Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB

This article was updated November 23, 2020 to include all authors.

Opioid use in the United States has evolved significantly during a recognized opioid epidemic. Related morbidity and mortality, along with regulatory scrutiny, have led to fear of opioid prescribing among clinicians. Within this landscape, opioid stewardship programs in hospitals have become popular, particularly to reduce overall daily morphine equivalent doses, traditional opioid use, and total days of therapy.

 Moreover, pharmacists and physicians have favored the use of nonopioid adjuvants for preemptive analgesia, such as acetaminophen, nerve blocks, nonsteroidal anti-inflammatory drugs, and various sedative-hypnotics.

The FDA approved oliceridine (Olinvyk), a novel centrally acting μ-opioid receptor agonist with reduced β-arrestin recruitment, on August 7, 2020, for managing moderate to severe acute pain in adults who require an intravenous (IV) opioid and for whom alternative treatment is inadequate.

 Oliceridine is a schedule II ethanamine opioid medication structurally different from natural (ie, morphine) and semisynthetic (ie, hydromorphone) opioids and other opioid classes. Conventional opioids activate the μ-opioid receptor, resulting in G protein—mediated analgesia. The receptor activation by established full agonist opioids also leads to recruitment of β-arrestin, which is associated with receptor downregulation and respiratory depression, constipation, and nausea, adverse effects (AEs) of opioids, though the latter 3 have been called into question.

Compared with conventional opioids, oliceridine stimulates G protein signaling with profoundly less β-arrestin activation. The understood receptor activity of a G protein—biased μ-opioid receptor agonism with less β-arrestin recruitment allows this agent to provide analgesia while potentially mitigating the risks of respiratory depression and gastrointestinal (GI) AEs.

Buprenorphine also stimulates the μ-opioid receptor with less β-arrestin recruitment compared with traditional opioids. However, it is more difficult to overcome receptor occupation by buprenorphine with naloxone reversal because the latter has a lower binding affinity compared with buprenorphine. Conversely, oliceridine has been shown be reversed handily by naloxone.

Onset of action for oliceridine is 1 to 3 minutes, making it optimal for managing acute pain. Oliceridine has the same boxed warnings as other opioids, including risks of abuse, addiction, life-threatening respiratory depression, misuse, neonatal opioid withdrawal syndrome if abruptly discontinued, and profound sedation with concomitant use of central nervous system depressants. There is also a risk of QT interval prolongation in doses greater than 27 mg, though studies did not find significant QT interval changes at FDA-approved doses.

Oliceridine is metabolized by cytochrome P450 (CYP) 2D6 and 3A4 to inactive metabolites, and renal dose adjustment is not required. Concomitant use of oliceridine and strong to moderate CYP2D6 (ie, fluoxetine) and CYP3A4 (ie, clarithromycin) inhibitors, along with discontinuation of CYP3A4 inducers, can result in increased plasma concentration of oliceridine, raising the risk of opioid-related AEs and exacerbated respiratory depression. Similarly, there is a greater risk of toxicity in patients expressing CYP2D6 poor metabolizer phenotypes.

 Of note, the effects of enzyme induction are delayed about 3 weeks; enzyme inhibition, about 48 hours.

 Additionally, this medication is intended for acute use in controlled settings, where patients are closely monitored, mitigating some of the risk.

Findings of pivotal trials indicated the efficacy and safety of oliceridine, ultimately leading to its FDA approval. The study results showed improved analgesia with oliceridine compared with the placebo and similar efficacy to morphine. Additionally, less potential for nausea and lower rates of respiratory risk were reported in the oliceridine group than with those receiving morphine. Notably, the trials also showed that AEs of oliceridine, though of less risk than morphine, are dose dependent. Doses greater than 27 mg/day were not evaluated. Oliceridine was not evaluated in several patient populations, including those who have sleep apnea, are obese, or were already receiving chronic opioid therapy; therefore, clinical judgment is required when considering use in these populations.

The novel approach of limiting β-arrestin recruitment has been shown to limit GI and respiratory AEs.6 Oliceridine may be used in emergency department settings or after surgery in patients who require acute pain management. Overall, oliceridine offers an alternative for patients in hospitals or other controlled settings, with moderate to severe acute pain when nonpharmacological and nonopioid options are inappropriate.

 Pharmacists can help ensure the safe use of oliceridine by identifying and appropriately managing drug-drug interactions, particularly CYP medication issues and concomitant use of corrected QT interval—elevating drugs, such as fluoroquinolones. They can also present cost considerations and a risk-versus-benefit evaluation to the team.

, PharmD is a PGY-2 pain and palliative care pharmacy resident, both at Albany Stratton VA Medical Center in New York. 

