjustment necessary
Note: AUC =Area under the curve, used as a measure of overall drug exposure; Cmin = Minimum concentration, often referred to as the trough concentration
abacavir (Ziagen®) .........................................................................11, 14
abacavir/lamivudine (Epzicom®) .................................................... 7, 15
abacavir/lamivudine/zidovudine (Trizivir®) ....................................... 16
atazanavir (Reyataz®) ........................................................... 7, 8, 27, 31
bocepravir (Victrelis®) ......................................................................... 39
cobicistat (component of Stribild™) ..............................................35, 37
darunavir (Prezista®) ................................................ 7,8, 27, 31, 39, 40
delavirdine (Rescriptor®) ...............................................................17, 20
didanosine (Videx®, Videx EC®) ...................................................11, 14
efavirenz (Sustiva®) ..................................................... 7, 17, 20, 39, 40
elvitegravir (component of Stribild™) ............................................25, 26
emtricitabine (Emtriva®) ...............................................................12, 14
emtricitabine/tenofovir (Truvada®) ................................................ 7, 15
emtricitabine/tenofovir/rilpivirine (Complera™) ................................ 38
emtricitabine/tenofovir/elvitegravir/cobicistat (Stribild™) ................ 38
enfuvirtide (Fuzeon®) ....................................................................23, 24
etravirine (Intelence®) ...................................................................18, 21
fosamprenavir (Lexiva®) .....................................................8, 28, 32, 40
Indinavir (Crixivan®) .......................................................................28, 32
lamivudine (Epivir®) .......................................................................12, 14
lamivudine/zidovudine (Combivir®) ..............................................7, 15
lopinavir + ritonavir (Kaletra®) .................................... 8, 29, 33, 39, 40
maraviroc (Selzentry®) ..................................................................23, 24
nelfinavir (Viracept®) .....................................................................29, 33
nevirapine (Viramune®) .................................................................18, 21
raltegravir (Isentress®) .................................................... 25, 26, 39, 40
rilpivirine (Edurant™) ..................................................................7, 19, 22
ritonavir (Norvir®)....................................................................35, 36, 39
saquinavir (Invirase®) ....................................................................29, 34
stavudine (Zerit®) ..........................................................................12, 14
telaprevir (Incivek®) ............................................................................. 40
tenofovir (Viread®) .......................................................... 13, 14, 39, 40
tenofovir/emtricitabine/efavirenz (Atripla®) ...................................... 38
tipranavir (Aptivus®) ......................................................................30, 34
zidovudine (Retrovir®) ...................................................................13, 14
iNDEx By DRUG (GENERiC NAME)
Mountain Plains AIDS Education and Training Center • 2013 41
MountainPlainsAIDS EDUCATION AND TRAINING CENTER
Mountain Plains AIDS Education and Training CenterUniversity of Colorado ● Anschutz Medical Campus
303.724.0867www.mpaetc.org
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