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A Pharmacist’s Guide to

ANTIRETROVIRAL MEDICATIONS FOR HIV INFECTED ADULTS AND ADOLESCENTS

H I V PROV IDER RE F E R E N C E S E R I E S

A PUBLICATION OF THE MOUNTAIN PLAINS AIDS EDUCATION AND TRAINING CENTER

MountainPlains AIDS EDUCATION AND TRAINING CENTER

A Pharmaci st ’s Gui de to Anti retroviral Medicati ons AUTHORS:

ADDITIONAL RESOURCES:

Whitney Marie Starr, FNP Clinical Education Coordinator, Mountain Plains AETC Instructor, School of Medicine, Division of Infectious Diseases University of Colorado School of Medicine

Mountain Plains AIDS Education and Training Center www.mpaetc.org School of Medicine, Division of Infectious Diseases University of Colorado School of Medicine, Anschutz Medical Campus Aurora, CO 80045 (303) 724-0867

Steven C. Johnson, MD Medical Director, Mountain Plains AETC Professor, School of Medicine, Division of Infectious Diseases University of Colorado School of Medicine

AIDS Drug Assistance Program (ADAP) Numbers: Colorado................................................... (303) 724-0644 Kansas...................................................... (316) 293-2682 Nebraska.................................................. (402) 559-6681 New Mexico.............................................. (505) 776-8032 North Dakota............................................ (701) 234-4852 South Dakota............................................ (605) 582-6246 Utah........................................................... (801) 581-5310 Wyoming................................................... (307) 265-0413

Jasjit Gill, PharmD Pharmacy Manager and Clinical Pharmacy Specialist, Infectious Disease Group Practice Pharmacy Faculty and Clinical Instructor, Skaggs School of Pharmacy University of Colorado Hospital Editor: Lucy Bradley-Springer, PhD, RN, ACRN, FAAN PI & Director, Mountain Plains AETC Associate Professor, School of Medicine, Division of Infectious Diseases University of Colorado School of Medicine Design: Lindsay O’Connell, MS, CHES Program Manager, Mountain-Midwest HIV Telehealth Center Mountain Plains AIDS Education and Training Center Instructor, School of Medicine, Division of Infectious Diseases University of Colorado School of Medicine

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 – 1-800-933-3413 Post-exposure Prophylaxis – 1-888-448-4911 Perinatal Transmission – 1-888-448-8765 Check Website for training/education tools and links to more sites with specific information regarding drug interactions and ART.

Table of C ontents

Introduction............................................................................................3

Table 6. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)... 17

Currently Available Antiretroviral Drugs................................................3

Table 7. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

ART Recommendations.........................................................................4

Metabolism and Drug Interactions................................................. 20

Starting ART............................................................................................4

Table 8. Entry Inhibitors....................................................................... 23

Laboratory Tests.....................................................................................4

Table 9. Entry Inhibitors Metabolism and Drug Interactions............. 24

ART Regimens........................................................................................6

Table 10. Integrase Inhibitors (INSTI)................................................. 25

Drug Resistance and Cross-Resistance................................................9

Table 11. Integrase Inhibitors (INSTI) Metabolism and Drug

The Vital Role of Pharmacists...............................................................9

Interactions....................................................................................... 26

Index by drug (Generic name)............................................................. 41

Table 12. Protease Inhibitors (PI) ....................................................... 27 Table 13. Protease Inhibitors (PI) Metabolism and Drug

List of Tables

Interactions....................................................................................... 31

Table 1. Therapy for The Chronically HIV-1 Infected Patient...............5

Table 14. Boosting Agents................................................................... 35

Table 2. Antiretroviral Regimens Recommended for Treatment of

Table 15. Boosting Agents Metabolism and Drug Interactions........ 36

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 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

A Pharmacist’s Guide to Antiretroviral Medications for HIV-Infected Adults and Adolescents 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. Mountain Plains AIDS Education and Training Center • 2013

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. 3

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 tropism 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 recommendations 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. Mountain Plains AIDS Education and Training Center • 2013

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 individual 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 and CD4+ T cell testing provides the best information for initiating, monitoring,

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and changing ART. For patients stable on ART, the CD4+ T cell count and HIV viral load are repeated every 3-6 months.

viral load does not decrease by 1 log10 copies/mL at 8 weeks, drug resistance or nonadherence are the major concerns.

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 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 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.

3

*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 Mountain Plains AIDS Education and Training Center • 2013

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with a CD4+ T cell count >500/mm3 and 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. 1 2

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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-mycobacterials, 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):

Mountain Plains AIDS Education and Training Center • 2013

• 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. 9

• 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.