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB

, is CEO and founder of Remitigate Therapeutics, LLC, and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts; an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in New York; and the director of the PGY-2 pain and palliative care residency at Albany Stratton VA Medical Center.

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Kliewer A, Gillis A, Hill R, et al. Morphine‐induced respiratory depression is independent of β‐arrestin2 signalling. 

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Olinvyk (oliceridine). Prescribing information. Trevena Inc; 2020. Accessed October 15, 2020. https://www.drugs.com/pro/olinvyk.html

Gudin J, Fudin J. Peripheral opioid receptor antagonists for opioid-induced constipation: a primer on pharmacokinetic variabilities with a focus on drug interactions. 

. 2020;13:447-456. doi:10.2147/JPR.S220859

Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N. APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the μ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. 

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Singla NK, Skobieranda F, Soergel D, et. al. APOLLO-2: a randomized, placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-based ligand at the μ‐opioid receptor, for management of moderate to severe acute pain following abdominoplasty. 

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Articles

Oliceridine (Olinvyk) expands options for managing moderate to severe acute pain, but cost, drug-drug interactions, and other factors come into play.

Pharmacists Can Help Assess New FDA-Approved IV Opioid

The introduction of peripherally acting μ-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation brought opportunity for improved health and quality of life for patients on long-term opioid therapy.

Constipation is a bothersome, common, and underrecognized adverse effect (AE) of long-term opioid therapy. PAMORAs offer treatment for this condition and can improve patient adherence to the prescribed opioid therapy. However, it is crucial to understand the pharmacokinetic differences between the PAMORAs to aid in AE monitoring and minimize potentially strong drug-drug interactions (DDIs).

The 3 PAMORAs on the US market indicated for treating opioid-induced constipation from long-term opioid use are methylnaltrexone, naldemedine, and naloxegol. Each agent is available as oral tablets, and methylnaltrexone is also available as a subcutaneous injection. PAMORAs work by inhibiting the action of opioids in the gastrointestinal tract by combining with μ-receptors, thereby decreasing the constipating effects of opioids without compromising the analgesic effects in the central nervous system. These medications do not interfere with analgesia or cause opioid withdrawal, as they cannot cross the blood-brain barrier (BBB), because of their increased efflux across the BBB, large chemical structure, lipid solubility, and/or reduced permeability.

 Despite their overlapping mechanisms of action, the 3 PAMORAs differ in their pharmacokinetic properties. These properties can be harnessed based on a patient’s concomitant medications to help mitigate the risk of clinically relevant DDIs. The article “Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions,” evaluates the subtle pharmacokinetic differences among these PAMORAs.

PAMORA DDIs may occur when a drug alters the absorption, distribution, metabolism, or elimination of another drug,

 such as with cytochrome P450 enzymes and P-glycoprotein (P-gp), the latter of which has significance within the gut and passage through the BBB. Evaluating each PAMORA’s unique profile can assist clinicians in selecting the optimal therapy for their patients, especially those with polypharmacy.

Study results have shown that methylnaltrexone does not significantly inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4 enzymes. Methylnaltrexone is metabolized by CYP2D6 to a small extent. However, this has no relevance nor is it affected by drug interactions. In healthy volunteers, methylnaltrexone did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. Cimetidine is a moderate CYP3A4 inhibitor, and in healthy adults, cimetidine did not cause a clinically significant increase in the systemic exposure of methylnaltrexone.

 Therefore, methylnaltrexone’s pharmacokinetic profile is not affected by DDIs in a clinically significant manner (Table).

Naloxegol is a substrate of P-gp and is mainly metabolized by CYP3A4 enzymes. Moderate and strong CYP3A4 inhibitors significantly increase the plasma concentration of naloxegol, therefore potentiating the risk of AEs. In fact, concomitant use of naloxegol and strong CYP3A4 inhibitors, such as clarithromycin, itraconazole, and ketoconazole is contraindicated.

 Increasing the plasma concentration of naloxegol may precipitate opioid withdrawal symptoms. Similarly, moderate CYP3A4 inhibitors, such as diltiazem, erythromycin, and verapamil, should be avoided when using naloxegol. If coadministration of moderate CYP3A4 inhibitors cannot be avoided, naloxegol dose reduction is recommended, along with monitoring for toxicity, including opioid withdrawal symptoms, such as chills, diarrhea, hyperhidrosis, and irritability.

On the other hand, CYP3A4 inducers and P-gp inducers have not been shown to significantly decrease the plasma concentration of naloxegol. For example, efavirenz, a moderate CYP3A4 inducer, does not affect the concentration of naloxegol, whereas rifampin, a strong CYP3A4 inducer, may slightly decrease the exposure of naloxegol (but clinical significance has not been established) (Table). In healthy subjects, morphine and its major metabolites were not affected by naloxegol.

