November 2014 FAQs
November 2014 FAQs
What is the status of biosimilars in the United States?
What is the status of biosimilars in the United States?
Since first introduced to the market over 20 years ago, therapeutic agents produced by biotechnology—or biologics—have become an essential part of pharmacologic treatments for many disease states.1 The Food and Drug Administration (FDA) defines a biologic as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”1 Included as biologics are monoclonal antibodies and therapeutic proteins. Biologics have a greater complexity than conventional drugs, making cost an important consideration in their selection and use. In 2013, total drug expenditure in the United States was estimated at $326 billion. Of the top 15 drugs contributing to this cost, 8 were biologics, representing 9% of the total drug expenditure.2 To help reduce the cost of biologics, the Biologics Price Competition and Innovation (BPCI) Act was implemented to allow for a streamlined approval process for biologics that are similar to existing agents, in the expectation of reducing the cost of development of these agents. This FAQ will provide an overview of biosimilars and formulary considerations associated with their use.
The Biologics Price Competition and Innovation Act
In the mid 1980s, generic versions of conventional branded drugs were introduced to help reduce the costs of drug therapy, with substitution based on bioequivalence between generics and brands.3 While not true generics, the BPCI Act has allowed for biosimilars—new biologics considered highly similar to approved biologics—to be approved and which could be interchangeable with marketed biologic products, potentially at a lower cost. Similar to conventional drugs, biologics undergo analytical and preclinical trials to determine pharmacodynamic and pharmacokinetic characteristics and safety for use in humans; this is followed by clinical trials on efficacy as well as safety of the agent. This information is submitted to the FDA as a biologic license application or BLA 351(a).1
When developed as a biosimilar, biologics require less product-specific preclinical and clinical data in the abbreviated approval pathway (the 351(k) application).4 In addition, evidence for a biosimilar approval can include publicly-available information from previous FDA applications for a biologic. Only biologics intended as biosimilars can use this abbreviated pathway. The requirements for a biosimilar as described in the BPCI Act are summarized in the Table. Overall, for biosimilars, the FDA is taking a “totality of evidence” approach to approval of these agents, with the amount and extent of evidence needed to show biosimilarity being product-specific.5
Table. Biologics Price Competition and Innovation Act requirements for a biosimilar designation.4
- Mechanism of action of the biologic product and the reference biologic are the same.
- Use has been previously approved in the labeling of the reference biologic product.
- Route, dosage form, and strength of the biologic product are the same as the reference biologic product.
- Manufacturer’s facility for the biologic meets same standards as the reference biologic product.
- Analytical studies: demonstrating biologic is “highly similar” to reference biologic.
- Any differences should be described and discussed.
- Potential effects of differences should be addressed and supported by data.
- Animal studies: including toxicity assessment.
- Clinical study or studies: demonstrating safety, purity, and potency in one or more approved indications of the reference biologic, as well as demonstrating pharmacokinetic/pharmacodynamic properties and immunogenicity.
The BCPI Act also defines what it means for a biosimilar to be interchangeable with a biologic reference product. To be interchangeable means that the biosimilar must produce the same expected clinical results as the reference biologic; and if meant to be given more than once, it should not have a greater risk of diminished efficacy or safety concerns than the reference biologic.4,6 If interchangeable, the biosimilar may be substituted with the reference biologic without intervention by the prescriber.4
Other provisions of the BCPI Act give a 12-year exclusivity period for a reference biologic, beginning from the date the biologic was first licensed, during which a biosimilar will not be approved; and a 4-year exclusivity during which time an application for a biosimilar cannot be submitted to the FDA. 5 As an example, if a biologic was first approved for use by the FDA in 2014, an application for a biosimilar agent cannot be submitted until 2018 and cannot be approved until 2026. The Act also provides for a 12-month exclusivity for a first interchangeable biosimilar, during which no other biosimilar can be considered interchangeable with the same reference biologic.7
In addition to provisions of the BCPI Act, some states have enacted legislature specific to biosimilars.8 Key features of state legislation include: prevention by a prescriber of substitution with a biosimilar, notification of the prescriber of a substitution with a biosimilar, notification of or consent by the patient regarding the substitution, and recordkeeping of substituted biologics. Additional information on state legislation regarding biosimilars, including state-specific legislation, is available from the National Conference of State Legislatures ( www.ncsl.org) .
