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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

Mountain Plains AIDS Education and Training Center • 2013 3

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


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,


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


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.


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


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.


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.


• 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.


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


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





Missed Dose




emtricitabine (FTC)

Emtriva®

200 mg capsule

10 mg/mL oral suspension

200 mg daily [capsule]

240 mg daily [suspension]



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 contain sucrose

Nausea, headache, diarrhea, abdominal pain, and alopecia

Lactic acidosis with hepatic steatosis

stavudine (d4T)

Zerit®

15, 20, 30, and 40 mg capsules


>60 kg: 40 mg twice daily

<60 kg: 30 mg twice daily


Avoid alcohol

May contain sucrose



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


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


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




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


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


TABLE 5. FixED DOSE COMBiNATiON NRTiS




Missed Dose




lamivudine/zidovudine(AZT/3TC)

Combivir®

3TC 150 mg + AZT 300 mg [scored]

1 tablet every 12 hours



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


Not recommended for CrCl <50 mL/min

Risk of hypersensitivity reaction


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


CrCl 30-49 mL/min: increase dosing interval to every 48h

CrCl <30 mL/min or hemo- dialysis: not recommended






Missed Dose




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


Note. CrCL = creatine clearance +This list is not all-inclusive


TABLE 6. NON-NUCLEOSiDE REVERSE TRANSCRiPTASE iNHiBiTORS (NNRTi)




Missed Dose




delavirdine (DLV)

Rescriptor®

100, 200 mg tablets 400 mg 3 times a day

May be taken with or without meals


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


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





Missed Dose




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



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


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.



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


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


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



TABLE 8. ENTRy iNHiBiTORS




Missed Dose




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


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


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.)



TABLE 10. iNTEGRASE iNHiBiTORS ( iNSTi)




Missed Dose




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


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


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



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.



TABLE 12. PROTEASE iNHiBiTORS (Pi)




Missed Dose




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





Missed Dose




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


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


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


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


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


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





Missed Dose




tipranavir (TPV)

Aptivus®

250 mg capsules


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


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, hyperglycemia, hyperlipidemia, body fat changes, possible increased bleeding in patients with hemophilia, increased risk of rash with estrogen use



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




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®



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


lopinavir + ritonavir (LPV/RTV)

Kaletra®


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®


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




saquinavir (SQV)

invirase®

Strong Inhibitor of CYP3A4 & P-gp


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


TABLE 14. BOOSTiNG AGENTS




Missed Dose




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


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



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


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


TABLE 16. FixED-DOSE MULTi-CLASS AGENTS: SiNGLE TABLET REGiMENS




Missed Dose




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


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


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


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




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%


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%


efarivenz (EFV)

Sustiva®

efavirenz AUC increased 20%boceprevir AUC decreased 19%boceprevir Cmin decreased 44%


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


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%


fosamprenavir/ritonavir (FPV/RTV)

Lexiva®/Norvir®

amprenavir AUC decreased 47%telaprevir AUC decreased 32%


lopinavir/ritonavir (LPV/RTV)

Kaletra®

lopinavir levels unchangedtelaprevir AUC decreased 54%


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)


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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