Although naldemedine is a substrate of CYP 3A4, it does not inhibit or induce CYP450 enzymes and does not inhibit P-gp. To prevent decreased efficacy, coadministration of naldemedine and strong CYP3A4 inducers, such as rifampin, should be avoided. Decreasing naldemedine’s dose to counteract the effects of rifampin is not recommended, as it puts the patient at risk of gastrointestinal-related AEs. CYP3A4 inhibitors and P-gp inhibitors moderately increase the plasma concentration of naldemedine but dose adjustments are not recommended (Table). In this case, clinicians should monitor for AEs, such as abdominal pain, diarrhea, and nausea.

PAMORAs can interact with other medications, resulting in decreased efficacy or toxicity. Understanding the pharmacokinetic relationship between each PAMORA and other medications could affect drug selection. Pharmacists play a pivotal role in identifying and preventing DDIs. Their detailed knowledge about drugs allows them to educate caregivers, health care professionals, and patients regarding clinically significant drug interactions. They can assist clinicians with therapy selection, as well as recommend appropriate course of action when DDIs occur. As a key part of the health care team, pharmacists can equip patients with knowledge about potential AEs, expectations, goals of therapy, and interactions to ensure safe medication administration.

, is a PGY-1 pharmacy resident at Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania.

, is a PGY-2 pain and palliative care pharmacy resident at Stratton VA Medical Center in Albany, New York.

, is president of Remitigate Therapeutics, LLC and the managing editor and owner of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

. 2020;13:447-456 doi:10.2147/JPR.S220859

Gunaratna C. Drug metabolism & pharmacokinetics in drugdiscovery: a primer for bioanalytical chemists, part I.

Relistor. Prescribing information. Salix Pharmaceuticals, Inc; 2014. Accessed May 26, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2014/021964s010lbl.pdf

Movantik. Prescribing information. AstraZeneca Pharmaceuticals; 2020. Accessed May 26, 2020. azpicentral.com/movantik/movantik.pdf

Zhou D, Bui K, Sostek M, Al-Huniti N. Simulation and prediction of the drug—drug interaction potential of naloxegol by physiologically based pharmacokinetic modeling. 

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Symproic. Prescribing information. Shionogi, Inc; 2017. Accessed May 26, 2020. symproic.com/docs/symproic-PI.pdf

Naldemedine clinical pharmacology and biopharmaceutics review. Center for Drug Evaluation and Research. Published 2008. Accessed March 30, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021964s000_PharmR_P1.pdf

Peripherally acting M-opioid receptor antagonists can improve quality of life but differ variably by impact from concomitant medications.

Toxicity Is a Risk of PAMORA Interactions

New information on the severe acute respiratory syndrome coronavirus (sars-cov-2), which causes the coronavirus disease 2019 (COVID- 19), continues to emerge daily.

As health care providers navigate the most severe global pandemic in more than a century, concerns arise among those who care for some of our most vulnerable populations. One such population is patients with rheumatologic conditions who take immunosuppressant medications. Patients with conditions such as ankylosing spondylitis (AS), lupus, psoriatic arthritis (PSA), rheumatoid arthritis (RA), and scleroderma may have a higher risk of contracting SARS-CoV-2, regardless of whether they are prescribed immunosuppressants.

Patients on disease-modifying antirheumatic drugs (DMARDs) are at higher risk of infections, including SARS-CoV-2, as well as secondary infections and poor outcomes. Initial mortality reports from the SARS-CoV-2 pandemic have also been higher for this population.

 The risks of infection for patients on DMARDs (biologics and other immunosuppressive agents) are well described in the literature. A study by Quartuccio et al using administrative data from 5596 patients with AS, PSA, or RA identified a relationship between the recent initiation of a biologic and hospitalization for an infection.

 The most common types of infection identified were upper and lower respiratory tract infections. This is particularly important considering that SARS-CoV-2 is a virus of the lower respiratory tract.

Furthermore, patients on DMARDs may overlook their initial infection state. Patients who are immunosuppressed may present with different symptoms than their immunocompetent counterparts. For example, because of decreased ability to mount an immune response, this population may not present with a fever when infected with SARS-CoV-2.

The PSOLAR study (NCT00508547) reported the incidence rate of serious infection for patients undergoing treatment with tumor necrosis factor inhibitors (TNFIs; adalimumab, etanercept, infliximab), ustekinumab, methotrexate, and other DMARDs, such as cyclosporine.

 Serious infection incidence was numerically higher with TNFIs than with other biologics, but these differences were not statistically significant. To date, no confirmative data are available to support relative infection risks among different biologic DMARDs.

The PSOLAR study also reported that diabetes, history of infection, older age, and a level 4 or 5 Physician’s Global Assessment were statistically significant factors for increased risk for serious infection. Importantly, the additional risk factors listed above could increase infection risk even further.