Considerations for use of biosimilars
Biologics are often complex structures, and even small differences in production techniques or formulations may have a big impact on the efficacy, safety, immunogenicity, and stability of a biosimilar in comparison to an approved reference biologic. This is especially true for therapeutic proteins; extensive protein folding and glycosylation make these structures difficult to reproduce.7 It is unknown how small differences in these or other characteristics would affect the efficacy of a biologic or what effects these differences might have on immunogenicity and safety.9 In addition, various host cell lines are available for the production of recombinant products, including bacteria, yeasts, and mammalian cells, which may also result in subtle differenced between biologics, as may the environment in which these cell lines are grown.10
Given the high cost of development of a biologic—estimated at $100 to $250 million—it is unknown how much less a biosimilar may cost compared to the reference biologic.7 One source suggested a discount of up to 35% with biosimilars versus a reference biologic.10 Although this is less of a reduction in cost compared to generic versions of conventional drugs, it may still result in a substantial cost reduction. The US Congressional Budget Office estimated that price competition from biosimilars would reduce total expenditures on biologics in the United States by $25 billion over a 10-year period, with a decrease in federal government spending of nearly $6 billion.11
Indications, dosage forms, and routes of administration
Under the BCPI Act, a biosimilar is not required to seek approval for all of the labeled indications of the reference biologic.3,7,12,13 In addition, the delivery device or container of a biosimilar may differ from that of the reference biologic, as can the routes of administration. As an example, if a reference biologic is approved for 3 different indications and is available in both a vial and syringe, the biosimilar might only be approved for one of the indications of the reference biologic and might only be available in a vial. Similarly, if a reference biologic is approved for both intravenous and subcutaneous injection, a biosimilar might choose to seek approval only for an intravenous route of administration. These differences may require off-label use of a biosimilar if used in place of the reference biologic.
As an example, in Canada, Remicade is approved for use in rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and plaque psoriasis.14 In early 2014, Celltrion’s biosimilar, Remsima, was approved as a “subsequent entry biologic” with approval only for 4 of Remicade’s indications (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis) despite application for all indications.15 Per Health Canada, extrapolation of submitted evidence for Remsima’s use in Crohn’s disease and ulcerative colitis could not be recommended due to differences between the 2 products that may “have an impact on the clinical safety and efficacy of these products” for these other indications.
Current biosimilar applications
As of September 2014, 2 BLA 351(k) applications have been submitted to the FDA under the BCPI Act pathway. In July 2014, the FDA accepted a BLA from Sandoz for filgrastim, as a biosimilar to the reference biologic Neupogen.16 Sandoz’s filgrastim has been available in Europe since 2009 as a biosimilar under the name Zarzio and has overtaken sales of Neupogen as well as a European competitor as of 2013.17 In August 2014, Celltrion filed a BLA for infliximab (Remsima) as a biosimilar to the reference biologic Remicade.18 Similar to Zarzio, Celltrion already has approval for an infliximab biosimilar in Europe, Japan, and Canada, under the name Remsima.
For many disease states, biologics represent new and innovative therapies and in some cases the most effective treatment of a disease. However, biologics are associated with considerable costs. In 2009, the BCPI Act was implemented to provide an abbreviated approval pathway for new biologics that are highly similar to currently marketed biologics. These biosimilars are expected to have similar efficacy and safety with a lower acquisition cost.
Currently no biosimilars have been approved in the United States making an assessment of the role of biosimilars difficult. Several key points to consider are that:
- Biologics are complex structures that are difficult to reproduce; the effects of small changes on efficacy and safety may not be predictable.
- Unlike generic drugs, biosimilars are not therapeutic equivalents of a reference biologic.
- Biosimilars are not required to seek approval for the all of the indications or dosage forms of a reference biologic.
- A “totality of evidence” approach is being taken by the FDA in regards to data for approval of a biosimilar, meaning that a variety of sources of data can be used for a biosimilar approval.
- Biosimilars are not automatically interchangeable with a reference biologic.
Addition information in biosimilars is available at these websites.
- American Society of Health-System Pharmacists Resource Center on Biosimilars.
- American Journal of Managed Care-Biosimilars Essentials.
1. Food and Drug Administration. Frequently asked questions about therapeutic biological products. Accessed September 22, 2014.
2. Schumock GT, Li EC, Suda KJ. National trends in prescription drug expenditures and projections for 2014. Am J Health-Syst Pharm. 2014;71():e6-23.
3. Food and Drug Administration. Guidance for Industry. Biosimilars: questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. Accessed September 22, 2014.
4. Christl L. Biologics Price Competition and Innovation Act of 2009. FDA’s overview of the regulatory guidance for the development and approval of biosimilar products in the US. Accessed September 22, 2014.
5. Food and Drug Administration. Fact sheet: Issuance of draft guidances on biosimilar product development. Accessed September 22, 2014.
6. H.R. 3590. Title VII—Improving access to innovative medical therapies. Subtitle A—Biologics Price Competition and Innovation. US Government Printing Office. Accessed September 22, 2014.
7. Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health-system pharmacists. Am J Health-Sys Pharm. 2013;70(): 2004-2017.
8. National Conference of State Legislatures. State laws and legislation related to biologic medications and substitution of biosimilars. Accessed October 14,2 014.
9. McBride A. Evolving biosimilar marketplace. Hosp Pharm. 2014;49(suppl 1):S1-S5.
10. Ventola CL. Biosimilars. Part 2: Potential concerns and challenges for P&T Committees. P&T. 2013;38(6):329-335.
11. Congressional Budget Office Cost Estimate. S.1695. Biologics Price Competition and Innovation Act of 2007. June 25, 2008. http://www.cbo.gov/publication/41712 . Accessed September 22, 2014.
12. Weise M, Bielsky M, DeSmit K, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-5117.
13. Stevenson JG. Preparing for the arrival of biosimilars in the United States. What pharmacists need to know. Accessed September 22, 2014.