• 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.

• 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. Mountain Plains AIDS Education and Training Center • 2013

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Table 3. Nucleosi de / N ucleot i de R everse Transcri ptase Inh i b itors ( N R T I ) Generic Name (abbreviation) Trade Name®

Available Dosage Forms

Usual Dose*

Dietary Consideration Missed Dose

abacavir (ABC)

300 mg tablets [scored]

300 mg twice daily or 600 mg once daily

May be taken with or without food

Ziagen®

20 mg/mL oral solution

Child Pugh 5-6: 200mg BID

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.

+

Special Dosing Considerations

Common Adverse Effects

5-9% risk of hypersensitivity reaction that may be fatal: signs/symptoms may include rash, fever, nausea, vomiting, 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

Nausea, headache, abdominal pain, malaise

Hepatically metabolized

Lactic acidosis

+

Serious Adverse Effects

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.

Dose reduction in mild hepatic impairment; Contraindicated in moderate-severe hepatic impairment didanosine (ddl) Videx® Videx EC®

Videx EC® 125, 200, 250, or 400 mg capsules

Body weight ≥60 kg: 400 mg once daily EC capsule With TDF: 250 mg daily

Videx® 100, 167 or 150 mg packet/powder Body weight 50 kg: 300 mg daily or 150 mg twice daily and 300 mg tablets

Epivir®

10 mg/mL suspension

60 kg: 40 mg twice daily

May be taken with or without food

Zerit®

1 mg/mL oral solution

400 cells/mm3 in Maximum induction takes males) place in 14 to 28 days Lead-in dosing should be repeated if drug is interrupted for any reason for more than 7 days

Stevens-Johnson Syndrome, erythema multiforme, toxic epidermal necrolysis

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.

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rilpivirine (RPV)

25 mg tablet

25 mg once daily

EdurantTM

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 possible. 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

Rash, insomnia, headache, depression, hyperlipidemia; increases hepatic enzymes, increases creatinine, body fat changes Glomerulonephritis. QTc prolongation

Resistance patterns are very similar to ETV

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. +

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This list is not all-inclusive

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Table 7. Non -Nucleos i de R everse Transcr i ptase Inh i b i tors ( N N R T I ) Metabolism and D rug Interact i ons Metabolism of NNRTIs delavirdine (DLV) Rescriptor®

Strong Inhibitor of CYP3A4, CYP2C19, CYP2C9, CYP2D6 CYP3A4 Substrate

efavirenz (EFV)

Strong Inducer of CYP3A4

Sustiva®

Moderate Inhibitor of CYP2C19, CYP2C9, & CYP3A4 CYP2B6 & CYP3A4 Substrate

Medications That Should NOT be Administered With NNRTIs

Medications That Have Clinically Significant Drug Interactions With NNRTIs+

Antihistamine: astemizole, terfenadine Benzodiazepines: alprazolam, midazolam, triazolam Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Agents: cisapride Neuroleptics: pimozide

Acid Reducers: antacids, H2RA, PPI Anticoagulants: warfarin Antidepressants: trazodone Antimycobacterials: clarithromycin Cardiac: bepridil, amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone, DHP-CCB Corticosteroids: dexamethasone, fluticasone Herbs: St. John’s Wort Immunosuppressants: cyclosporine, tacrolimus Narcotics: methadone Statins: atorvastatin, fluvastatin Other: amphetamines, sildenafil, hormonal contraceptives

Antimycobacterials: rifapentine Benzodiazepine: midazolam, triazolam Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Agents: cisapride Herbs: St John’s Wort Neuroleptics: pimozide

Anticoagulants: warfarin Antibiotics: clarithromycin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Antidepressants: buproprion, paroxetine, sertraline Antifungals: fluconazole, itraconazole, posaconazole, voriconazole Antimycobacterials: rifabutin, rifampin Benzodiazepines: alprazolam, lorazepam, midazolam, triazolam Cardiac: DHP-CCB, diltiazem, verapamil Corticosteroids: dexamethasone, fluticasone Hepatitis Medications: boceprevir, telaprevir Narcotics: buprenorphine, methadone Statins: atorvastatin, lovastatin, simvastatin, pitavastatin, pravastatin, rosuvastatin Other: hormonal contraceptives, atovaquone/proguanil

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etravirine (ETV)

Moderate inhibitor of CYP2C19 & CYP2C9

Intelence®

Strong Inducer of CYP3A4 CYP2C19, CYP2C9, & CYP3A4 Substrate

nevirapine (NVP)