TNFIs have been on the market for 2 decades and are known to increase the risk of infection of SARSCoV- 2.1 Other biologics used in rheumatology, such as B-cell modulators, IL-6 inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, Janus kinase inhibitors, and T-cell modulators, are also immunosuppressive and increase infection risk. The American College of Rheumatology 2015 guidelines for RA recommended the use of combination DMARDs over TNFIs and abatacept over TNFIs if a patient had a history of previous serious infections.

General recommendations remain that first, an individual should choose strategies to minimize the risk of infection, by receiving an annual influenza vaccination, for example, and practicing self-hygiene. If a patient on a biologic or other immunosuppressive agent becomes ill, they should discontinue the medication until resolution of the infection. If a patient was prescribed an antibiotic, antifungal, or antiviral agent to treat an acute infection, the individual should remain off the immunocompromising biologics until they finish their course of the prescribed regimen and the infection resolves before reinitiating biologics.

At this time during the SARS-CoV-2 outbreak, CDC recommendations for patients on immunosuppressive medications do not differ greatly from those for the general population. Patients are advised to avoid contact with people who are sick; to not touch the eyes, mouth, or nose with unwashed hands; to wash hands with soap and water often for at least 20 seconds; and to use alcohol-based hand sanitizer when not near soap and water. All immunocompromised patients should also inform their provider of any travel destinations if they become ill after having traveled abroad or locally and of any acute infection or injury, which could lead to further infection. Patients should also evaluate their health condition prior to each injection of a biologic agent, during which practitioners assess for general wellness, fever symptoms, significant cuts and injuries, and sores. Finally, remind patients frequently of the importance of routine immunizations such as the influenza vaccine and to receive only inactivated vaccines. Patients with planned surgical procedures should discontinue biologic agents for the appropriate period determined by their providers prior to the procedure.

In the backdrop of the pandemic, panic has led many people to seek chloroquine or hydroxychloroquine to either treat their infection or use as prophylaxis against COVID- 19.

 Hydroxychloroquine is a DMARD that serves as the cornerstone of pharmacotherapy for patients with multiple rheumatologic conditions, including lupus and RA. The World Health Organization is in the midst of exploring the potential role of chloroquine and hydroxychloroquine in the management of COVID-19. In the meantime, federal and state authorities have enacted mandates, such as New York State Executive Order 202.10, to preclude dispensation of these medications for other than their FDA-approved indications, unless the patient is enrolled in a bona fide study.

 Large community pharmacy chains, such as CVS Health, Express Scripts, and Walgreens, have also set policies to halt hoarding of chloroquine and hydroxychloroquine.

 These mandates are an effort to reduce drug shortages for those who require these medications chronically for an established rheumatologic disorder.6 Pharmacists have become an important gatekeeper in this regard, as even health care clinicians have been noted to hoard these medications for themselves, their family members, or their friends.

Pharmacists play a key role in educating the public and controlling distribution of medications. It is imperative that health care providers and patients are aware that DMARD use may lead to immunosuppression that could increase infection risk during this unprecedented public health crisis. Critically, they should also realize the potential for afebrile presentation of infection, the importance of holding biologics if an infection is present, and the need to seek health care promptly. Furthermore, the general population must understand the risks imposed on patients with rheumatologic disorders if their maintenance medications are depleted.

, is a PGY-2 pain and palliative care pharmacy resident, and 

, is a clinical pharmacy specialist for rheumatology, both at Albany Stratton VA Medical Center in Albany, New York.

, is CEO and founder of Remitigate LLC and the owner and managing editor of paindr. com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

Quartuccio L, Zabotti A, Del Zotto S, Zanier L, De Vita S, Valent F. Risk of serious infection among patients receiving biologics for chronic inflammatory diseases: usefulness of administrative data. 

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Ritchlin CT, Stahle M, Poulin Y, et al. Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics. 

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Singh JA, Saag KG, Bridge SL Jr, et al; American College of Rheumatology. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. 

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World Health Organization. COVID-1 informal consultation on the potential role of chloroquine in the clinical management of COVID19 Infection. who.int/blueprint/ priority-diseases/key-action/RD-Blueprint-expert-group-on- CQ-call-Mar-13-2020.pdf?ua=1. Published March 13, 2020. Accessed March 26, 2020.

No. 202.10: continuing temporary suspension and modification of laws relating to the disaster emergency. New York State website. governor.ny.gov/news/no-20210-continuing-temporary- suspension-and-modification-laws-relating-disaster-emergency. Published March 23, 2020. Accessed March 26, 2020.

Humer C, Mishra M. Pharmacies set policies to stop U.S. hoarding of potential coronavirus treatments. Reuters website. reuters.com/article/us-health-coronavirus-cvs-health/pharmacies- set-policies-to-stop-u-s-hoarding-of-potential-coronavirus- treatments-idUSKBN21C2CQ. Published March 25, 2020. Accessed March 26, 2020.