14. Remicade product monograph. Janssen. http://www.janssen.ca/product/183. Accessed October 14, 2014.
15. Health Canada. Drug and Health Products. Remsima. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2014_remsima_160195-eng.php Accessed October 14, 2014.
16. Sandoz Media Center. FDA accepts Sandoz application for biosimilar filgrastim. Accessed September 22, 2014.
17. Sandoz Media Center. Zarzio overtakes Neupogen and Granocyte to become the most prescribed daily G-CSF in Europe. Accessed September 22, 2014.
18. Celltrion What’s New. Celltrion files for US FDA approval of Remsima.
Preexposure prophylaxis for HIV prevention: What are the new guidelines?
Preexposure prophylaxis for HIV prevention: What are the new guidelines?
Preexposure prophylaxis (PrEP) is the use of antiretroviral medications to prevent human immunodeficiency virus (HIV) acquisition in HIV-uninfected individuals.1 Clinical trials that aimed to assess the potential success of PrEP began in 2005.2-8 The first completed trial was the iPrEx trial which examined the efficacy and safety of daily tenofovir (TDF)/emtricitabine (FTC) for the prevention of HIV acquisition in men who have sex with men (MSM).2 The study also included transgender women who have sex with men, but this only accounted for 1% of the study population. Tenofovir and emtricitabine were considered to be favorable candidates for prophylaxis based on their safety profile, pharmacokinetics, and minimal drug interactions with common concomitant medications in the target population. The trial reported that TDF/FTC was associated with a 44% reduction in the incidence of HIV with no statistical differences for serious adverse events between TDF/FTC and placebo. Based on the results of this trial, the Centers for Disease Control and Prevention (CDC) provided interim guidance that PrEP (with TDF/FTC) may reduce HIV acquisition in MSM who are at high risk for infection.9 Men who do not consistently use other effective prevention methods, have frequent partner changes, or have concurrent partners in a location with high HIV prevalence were considered to be potential candidates for PrEP.
After the iPrEx trial, there were 4 trials conducted that examined the use of TDF/FTC or TDF alone in heterosexual adults.3-6 The data from the Partners PrEP trial and TDF2 trial demonstrated that PrEP use in this population was safe and effective in reducing the risk of HIV acquisition. 3,4 The FEM-PrEP and VOICE trials were terminated early due to interim monitoring reporting futility.5,6 Both of these trials reported low adherence rates. These results led to the Food and Drug Administration (FDA) approval for daily TDF 300 mg/FTC 200 mg (Truvada) as PrEP for MSM and heterosexual adults at high risk of HIV infection.10 The CDC also provided updated interim guidance based on the results.11 The use of daily PrEP was recommended in those at very high risk (high risk defined in a subsequent section), but it was stressed that adherence is essential to the efficacy of PrEP. It was also highlighted that PrEP should be one component in a multimodal approach to HIV prevention and long-term safety has yet to be established.
There was one additional pivotal trial that was published prior to the release of the new guidelines from the US Public Health service.7,12 The Bangkok tenofovir study examined the use of PrEP in injecting drug users (IDU). Participants in this study were randomized to receive daily TDF or placebo. The use of tenofovir was associated with a 48.9% reduction in HIV incidence. The results of these trials were considered by the Department of Health and Human Services and the CDC in the creation of the first comprehensive practice guideline for PrEP for the prevention of HIV in the United States. 2-8,12 It was released in May 2014 under the US Public Health Service. While there are several alternatives that have proven efficacy in the prevention of HIV acquisition, this guideline examines an alternative method for the prevention of HIV. The individual choice to utilize alternative methods, such as condoms and voluntary male circumcision, can be affected by consistent use and cultural, religious, and ethnic traditions.13,14 Therefore, the availability of PrEP provides another method to help reduce HIV incidence.
US Public Health Service guideline recommendations
Daily PrEP is recommended for those at high risk for HIV acquisition.12 Risk of HIV acquisition is based on an individual’s behaviors. The guideline recommendations for who should be considered high risk are presented below. The behaviors are evaluated for the previous 6 months.
- MSM: Men with any sex partners and not in a monogamous relationship with a HIV-uninfected partner with at least one of the following additional risk factors: anal sex without condoms, sexually transmitted infection (STI), or in a relationship with a HIV-positive partner.
- Heterosexual men and women: Adults with any sex partners and not in a monogamous relationship with a HIV-uninfected partner with at least one of the following additional risk factors: man who has sex with both women and men, infrequent condom use with partners of unknown HIV status or who are known to be at higher risk of HIV infection (IDU or bisexual male partner), or in a relationship with a HIV-positive partner.
- IDU: An adult who has injected an illicit drug with at least one of the following additional risk factors: sharing of injection or drug preparation equipment, presence in a methadone, buprenorphine, or suboxone treatment program, or at high risk of sexual acquisition as defined for MSM and heterosexual adults.
The populations that are considered appropriate for PrEP include MSM, heterosexual men and women, and IDU. This recommendation is based on the efficacy and safety of PrEP that was demonstrated in randomized, placebo-controlled trials that are summarized in the Table.