Strong inducer of CYP2B6 & CYP3A4

ViramuneTM

CYP3A4 Substrate

Antimycobacterials: rifampin, rifapentine Anticonvulsants: carbamazepine, phenobarbital, phenytoin Hepatitis Medications: boceprevir, telaprevir Herbs: St John’s Wort Others: clopidogrel

Antibiotics: clarithromycin Anticoagulants: warfarin, clopidogrel Anticonvulsants: carbamazepine, phenobarbital, phenytoin Antidepressants: paroxetine Antifungals: fluconazole, itraconazole, posaconazole, voriconazole Antimycobacterials: clarithromycin, rifabutin, rifampin, rifapentine Benzodiazepines: alprazolam, diazepam Cardiac: amiodirone, flecanide, propafenone, quinidine Corticosteroids: dexamethasone Herbs: St. John’s Wort Narcotics: buprenorphine, methadone Statins: atorvastatin, fluvastatin, lovastatin, simvastatin, pitavastatin, pravastatin, rosuvastatin Other: hormonal contraceptives, PDE5 inhibitors

Antiretrovirals: atazanavir Antifungals: ketoconazole Antimycobacterials: rifampin, rifapentine Hepatitis Medications: boceprevir, telaprevir Herbs: St John’s Wort

Antibiotics: clarithromycin Anticoagulants: warfarin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Antifungals: fluconazole, itraconazole, voriconazole Antimycobacterials: rifabutin Benzodiazepines: alprazolam, diazepam Cardiac: DHP-CCB, diltiazem, verapamil Corticosteroids: dexamethasone Herbs: St. John’s Wort Narcotics: buprenorphine, methadone Statins: lovastatin, simvastatin, pitavastatin Other: hormonal contraceptives

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Metabolism of NNRTIs rilpivirine (RPV) EdurantTM

CYP3A4 Substrate

Medications That Should NOT be Administered With NNRTIs Acid Reducers: PPI Antiretrovirals: Efavirenz Antimycobacterials: rifabutin, rifampin, rifapentine Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin Hepatitis Medications: boceprevir, telaprevir Herbs: St John’s Wort

Medications That Have Clinically Significant Drug Interactions With NNRTIs+ Antiretrovirals: NNRTI Acid Reducers: antacids, H2RA Antibiotics: clarithromycin, erythromycin Antifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole Antimycobacterials: rifabutin,rifampin, rifapentine Benzodiazepines: alprazolam Corticosteroids: dexamethasone Herbs: St. John’s Wort Narcotics: methadone Statins: atorvastatin, pitavastatin Other: hormonal contraceptives, sildenafil +

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This list is not all-inclusive

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Table 8. E ntry Inhi b i tors Generic Name (abbreviation) Trade Name®

Available Dosage Forms

enfuvirtide (T-20)

108 mg vials

Fuzeon®

reconstitute with 1.1 mL sterile water (90 mg/mL)

Usual Dose*

Dietary Consideration Missed Dose

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.

Special Dosing Considerations Patients must be willing and capable of preparing and administering injections

+

Common Adverse Effects +

Serious Adverse Effects

Local injection site reactions, diarrhea, nausea, fatigue, abdominal pain, pneumonia

Requires thorough education Hypersensitivity reaction, bacterial pneumonia 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

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 12h since the last scheduled dose, wait and take the next dose. 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 0.4 mg/dL increase in Scr from baseline headache, anxiety, nausea, abdominal distention, rash, flatulence Lactic acidosis, pancreatitis, Hepatitis B, hepatomegaly with steatosis, hepatotoxicity, immune reconstitution syndrome, rhabdomyolysis, Fanconi syndrome, renal impairment

TM

ritonavir (RTV)

100 mg tablets and capsules

Norvir

80 mg/mL solution

®

Usual Dose*

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.