Rowland C. As Trump touts an unproven coronavirus treatment, supplies evaporate for patients who need those drugs. 

. March 23, 2020. washingtonpost.com/ business/2020/03/20/hospitals-doctors-are-wiping-out-supplies- an-unproven-coronavirus-treatment/. Accessed March 26, 2020.

Panic and a host of interactions are entwined with disease-modifying antirheumatic drugs.

Exercise Caution Amid the COVID-19 Pandemic

Cannabidiol (CBD) has been gaining popularity over the past few years and is now found in many pharmacies, supermarkets, and gas stations throughout the United States.

Cannabidiol is a substance isolated from the cannabis plant, which is the same plant from which tetrahydrocannabinol (THC), the psychoactive component of marijuana, is derived. The major difference between CBD and THC is that the former does not produce the euphoric and mind-altering effects attributed to the latter. Cannabidiol is touted as helping with a number of different conditions, such as anxiety, pain, and seizures, and is available in a variety of different formulations including food products, oral tinctures, and topical creams. Nevertheless, the FDA has not approved them, nor does it advocate CBD’s efficacy for these conditions.

 A majority of OTC formulations found in stores are not regulated by the FDA and may not contain the amount of CBD that they claim to contain.

As none of these CBD natural supplements are regulated and as there are no long-term studies to endorse efficacy and safety, these products should be used cautiously. Like other OTC products, CBD can interact with medications, yet many people do not tell their health care providers about their use of CBD products. CBD undergoes hepatic metabolism via the cytochrome P450 enzymes. Specific CYP enzymes found to be responsible for CBD metabolism include CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. Upon further evaluation, it was shown that CYP3A4 and CYP2C19 are the 2 major enzymes responsible for the metabolism of CBD; they are also responsible for the metabolism of many different drugs.

CYP3A4 is a major cytochrome P450 enzyme that is abundantly expressed in the liver and is responsible for the metabolism of more than 50% of all commonly prescribed drugs.

 CBD is included as 1 of those drugs and is a known CYP3A4 substrate, which carries the risk of many drug interactions. CYP3A4 inducers, such as carbamazepine, phenytoin, and rifampin, may diminish the effects of CBD,

 whereas CYP3A4 inhibitors, such as amiodarone, azithromycin, diltiazem, erythromycin, and grapefruit juice, may increase the concentration of CBD and increase the risk of adverse effects.

 The interactions with CYP3A4 inducers and inhibitors are theoretical, based on the pharmacology of CBD, and have yet to be proven in human studies, but caution should be used if combining these medications.

Animal studies have shown that CBD is also a CYP3A4 inhibitor, but this effect is still being evaluated in human studies. In past case reports and studies, CBD has been found to increase the plasma levels of everolimus, tacrolimus, and zonisamide, which are all CYP3A4 substrates.

 Theoretically, it could increase the concentrations of other CYP3A4 substrates, such as alprazolam and triazolam, which could be dangerous. The use of CBD with CYP3A4 substrates should be done cautiously with close monitoring and should be evaluated by a pharmacist whenever the opportunity is available.

Although CYP2C19 is not as ubiquitous an enzyme in the liver, nor as commonplace a metabolic-drug pathway as CYP3A4, it is responsible for the metabolism of many commonly prescribed medications. Of particular interest are those with overlapping indications to CBD, such as are used in the treatment of anxiety, depression, and epilepsy. A few of the more common CYP2C19 substrates include carisoprodol, citalopram, clobazam, fluoxetine, and phenytoin.

 Cannabidiol is both a minor substrate and a moderate inhibitor of CYP2C19. With enzyme inhibition, patients taking the aforementioned medications are at risk of increased adverse effects and may require lower doses and/or more frequent monitoring.

Cilostazol and clopidogrel are also metabolized by CYP2C19, and it is important to consider the patient’s bleeding or clotting risk before combining the use of these medications with CBD products.

 Cilostazol and clopidogrel act to prevent platelet aggregation but are mechanistically different from each other. Cilostazol is active upon administration and requires CYP2C19 metabolism into inactive compounds. Clopidogrel, on the other hand, is a prodrug dependent on CYP2C19 for conversion to the active form. This means the inhibition of CYP2C19 by CBD may increase the risk of bleeding in patients taking cilostazol and may increase the risk of clotting in patients taking clopidogrel. Additionally, the oral anticoagulant warfarin is a minor substrate of CYP2C19, which means bleeding risk may be increased with concomitant CBD use, as described in a 2018 case report that showed a nonlinear increase in international normalized ratio with an increased dose of CBD.