Table. Pivotal trials examining the efficacy and safety of preexposure prophylaxis. Study Population Location Design Efficacy Safety Adherence iPrEx2 Men and transgender women who have sex with men (N=2499) Peru, Ecuador, South Africa, Brazil, Thailand, and the United States Phase 3, double-blind trial where subjects were randomized to TDF/FTC daily or placebo TDF/FTC was associated with a 44% RRR of HIV acquisition. Moderate nausea and unintentional weight loss occurred more frequently in the TDF/FTC group (p values of 0.04 and 0.04, respectively). In post-hoc analyses, when self-reported adherence to TDF/FTC was >90%, the RRR was increased to 73%. Partners PrEP3 Heterosexual couples with discordant HIV serostatus (N=4758) Kenya and Uganda Phase 3, double-blind trial where subjects were randomized 1:1:1 to daily TDF, TDF/FTC, or placebo TDF and TDF/FTC was associated with a 67% and 75% RRR, respectively, of HIV acquisition as compared to placebo. The difference between TDF and TDF/FTC was not statistically significant. The study medications were associated with increased GI side effects and fatigue, particularly in the first month. Study medication in use time was calculated to be 92.1% of the total follow-up time based on pill counts. TDF24 Heterosexual men and women (N=1219) Botswana Phase 3, double-blind trial where subjects were randomized to TDF/FTC daily or placebo TDF/FTC was associated with a 62% RRR of HIV acquisition. Nausea, vomiting, and dizziness were more common in those receiving TDF/FTC especially within the first month. Decline in BMD was also significantly lower in the TDF/FTC group. Adherence was measured by pill count and was 84% in both groups. FEM-PrEP5 Heterosexual women (N=2120) Kenya, South Africa, and Tanzania Phase 3, double-blind trial where subjects were randomized to TDF/FTC daily or placebo The trial was terminated early due to futility. TDF/FTC was not associated with reduction in HIV acquisition with a HR of 0.94 (95% CI, 0.59-1.52). Nausea, vomiting, nasopharyngitis, genital ulceration, and ALT elevation were significantly more frequent with TDF/FTC. The adherence, based on tenofovir plasma levels, was low in this trial. In the HIV infections that occurred in the TDF/FTC arm, the target tenofovir level was detected in only 26% of women at the start of the infection window. VOICE6 Heterosexual women (N=5029) South Africa, Uganda, and Zimbabwe Phase 2, double-blind trial where subjects were randomized to TDF/FTC daily, TDF daily, TDF topical vaginal gel, or matching placebos The trial was terminated early due to futility. TDF alone or TDF/FTC did not result in a statistically significant reduction in HIV acquisition. Creatinine elevation more frequent with TDF/FTC group. Detectable drug levels were less than 40% for all study groups. Bangkok tenofovir study7 Injecting drug users (N=2413) Thailand Phase 3, double-blind trial where subjects were randomized to TDF daily or placebo TDF daily was associated with a 48.9% RRR of HIV acquisition in the modified intention to treat analysis. TDF was associated with significantly more nausea/vomiting and ALT elevations. Post-hoc analysis showed that patients on DOT with high adherence (receiving TDF at least 71% of days and not missing consecutive doses) and detectable levels of TDF in their blood had a 73.5% reduction in the risk of HIV acquisition. US MSM safety trial8 Men who have sex with men (N=400) Atlanta, Boston, and San Francisco Phase 2, double-blind trial where subjects were randomized 1:1:1:1 to immediate or delayed (9 months) daily TDF or placebo Efficacy not assessed. Trial designed to detect differences in adverse effects between groups. Clinical or laboratory adverse events were recorded for 90% of participants. The majority (97%) were classified as grade 1 or 2. Of the adverse events recorded, only back pain (11.4% vs 5.4%) and BMD decrease (1.1% vs 0.8%) was statistically associated with TDF therapy. Exposure to study drug was 92% and 77% when estimated by pill count and MEMS data, respectively. Abbreviations: ALT, alanine aminotransferase; BMD, bone mineral density; CI, confidence interval; DOT, directly observed therapy; GI, gastrointestinal; HIV, human immunodeficiency virus; HR, hazard ratio; MEMS, medication event monitoring system; RRR, relative risk reduction; TDF/FTC, tenofovir/emtricitabine.
