Silas Inman

With the legalization of CBD products in 2018, many questions have emerged, not only on the laws governing these products, but on how to integrate CBD into community pharmacies. A presentation at the 2019 NCPA Annual Convention covered legal issues and strategies for how these products fit into a pharmacy. 

Despite not being illegal by federal law, the FDA still has the authority to regulate cannabis and cannabis-derived compounds. Moreover, the FDA has announced that it is unlawful to introduce food containing CBD or THC into interstate commerce or to market CBD or THC-containing materials as a dietary supplement. While it is not illegal, FDA can and will still take enforcement action.

“Be careful what you say about CBD. Be careful what you communicate about CBD. Pay attention to your state and the federal regulations of CBD as well,” said Karla L. Palmer, Esq, director, Hyman Phelps & McNamara, P.C, at the NCPA meeting. “Pay attention to the FDA’s website for warning letters. This is a very gray area, in terms of what is permitted, and what isn’t permitted. It’s legal, but we don’t know what you can and cannot do with it, but FDA is making headway about what you can and cannot say about CBD. Pharmacists need to be careful.”

With the passage of the Hemp Farming Act of 2018, regulation of cannabis became based on THC content. Under the law, if the THC content is below 0.3%, it is considered hemp and no longer defined as marijuana. This allows hemp to no longer be defined as a controlled substance by the Drug Enforcement Agency. The passage of this law allowed for interstate commerce of hemp-derived products and established a framework for regulation of hemp production, although regulation is still in its infancy. For the most part, the law leaves it up to the states to regulate hemp production and marketing.

Although the federal law allows for hemp, other laws still greatly vary from state to state, as does the definition of hemp. Staying up to date on the regulations is one of the more challenging issues, as the laws around cannabis, CBD, and hemp are evolving rapidly, Palmer noted.

"The best thing to do is to lay low on what you're claiming for your CBD. Be careful of your website and social media claims," Palmer said. "Disease claims are not permitted for dietary supplements, food, or cosmetics. Since Epidiolex is approved, CBD cannot be a supplement. You can say you have it, but be very careful not to say it is for anything."

Unlike marijuana, CBD is nonpsychoactive and does not result in feelings of euphoria or intoxication, even if large quantities are taken. In addition to the endocannabinoid receptors CB1 and CB2, CBD also acts on the serotonin receptor, vanilloid receptors, orphan receptor, and nuclear receptor.

"CBD interacts with our endocannabinoid system at CB1 and CB2 receptors. It interacts indirectly, unlike marijuana, and in 2019 we really aren't sure how it works," said Jesica Thomason Mills, PharmD, MBA, RPh, CNHP, Pharmacist, Naturopath, Hemp Expert, Owner, Owensboro Family Pharmacy and Wellness. "The endocannabinoid system uses neuromodulatory lipids to wake and strengthen the immune system, nervous system, and digestive system."

Since its legalization, many formulations of CBD have emerged, some with low levels (<0.3%) of THC (labeled as full spectrum) or THC-free isolates. Additionally, differences exist between products, based on extraction method. CBD has been formulated into different methods, including oils, capsules, balms and salves, vape or flowers, and edibles. The edibles, since added to food, can present potential regulatory issues, Mills warned. The quickest acting method are the oils, she added, but the method with the highest bioavailability is through the lungs.

Although CBD is not meant to treat, mitigate, or prevent a disease, many patients believe in its effects. In most cases, they take oils for systemic issues, such as chronic inflammation, and balms for localized concerns, like joint pain. Moreover, the THC-free isolate version of the oil allows individuals to take CBD without failing a drug test, Mills noted. However, all full spectrum varieties of CBD will cause a positive drug test result.

Some of the adverse effects of CBD could include drowsiness, GI upset, and drug interactions, as CBD uses CYP enzymes for metabolism. There have been signs of liver issues in some studies, Mills noted. If an individual is on a narrow therapeutic index drug, continue to monitor the patient once the begin taking CBD.

"It does mess with other drugs, there are studies that show this,” she added.