With the growing popularity of CBD products, it is important to ensure that patients are aware of the risks associated with its use in combination with other drugs. Patients should talk to their providers before starting any CBD, OTC, or prescription medications. Upon dispensing, pharmacists should routinely ask patients about new or regular use of any natural-food products or nutraceuticals, with specific mention of CBD. Prospective in vivo studies are needed to assess the true clinical impact of these potential drug interactions. Until then, CBD’s benefits must be weighed against the risks for drug interactions, with appropriate cautionary dose adjustments for concomitant therapies where indicated.

 are PGY-1 pharmacy residents at the Albany Stratton VA Medical Center in Albany, New York.

 is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at Albany Stratton VA Medical Center. She coordinates are precepts in the VALOR intern program and is an adjunct advanced pharmacy practice experience preceptor for Albany College of Pharmacy and Health Sciences and Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB,

 is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

FDA. FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). www.fda.gov/newsevents/public-health-focus/fda-regulation-cannabis-andcannabis-derived-products-including-cannabidiol-cbd. Updated January 15, 2019. Accessed February 10, 2019.

FDA. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds, including CBD. www.fda.gov/consumers/consumerupdates/what-you-need-knowand-what-were-working-find-out-about-products-containingcannabis-or-cannabis. Updated November 25, 2019. Accessed February 10, 2020.

Brown JD, Winterstein AG. Potential adverse drug events and drug—drug interactions with medical and consumer cannabidiol (CBD) use.

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Epidiolex [prescribing information]. Carlsbad, CA: Greenwich Biosciences, Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed February 6, 2020.

Marinol [prescribing information]. North Chicago, IL: AbbVie; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf. Updated August 2017. Accessed February 10, 2020.

Cannabidiol. Natural medicines. naturalmedicines.therapeuticresearch.com. Updated November 13, 2019. Accessed November 25, 2019.

Grayson L, Vines B, Nichol K, Szaflarski JP; UAB CBD Program. An interaction between warfarin and cannabidiol, a case report. 

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Recent federal legalization and increases sales of CBD underscore the importance of considering its pharmacologic impact.

Cannabidiol Presents Conundrums

Dolutegravir (Tivicay), a second-generation integrase strand transfer inhibitor, is FDA approved for the treatment of HIV-1 in combination with other antiretrovirals for both treatment-experienced and treatment-naïve patients.

Mechanistically, dolutegravir works to impede HIV DNA integration by binding to magnesium at the integrase active site, thus preventing the strand transfer step and completion of the HIV replication cycle.

With all antiretrovirals, it is important to be mindful of concomitant medications that may interact with dolutegravir, resulting in either supra- or subtherapeutic doses of the latter.

Of note, with dolutegravir and other agents in its class, polyvalent drugs have been shown to cause chelation-type drug interactions.

Common di- and trivalent cations, such as aluminum, calcium, magnesium, and iron-containing products, can bind with dolutegravir, resulting in a poorly absorbable complex formed in the gastrointestinal tract, subsequently leading to decreased absorption of the integrase strand transfer inhibitor.

Examples of these agents include antacids, laxatives, sucralfate, and supplements. Sucralfate works to protect the gastrointestinal tract by forming a complex with positively charged proteins, often leading to decreased absorption of many oral medications.

The package insert of dolutegravir recommends separating administration of dolutegravir by at least 2 hours before or 6 hours after sucralfate to prevent this interaction.

A cross-over, open-label, randomized trial conducted by Song et al analyzed the pharmacokinetics of dolutegravir in 24 healthy subjects after receiving either 1200-mg calcium carbonate (480-mg elemental calcium), 324-mg ferrous fumarate (107-mg elemental iron), or antiretroviral drug alone.

Dolutegravir plasma concentrations were decreased with both calcium carbonate and ferrous fumarate under fasted conditions by 37% to 39% and 54% to 57%, respectively.

 The authors hypothesized that the differences seen in bioavailability between the 2 combinations may be the result of solubility differences in the dolutegravir-polyvalent complexes formed and/or iron’s greater affinity for the antiretroviral integrase binding site.

 On the contrary, under fed conditions with concomitant therapy, plasma concentrations of dolutegravir were similar to that of the antiretroviral’s concentration alone.

 The same was true when dolutegravir was administered 2 hours prior to the polyvalent dose.

 Therefore, the authors suggested that calcium and dolutegravir can be coadministered if taken with a meal or should be separated if under fasting conditions for best absorption and efficacy of dolutegravir.

Similarly, a study conducted by Patel et al examined the effects of metal cation-containing antacids on the plasma concentration of dolutegravir.