Adolescents and HIV-negative women who are pregnant or breastfeeding are populations where more research is required to make strong recommendations for the use of PrEP.12 There is a lack of information regarding these populations as currently available trials excluded minors and discontinued PrEP for cases of pregnancy or breastfeeding.2-8 Considerations for use of PrEP in those < 18 years should include the lack of efficacy and safety data and the potential laws that may apply to the prescribing or testing required for PrEP.12 Procedures for consent, parental disclosure, and mandatory reporting to local agencies can vary on the state level. The use of PrEP in the periconception period in HIV-discordant couples can be considered to prevent HIV acquisition for the uninfected partner. The Partners PrEP study team conducted an analysis of the patients who became pregnant during the trial.15 There were 431 pregnancies reported. There was no statistical difference for pregnancy incidence, pregnancy loss, congenital anomalies, or infant growth within the first year for women who received PrEP versus placebo in the periconception period. It is encouraged that any women who use PrEP during their pregnancies register with the Antiretroviral Pregnancy Registry.12 The registry is designed to collect and monitor data on the outcomes of pregnancies when antiretroviral drugs are used.16 The potential benefits and risks of PrEP during periconception, pregnancy, or breastfeeding should be considered on an individual basis.12
The current FDA-approved medication for PrEP is the fixed dose combination of TDF 300 mg and FTC 200 mg as a once daily medication.10 Clinicians can also consider tenofovir 300 mg alone as an alternative regimen for heterosexual men and women or IDU as this regimen was evaluated in the Partners PrEP study and the Bangkok tenofovir study.12 The use of tenofovir alone has not been studied in MSM and the results of trials in other populations should not be extrapolated to MSM. The use of any other antiretroviral or an alternative schedule (eg, intermittent, pre- or post-coital) should not be used.
The use of PrEP is only one component of a multimodal approach to reduce the risk of HIV acquisition.12 In clinical trials, the participants also received standard methods of prevention. Each trial employed several alternative methods for both active treatment and placebo groups including risk reduction counseling, free condoms and training, STI testing and treatment, adherence counseling, and referral for male circumcision. A particular emphasis should be placed on medication adherence. The iPrEx trial post-hoc analysis of the effect of adherence on efficacy showed that when self-reported adherence to TDF/FTC was >90%, the RRR was increased to 73% as compared to 44% for the entire study group.2 The failure of the FEM-PrEP and VOICE trials to demonstrate efficacy has been partially attributed to the low adherence rates.12
Before initiating PrEP, HIV status must be determined as the use of PrEP in patients with an acute infection has led to resistance.12 The iPrEx, Partners PrEP, and TDF2 trials reported TDF- or FTC-resistant virus, but all the patients who developed resistance in the antiretroviral arm were found to be infected at enrollment.2-4 These results highlight the importance of determining HIV status prior to prescribing PrEP as the use of TDF/FTC alone is not indicated for the treatment of HIV and could lead to resistance.
Other required laboratory tests include hepatitis B status, hepatitis C status, and renal function.12 For hepatitis B, patients should be offered vaccination if determined to be at high risk for acquisition. If it is determined that a patient has an active hepatitis B infection, then there are a few additional considerations for the use of PrEP in this population. The use of TDF/FTC may confer additional benefits as it is active against the hepatitis B virus as well. However, a clinician should also consider that poor adherence or stopping PrEP could reactivate the hepatitis B virus and result in hepatic injury. It is also important to determine the patient’s estimated creatinine clearance (eCrCl). Adults with an eCrCl < 60 ml/min were not included in PrEP trials, therefore it is not recommended to prescribe PrEP to these populations. Both TDF and FTC are renally eliminated; TDF has been associated with the development of renal impairment and Fanconi syndrome.17
PrEP prescriptions should be limited to a 90 day supply so that follow-up assessments occur every 3 months.12 Prior to issuing a new refill, HIV and pregnancy testing should be conducted. It is also recommended that sexual behaviors, adherence, and side effects be assessed at each visit. Addressing side effects and providing management options for patients is an important component of achieving acceptable adherence. Renal function and STI testing should be conducted at least every 6 months. Finally the need for PrEP should be reevaluated at least every year. Currently the need to assess bone mineral density (BMD) at baseline or during therapy is not indicated.12 The US MSM safety trial and the TDF2 trial reported a small, statistically significant decline in BMD with no reported fragility fractures with PrEP as compared to placebo.18,19 Given the lack of evidence for increased risk of fragility fractures, the guidelines steer clinicians away from BMD monitoring, but referral for further management is recommended if patients do have significant risk factors for osteoporosis or have a history of fragility fractures.12 Therapeutic drug monitoring may be considered as a method to assess adherence, but it should be noted that any detectable levels only reflect recent doses.
There are currently several methods for HIV protection. Behavioral counseling, condoms, diagnosis and treatment of STI, and voluntary male circumcision are options for adults. The use of PrEP provides an additional method to prevent HIV acquisition. It is recommended for MSM, heterosexual adults, and IDU who are at high risk for HIV infection. The only FDA-approved drug combination for PrEP is TDF/FTC. The potential benefits and risks of PrEP should be considered prior to initiation as well as the importance of adherence. Adults should also be encouraged to reduce HIV risk behaviors.
1. Guidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex with men at high risk of HIV: recommendations for use in the context of demonstration projects. World Health Organization website. http://www.who.int/hiv/pub/guidance_prep/en/. Updated July 2012. Accessed July 21, 2014.
2. Grant RM, Lama JR, Anderson PL, et al; iPrEx study team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.
3. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP study team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410.
4. Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 study group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423-434.
5. Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP study group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422.
6. Marrazzo J, Ramjee G, Nair G, et al; VOICE team. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; March 2013; Atlanta, GA.
7. Choopanya K, Martin M, Suntharasamai P, et al; Bangkok tenofovir study group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok tenofovir study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083-2090.
8. Grohskopf LA, Chillag KL, Gvetadze R, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Defic Syndr. 2013;64(1):79-86.