Nausea, vomiting, diarrhea, taste perversion, extremity Tablets: If stored outside of original and circumoral paresthesia container discard after 2 weeks Tablets do not require refrigeration

Do not refrigerate oral solution. Solution contains 43% ethanol by volume Potent CYP3A4 Inhibitor; Many drug interactions

Elevated transaminases, hyperglycemia, hyperlipidemia, body fat changes, possible increased bleeding in patients with hemophilia. QTc elongation, and PR interval

Capsules must be refrigerated, but may be stored at controlled room temperature for 30 days +

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Table 1 5. Boosti ng Agents - M etaboli sm and D rug Interactions Metabolism of Boosting Agents ritonavir (RTV) Norvir

®

Major inhibitor of CYP3A CYP3A (major) and CYP2D6 (minor) substrate

Medications That Should NOT Be Administered With Boosting Agents Alpha Adrenergic Antagonists: alfuzosin Cardiac: amiodarone, flecainide, propafenone, quinidine Antifungals: voriconazole Benzodiazepines: midazolam, triazolam Cardiac: amiodarone, flecainide, propafenone, quinidine Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents: cisapride Herbals: St. John’s Wort Neuroleptics: pimozide PDE5 inhibitors: sildenafil (when used for pulmonary hypertension) Statins: lovastatin, simvistatin

Mountain Plains AIDS Education and Training Center • 2013

Medications That Have Clinically Significant Drug Interactions With Boosting Agents Drugs metabolized by CYP3A Analgesics: tramadol, propoxyphene, methadone, fentanyl Anesthetics: meperidine Anticoagulants: warfarin Anticonvulsants: carbamazepine, clonazepam, ethosuximide, divalproex, lamotrigine, phenytoin Antidepressants: SSRIs, TCA s, nefazadone, bupropion, desipramine, trazodone Antiemetics: dronabinol Antifungals: ketoconazole, itraconazole, voriconazole Anti-gout: colchicine Antibiotics: clarithromycin, metronidazole, rifabutin, rifampin Antineoplastics: dasatinib, nilotinib, vincristine, vinblastine Antiretrovirals: protease inhibitors (all except nelfinavir), NNRTIs (delavirdine), entry inhibitors maraviroc Antiparasitic: atovaquone, quinidine Bronchodilators: theophylline Benzodiazepines: midazalom Cardiac: disopyramide, lidocaine, mexiletine, metoprolol, timolol, diltiazem, nifedipine, verapamil Immunosuppressants: cyclosporine, tacrolimus, sirolimus Inhaled Steroids: fluticasone Long-acting beta adrenoceptor agonists: salmeterol Neuroleptics: perphenazine, risperidone, thioridazone Oral contraceptives: ethinyl estradiol PDE5 inhibitors: sildenafil, tadalafil, vardenafil Statins: atorvastatin, rosuvastatin Steroids: dexamethasone, fluticasone, prednisone Stimulants: methamphetamine Others: disulfram 36

cobicistat (COBI) (Currently available in a combination single tablet regimen with tenofovir, emtricitabine, and cobicistat) StribildTM

Not established with cobicistat alone Drugs metabolized by CYP3A4 Note: Specific data on drug interactions is limited due to investigational drug status. Contraindications to StribildTM due to cobicistat component: Alpha Adrenergic Antagonists: alfuzosin Benzodiazepines: midazolam, triazolam Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents: cisapride Herbals: St. John’s Wort Neuroleptics: pimozide PDE5 inhibitors: sildenafil (when used for pulmonary hypertension) Statins: lovastatin, simvistatin

Mountain Plains AIDS Education and Training Center • 2013

Drugs metabolized by CYP3A4 Note: Specific data on drug interactions is limited due to investigational drug status.*Similar to ritonavir drug interaction profile* Antifungals: intraconazole, posaconazole, voriconazole Antibiotics: clarithromycin Antidepressants: SSRIs, TCAs Antiepileptics: carbamazepine, phenobarbital, phenytoin Antiretrovirals: rilpivirine, ritonovir, saquinavir Benzodiazepines: clonazepam, diazepam Cardiac: amiodarone, digoxin, flecanide, propafenone Statins: atorvastatin, rosuvastin Others: 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

37

Table 16. Fixed -D ose M ulti- class Agents: Single Tablet R eg imens Generic Name (abbreviation) Trade Name® tenofovir/ emtricitabine/ efavirenz (TDF/FTC/EFV)

Available Dosage Forms TDF 300 mg/ FTC 200 mg/ EFV 600 mg

Usual Dose*

Missed Dose 1 tablet once daily preferably at bedtime

Atripla®

emtricitabine/ rilpivirine/ tenofovir (FTC/RPV/TDF)

StribildTM

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.

FTC 200 mg/ RPV 25 mg/ TDF 300 mg

1 tablet once daily

CompleraTM

emtricitabine/ tenofovir/ elvitegravir/ cobicistat (FTC/TDF/EVG/ COBI)

Dietary Consideration

FTC 200 mg/ TDF 300 mg/ EVG 150 mg/ COBI 150 mg

1 tablet once daily

Special Dosing Considerations Do not use if CrCl