 When dolutegravir was administered simultaneously with Maalox Advanced, which contains 400 mg of aluminum hydroxide and 400 mg of magnesium hydroxide in 5 mL, the area under the curve of dolutegravir decreased by 74% compared with dolutegravir alone. However, with staggered administration of dolutegravir 2 hours before the antacid, the area under the curve of dolutegravir was diminished significantly less, a reduction of 26% compared with dolutegravir alone.

Dolutegravir’s package insert outlines that the antiretroviral should be administered 2 hours before or 6 hours after taking medications containing polyvalent cations.

 For patients using antacids to relieve heartburn symptoms, pharmacists may consider recommending the use of either an H2 receptor antagonist or a proton pump inhibitor instead. Although the latter 2 agents may not have as fast an onset of action, there are no associated drug interactions with dolutegravir as seen with polyvalentcontaining antacids. Switching to an H2 receptor antagonist or proton pump inhibitor from an antacid may also benefit patients who are unable to comply with the recommended dosing schedule as outlined by the dolutegravir package insert.

In addition, dolutegravir is metabolized by UDP glucuronosyltransferase 1A1 with minor contribution from cytochrome P450 3A4 (CYP3A4). Inducers of these pathways can result in decreased plasma concentration of the antiretroviral.

 For example, when administered with a CYP 3A4 inducer, rifampin, the dosing frequency of dolutegravir must be increased.

It is vital to consider all drug-drug interactions that may be present and may affect the concentration of dolutegravir. By following appropriate dosing adjustments in the setting of drug interactions, pharmacists can ensure that patients are receiving an effective and safe dose of dolutegravir.

 is a PharmD candidate at Albany College of Pharmacy and Health Sciences (ACPHS) in New York who has completed the VA Learning Opportunities Residency (VALOR) program at the Albany stratton VA Medical Center (ASVMC) in New York.

 is a PharmD candidate at ACPHS who is completing the VALOR program at the ASVMC.

 is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at the ASVMC. She coordinates and precepts in the VALOR intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University College of Pharmacy and Health Sciences (WNEUCPHS) in Springfield, Massachusetts.

 is chief executive officer and founder of Remitigate, LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at WNEUCPHS, and adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at ASVMC.

Dolutegravir (Tivicay) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2013. http://www.

accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf

Song I, Borland J, Arya N, Wynne B, Piscitelli S. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. 

 2015;55(5):490-496. doi: 10.1002/jcph.439. 

Mercadel CJ, Skelley JW, Kyle JA, Elmore LK. Dolutegravir: an integrase strand transfer inhibitor for the treatment of human immunodeficiency virus 1 in adults. 

US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. AIDS info website. http://www.

.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines. Updated December 18, 2019. Accessed January 13, 2020.

Sucralfate (Carafate) [prescribing information]. Bridgewater, NJ: Aptalis Pharma US, Inc; 2013. http://www.

accessdata.fda.gov/drugsatfda_docs/label/2013/018333s034,019183s016lbl.pdf

Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. 

 2011;66(7):1567-1572. doi.org/10.1093/jac/dkr139.

Common medications containing polyvalent cations should be separated to prevent decreased absorption of the HIV therapy.

Dolutegravir Is Susceptible to Chelation-Type Interactions

Oral contraceptives (OCs) are the most common method of birth control used by US women aged 15 to 44 years to suppress ovulation and prevent pregnancies.

OCs are absorbed in the gastrointestinal (GI) mucosa, which can be altered when OCs are taken with sequestrants and medications that slow motility. After absorption, ethinyl estradiol (EE) undergoes first-pass metabolism in the liver by cytochrome P450 (CYP) 3A4.3 CYP3A4 is responsible for most drug interactions, as it metabolizes more than 80% of all drugs affected by CYP.

 CYP3A4 inhibition occurs within 48 hours and can increase drug concentrations of CYP3A4 substrates. This is critical because of the significance of vascular complications with increased EE levels. Inducers of CYP3A4 may take up to 3 weeks, resulting in decreased substrate concentrations.

 Consequently, short-term use of CYP3A4 inducers generally will not have clinical significance. After the discontinuation of a CYP inducer, the induction may take several weeks to subside.

 Pharmacists are in a great position to suggest alternative therapies when presented with a patient receiving OCs who requires medications that may pose a drug interaction risk.

Many anticonvulsants can pose clinically significant interactions. Carbamazepine, oxcarbazepine, phenobarbital, and phenytoin, when taken with OCs, can decrease the efficacy of contraceptives through 2 mechanisms: first via the induction of EE serum concentrations that reduce CYP3A4 by about 50% for up to 4 weeks after discontinuation and second by potentially increasing sex hormone—binding globulin (SHBG) concentration.

 SHBG binds to progestin, decreasing free progestin concentration in plasma.

 Lamotrigine is not a CYP inducer. However, it has a dose-dependent effect on hormone plasma concentrations (see Table 1. Oral Contraceptives and Cyp Interactions).