9. Centers for Disease Control and Prevention (CDC). Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep. 2011;60(3):65-8.
10. Klein R, Struble K. Truvada approved to reduce the risk of sexually transmitted HIV in people who are not infected with the virus. U.S. Food and Drug Administration website. http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm312264.htm . Updated November 7, 2012. Accessed July 29, 2014.
11. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012;61(31):586-589.
12. U.S. Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States – 2014: a clinical practice guideline. Centers for Disease Control and Prevention website. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf Accessed July 16, 2014.
13. Lopez LM, Otterness C, Chen M, Steiner M, Gallo MF. Behavioral interventions for improving condom use for dual protection. Cochrane Database Syst Rev. 2013;10:CD010662.
14. Male circumcision. Centers for Disease Control and Prevention website. http://www.cdc.gov/hiv/prevention/research/malecircumcision/. Updated April 15, 2013. Accessed August 7, 2014.
15. Mugo NR, Hong T, Celum C, et al; Partners PrEP study team. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA. 2014;312(4):362-371.
16. The antiretroviral pregnancy registry website. http://www.apregistry.com/HCP.aspx. Accessed August 7, 2014.
17. Truvada [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.
18. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688.
19. Kasonde M, Niska RW, Rose C, et al. Bone mineral density changes among HIV-uninfected young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine or placebo in Botswana. PLoS One. 2014;9(3):e90111.
Samantha Spencer, PharmD
Drug Information Speciality
How should acute pain be managed in patients taking Suboxone?
How should acute pain be managed in patients taking Suboxone?
As modern medicine progresses, one of the major areas of focus is behavioral health. Behavioral health encompasses mental health (schizophrenia, depression, etc.) and substance use disorders. Every year the National Survey on Drug Use and Health studies the population in an attempt to quantify the extent of drug use throughout the United States (US).1 The purpose of this survey is to assist in the allocation of resources for substance abuse prevention and recovery efforts. In 2013, it was estimated that 24.6 million (9.4%) Americans aged 12 or older had used illicit drugs within the preceding month. This includes 4.5 million patients who had used prescription pain relievers for nonmedical reasons and the 289,000 heroin users in the United States. At the same time, 2.5 million Americans reported current treatment for substance use disorder, emphasizing the impact substance abuse has on the American healthcare system.
Pathophysiology of opioid addiction
Addiction to opioids arises as a direct consequence of the euphoria, stress relief, blunting of pain, or relief of anxiety or depression patients experience following opioid use.2 The positive effects patients experience, either from legitimate medical use or from nonmedical misuse, occur from activation of the dopaminergic pathways of the brain. This “high” usually occurs from rapid administration of opioids (via injection or inhalation), but can be experienced from the oral route as well, especially if the responsible effect is relief of pain and anxiety. Although there is a genetic predisposition to substance use, it is important to remember that patients can also be predisposed due to comorbid mental health conditions and environmental factors.3 Patients also develop a physical dependence to opioid therapy, mediated by opioid activity on adrenergic neurons. 2 When opioids are not available following extended periods of use, there is unsuppressed adrenergic activity, leading to the sympathetic withdrawal symptoms such as tachycardia, diarrhea, and diaphoresis.
Opioid use disorder treatment
The treatment of opioid use disorders is challenging, potentially combining pharmacologic therapy with psychosocial interventions such as Narcotics Anonymous or counseling.4 Pharmacologic therapy is utilized to reduce cravings for opioids, prevent the effects of withdrawal, block the effects of any opioids that may be misused, and facilitate participation in a plan directed toward rehabilitation. The ultimate goal is to achieve abstinence. Three pharmacologic agents are currently available in the US for this use. Methadone is a full mu-receptor agonist utilized in outpatient opioid use disorder therapy. Buprenorphine, a mixed agonist-antagonist at opioid receptors, is also used for opioid use disorders. It has a longer duration of action than methadone, allowing for dosing at up to 72-hour intervals. Naltrexone is an opioid antagonist which blocks the euphoria gained from doses of opioids. Its place in therapy differs from methadone and buprenorphine in that patients need to have already withdrawn from opioids, as naltrexone will induce withdrawal effects in active opioid users. It is effective, however, for preventing relapse in these patients.
In the US, outpatient buprenorphine treatment is available as a sublingual tablet or film co-formulated with naloxone, known as Suboxone.5 Naloxone is a full opioid antagonist that has no systemic activity when administered via the sublingual route. It has not been found to affect the opioid activity of buprenorphine, but it is added to the formulation as a deterrent to injection use. When injected it precipitates withdrawal in patients physically dependent on opioids.6 The sublingual route decreases the rate of absorption of buprenorphine into the bloodstream compared with injection which allows the recipient to achieve activation of the opioid receptors in the brain—allaying withdrawal effects—without achieving the intense pleasure obtained via parenteral administration.5
Apart from its formulation to prevent diversion, Suboxone presents unique benefits to therapy. It may be prescribed by physicians specializing in outpatient addiction treatment.7 This is in contrast to methadone therapy, which requires enrollment in an opioid treatment program. Methadone treatment programs require daily administration of the medication at the treatment site, potentially limiting travel and employment opportunities. Buprenorphine therapy allows for true outpatient treatment, with provisions for 30-day supplies of medication and true immersion in community life.
Buprenorphine treatment is not without limitations. Long-term therapy may affect acute and chronic pain sensation through neuroplastic changes.8 As the body receives repeated doses of buprenorphine, it develops tolerance and down regulates mu-opioid receptors. At the same time there is a hyperalgesic response to pain, creating a more acute pain response in patients. In addition, those who attempt to use Suboxone intranasally or via injection could acutely precipitate withdrawal symptoms due to the naloxone component.5 These setbacks should be viewed in context with the potential benefits patients may derive from buprenorphine therapy when determining appropriate opioid use disorder management.
Acute pain management
While patients are undergoing treatment for opioid use disorder, it is vitally important to address other comorbid conditions. One common comorbid condition in patients with opioid addiction is pain, whether it is acute or chronic. The Substance Abuse and Mental Health Services Administration (SAMHSA) reports that 32% of patients receiving treatment for chronic pain may also have a substance use disorder.3 They also estimate anywhere from 29% to 60% of patients living with an opioid addiction report experiencing chronic pain processes. It is imperative, therefore, that patients receiving therapy for opioid abuse are also assessed for pain.
When patients undergoing treatment with Suboxone present with acute pain, it is imperative to treat the pain, as it may negatively affect mood, anxiety, and successful addiction treatment.8 Pain treatment may be challenging, as patients who abuse opioids have been found to be less tolerant of pain than those who are in remission.
Patients with substance use disorders seeking pain-relief are often met with resistance from healthcare providers due to misconceptions regarding their outpatient therapy and their behavioral health conditions.8 Some believe that outpatient therapy with partial opioid-agonists should provide adequate analgesia, while fearing that additional opioids will have untoward effects. However, the opposite is in fact true. Patients receiving buprenorphine for addiction therapy are dosed more infrequently (usually once daily) than required for analgesia (2 to 3 times per day). These patients may also experience opioid-induced hyperalgesia which counteracts any pain-relief that may be obtained from the buprenorphine therapy.
Other practitioners may fear precipitating relapse in substance use disorder patients or worry about drug-seeking behavior in these patients who have a history of opioid abuse.8 It is interesting to note that patients who are treated with opioids in the setting of acute pain have no increase in the rate of relapse. Instead, patients who are not adequately treated are more likely to relapse secondary to the stress of the pain episode. For practitioners still worried about drug-seeking behavior, it is best to search for objective evidence of pain. It is important to note that partial opioid agonist therapy may block the euphoria normally experienced from opioid ingestion, which may allay the concerns of certain professionals. Above all, healthcare professionals must remember that patients with substance use disorders are not immune from pain.
An important set of treatment modalities for painful episodes are the non-opioid analgesics.8 This can include both pharmacologic and non-pharmacologic therapies, depending on the source of the pain. Some patients will respond to therapeutic exercise, physical therapy, or massage therapy. Others will require pharmacologic management of pain. It is important to maximize non-opioid therapies, especially for patients with chronic pain. Potential agents include acetaminophen, non-steroidal anti-inflammatory drugs, and topical analgesics, depending on the type of pain the patient is experiencing. It is also important to avoid benzodiazepine and cannabinoid use for these patients, due to the abuse potential these medications carry. 3
In some instances, opioid therapy may be necessary for control of acute pain in patients undergoing treatment for substance use disorders.8 This is challenging, however, as buprenorphine has high affinity for the mu-opioid receptor. This affinity has the potential to block full opioid analgesics when used in combination with buprenorphine. The combination of full mu-agonists with buprenorphine could potentially lead to respiratory depression in patients, owing to buprenorphine’s slightly unpredictable dissociation with the mu-receptor. As such, all patients receiving full mu-opioid agonist therapy should have naloxone available, regardless of whether buprenorphine is continued.
In the literature there are 4 potential treatment courses for inpatient management of acute pain in patients who are currently treated with buprenorphine (also applicable to those taking buprenorphine/naloxone).8 Keep in mind that these regimens should be individualized for each patient and must be part of a multi-modal treatment regimen for acute pain.
1. Continue buprenorphine at outpatient doses and titrate short-acting opioids to analgesic effect.8 This regimen carries the highest risk of respiratory depression, especially if buprenorphine is abruptly discontinued. Because buprenorphine has variable binding to mu-opioid receptors, discontinuation can increase the effects of opioids that have been added. If buprenorphine is discontinued, consider decreasing the dose of the short-acting opioids or initiating long-acting opioid therapy in addition. Treating patients in this manner is also the most likely to facilitate drug-seeking behavior because of the use of short-acting opioid agents.
2. Administer the daily dose of buprenorphine in divided analgesic doses every 6 to 8 hours.8 This regimen takes advantage of the analgesic properties of buprenorphine when administered frequently. It does not guarantee, however, that the patient will experience adequate analgesia. In this case, it would be necessary to supplement buprenorphine with full opioid agonists. If buprenorphine were inadvertently discontinued, patients are again at risk for respiratory depression due to heightened opioid effects from the full opioid agonist in the absence of a partial agonist.