Topiramate, a weak CYP inducer, reduces EE at higher doses. Although lamotrigine does not decrease the efficacy of OCs, its concentrations decrease when taken with OCs.

 Fortunately, patients can take other anticonvulsants and gabapentinoids with OCs safely with appropriate lab monitoring (see Table 1. Suggested Alternatives).

Antimicrobials may interact with OCs, but not all interactions are clinically significant. Macrolides, except for azithromycin, are CYP inhibitors. Unlike CYP inducers, CYP inhibitors potentially increase the risk of adverse effects (AEs) of EE, such as vascular disease complications within 48 hours, because of increased EE plasma concentration.

 This may be detrimental to women who already carry an increased risk of deep vein thrombosis or pulmonary embolism. In addition, the subclass azoles of the antifungals are known to be CYP inhibitors. Most reported cases reflect increased concentrations of EE. However, the clinical significance of these increased concentrations is questionable.

 Drug databases do not identify a clear contraindication, nor do they suggest an increased risk of AEs of EE.

Some antimycobacterials, including rifabutin, rifampin, and rifapentine, are strong CYP inducers. Rifampin’s induction can be prolonged. Therefore, women need a backup method of contraception for 6 weeks after discontinuing rifampin.

HIV requires lifelong treatment with antiretrovirals, such as efavirenz, nevirapine, and ritonavir, which are CYP inducers that decrease the efficacy of contraceptives. Uniquely, ritonavir reduces contraceptive efficacy through a dual mechanism by decreasing plasma concentrations of EE through induction of the CYP enzyme and by glucuronidation in phase 2 metabolism, which decreases progestogen’s plasma concentration. Female patients on ritonavir boosted should use an additional method of contraception because of decreased concentrations of EE.

 Cobicistat is used to enhance antivirals, such as atazanavir and darunavir, by inhibiting CYP3A enzymes, which are known to concordantly alter concentrations of EE and progestin from OCs.

Despite their lack of effect on CYP enzymes, colesevelam and exenatide interact with OCs by interfering with absorption. Colesevelam binds EE in the GI tract and inactivates it, so when taken, it should be separated from EE-containing OCs (see Table 1. Oral Contraceptives and Cyp Interactions).

Although OCs should be separated from exenatide by 1 hour because of decreased gastric emptying, exenatide is affected by multiple culprits, including food.

 Drospirenone, in OCs such as Yaz, has antimineralocorticoid activity, such that 3 mg of drospirenone is equivalent to 25 mg of spironolactone.

 Use caution, even in healthy women, when using drospirenone with potassium-sparing medications.

OCs containing EE should not be used with cyclosporine because of increased trough concentrations and should also not be used when treating hepatitis because of an increased risk of hepatoxicity.

 It is important to note that paritaprevir/ritonavir/ ombitasvir (Technivie) and paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak) are major substrates and strong inhibitors of CYP3A4, which can increase EE concentrations, exposing patients to increased vascular AEs in addition to an increased risk of elevated alanine aminotransferase and aspartate aminotransferase. Women should restart EE 2 weeks after discontinuing Technivie or Viekira Pak.

Herbals and nutraceuticals commonly interact with medications. Clinicians should therefore advise caution in patients taking herbals while receiving OCs. St John’s wort is a common offender of drug interactions, as it has been associated with an increased risk of breakthrough bleeding because of an approximately 50% decreased half-life of EE (see Table 1. Oral Contraceptives and Cyp Interactions).

OCs are the most common form of contraceptive used. Most OCs are metabolized by CYP3A enzymes and are subject to several drug interactions. Fortunately, not all drug interactions with OCs are deemed clinically significant, and not all forms of contraceptives exhibit the same extent of drug interactions, such as progestin-only injectables and intrauterine system contraceptives (see Table 2).

 Pharmacists play a crucial role in assessing drug—drug interactions for clinical significance and severity and, when appropriate, recommending alternative therapy for concurrent conditions (Table 1. Suggested Alternatives).

 is a 2019 PharmD candidate at the Albany College of Pharmacy and Health Sciences (ACPHS) in New York.

, is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at Albany Stratton VA Medical Center in New York. She coordinates and precepts in the VA Learning Opportunities Residency intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University in Springfield, Massachusetts.

, is CEO and chief medical officer of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

Jones J, Mosher W and Daniels K. Current contraceptive use in the United States, 2006—2010, and changes in patterns of use since 1995. 

National Center for Health Statistics. Contraceptive use. CDC website. 

. Updated July 15, 2016. Accessed April 18, 2019.c

Back DJ, Orme. ML. Pharmacokinetic drug interactions with oral Contraceptives. 

Pharmacists play a crucial role in assessing clinical significance and severity and, when appropriate, recommending alternative therapy.