3. Discontinue buprenorphine and titrate full opioid agonist agents to effect.8 The elimination half-life of buprenorphine is 24 to 42 hours; thus, it can take over a week to see the full effect of the opioid that was initiated because the new opioid will be partially blocked by the buprenorphine while it is in the body.6 It is important to ensure the patient has enough opioid to avoid withdrawal as well as to achieve adequate analgesia. 8 This can be accomplished through the use of medications with a longer duration of action (i.e. sustained-release morphine). As the effects of the buprenorphine begin to wear off, patients will need to be monitored for respiratory depression and potentially have their analgesic doses decreased. When the acute pain episode has ended, discontinue the full opioid agonist and resume buprenorphine therapy with an induction protocol.
Induction therapy is important for initiation and reinitiation of buprenorphine as it helps establish a minimum dose of buprenorphine necessary to control cravings and withdrawal symptoms.9 Initial induction doses should be observed under medical care for at least 2 hours. Induction therapy should not begin until the patient is exhibiting early signs of withdrawal. At this time the patient should be administered buprenorphine/naloxone at a dose of 4 mg/1 mg. If symptoms are not relieved, a single dose may be repeated. If at any time the patient experiences relief of withdrawal symptoms, the induction for that day can be stopped and the patient can be sent home with follow up the next day. When the patient returns, it is important to inquire whether withdrawal symptoms occurred since the last dose. If none are experienced, the patient can be prescribed the dose which controlled his or her withdrawal. If symptoms persist, the dose should be escalated by 2 to 4 mg of buprenorphine, with a maximum increase of 4 mg per day. The patient should continue to follow up until a daily dose is established or until the maximum dose of 32 mg of buprenorphine is reached. If withdrawal is experienced at this dose, alternate treatment strategies should be explored.
4. Convert to methadone.8 Patients can be converted to methadone 30 to 40 mg per day during hospitalization to prevent opioid withdrawal and manage opioid requirements. Methadone does not bind to the mu receptor as tightly as buprenorphine, thus allowing traditional dosing of full opioid analgesics. In these patients, increases in opioid therapy should directly correlate to increases in analgesia. If patients experience withdrawal during this treatment, the methadone dose can be increased in 5 to 10 mg increments each day until withdrawal is adequately managed. If patients must be discharged prior to cessation of acute pain, convert to full opioid agonists and titrate to adequate analgesia, as these patients are not enrolled in outpatient methadone treatment programs. However, if patients experience cessation of pain, they may be reinitiated on buprenorphine, titrating upwards at 2 to 4 mg per day until withdrawal is adequately controlled.9
The 4 approaches above have never been directly compared and should all be evaluated on their own merit. Each episode of acute pain should be managed according to a patient-specific treatment plan, utilizing the 4 regimens above as a guide. Multi-modal pain therapy should be a cornerstone of this approach, with utilization of opioids only if non-opioid analgesics fail to provide adequate pain control. If initiating opioids, discuss potential treatment options with the patient, determine if they have been managed a specific way in the past, and assess the risks and benefits of each strategy presented.
Opioid use disorder is a behavioral health problem commonly treated with outpatient Suboxone therapy. While undergoing treatment, it is not uncommon for patients to experience episodes of acute pain. Analgesic therapy in these patients is complicated by the binding of buprenorphine to the mu opioid receptor. Pain management in patients receiving buprenorphine should be multi-modal, including non-pharmacologic therapy and non-opioid analgesics. Opioid analgesic therapy should be utilized when adequate pain control cannot be obtained via other means. In this setting, buprenorphine may be continued and used as the analgesic or continued with supplemental full opioid agonists. Alternatively, buprenorphine may be discontinued in favor of methadone or full opioid analgesic treatment. Whenever opioid therapy is to be initiated, the risks and benefits of all treatment strategies should be assessed and approached on an individual patient basis.
1. Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. HHS Publication No. 14–4863, NSDUH Series H–48. . Published September 2014. Accessed September 22, 2014.
2. Kosten TR. Opioid Drug Abuse and Dependence. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012. Accessed September 25, 2014.
3. Substance Abuse and Mental Health Services Administration. Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders. HHS Publication No. 12-4671. Published January 2012. Accessed September 22, 2014.
4. Kleber HD, Weiss RD, Anton RF Jr, et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry. 2007 Apr;164(4 Suppl):5-123.
5. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare), Inc; 2013. http://www.thomsonhc.com/hcs/librarian. Accessed September 22, 2014.
6. Suboxone [package insert]. Richmond, VA: Reckitt Benckiser Pharmaceuticals Inc; 2014.
7. United States Department of Justice Drug Enforcement Administration Office of Diversion Control. DEA Requirements for DATA Waived Physicians (DWPs). Accessed September 22, 2014.
8. Alford DP, Compton P, Samet JH. Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy. Ann Intern Med. 2006;144(2):127-134.
9. Substance Abuse and Mental Health Service Administration. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. HHS Publication No. 04-3939. Published September 2004. Accessed September 11, 2014.
Matthew Duprey, PharmD