For her patients and even local providers, Mills holds educational events on CBD in her pharmacy, with samples available. She has also used social media to promote the availability of CBD at her pharmacy, but noted that potential issues have occurred on Facebook and with credit card vendors to process payments.

Although the prices per unit are near $60 to $70, Mills said she had no problem quickly selling out of CBD. She recommended placing the products near the register and within a locked case. If utilized with caution, CBD has the potential to substantially improve the revenue of a community pharmacy.

Mills J, Palmer K. Hemp: Positioning Yourself as the Truth Expert. Presented at: NCPA 2019 Annual Convention & Expo; October 26, 2019; San Diego, CA.

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With the legalization of CBD products in 2018, many questions have emerged, not only on the laws governing these products, but on how to integrate CBD into community pharmacies.

CBD Making Waves at Community Pharmacies

Utilizing many of the skills learned in pharmacy school could help to personalize care and enhance medication delivery for patients, potentially leading to reductions in adverse drug events and health care costs, according to a presentation by Calvin H. Knowlton, BScPharm, MDiv, PhD, at the 2019 NCPA Annual Convention.

"Community pharmacists can increase patient safety and revenue by putting science back into their practice," said Knowlton, founder, CEO, and chair, of Tabula Rasa Healthcare, Inc. "This means not just looking at 1-to-1 drug interactions but the mechanism underneath. Knowing a patient’s medication risk aids in personalizing a medication care plan."

Adverse drug events are the third leading cause of death in the United States, behind heart disease and cancer. There are 173,000 deaths per year related to adverse drug events, with 73,000 related to opioids alone. Some of the causes of adverse drug events are cognitive and functional changes in patients taking drugs with anticholinergic and sedative properties. Moreover, therapies interfering with calcium or potassium channels can cause cardiac issues, particularly QTc prolongation.

However, in some cases, adverse drug events are the direct result of competitive inhibition brought on by polypharmacy or prescription cascades. Knowlton noted that patients taking 7 or more medications have an 82% chance of having an adverse drug event. "And this does not include over the counter medications," he added. In the United States, 39% of seniors are on 5 or more medications, opening up a huge potential for events.

When dealing with multiple medications, there are science-driven strategies that can help reduce the risk of adverse drug events, Knowlton said. A simple cheek swab can reveal genetic information on an individual's ability to metabolize medications, which, when coupled with pharmacokinetics, pharmacodynamics, and chronopharmacology, could help improve the quality of care.

There are 10 to 12 genes that encode the enzymes that metabolize most medications, with some of the leading enzymes being CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2. However, not every individual has the genetics to encode all of these enzymes, calling for greater use of pharmacogenomics. "If we don't do a cheek swab, we would assume that everyone has normal metabolism," Knowlton said, adding that making assumptions is never good practice.

Even if a patient has genetics to indicate normal drug metabolism, the drugs taken can cause phenoconversion to a state of nonfunctional metabolism. Moreover, many drugs are metabolized by the same enzymes, causing backups and inappropriate absorption. This can lead to an increase in the dose at the physician level, which opens the door for an overdose, if the patient were to stop taking the competitive medication. To avoid this, the treatment could be changed to one that is metabolized by a different enzyme or by altering the time of day the dose is taken, to avoid competitive inhibition.

If medications are attempting to use the same gene/enzyme, and all the treatments have a similar affinity coefficient, the medication with a higher dosage will occupy the gene/enzyme first, Knowlton said. In an example, he noted that both metoprolol and diphenhydramine have a high affinity for CYP2D6, if 1 is given at 25 mg and the other at 50 mg the higher dose would be dissolved and circulate at full strength while the lower would have a diminished effect.

"This is low hanging fruit, but the only people who know this are pharmacists," Knowlton said.

Medical training for nurses and physicians does not include pharmacokinetics, pharmacodynamics, pharmacogenomics, and chronopharmacology, he noted, only pharmacists receive this training, making them the experts.

In 2016, $450 billion was spent on prescription medications, and another $528 billion to address adverse drug events. While polypharmacy and prescribing cascades have led to adverse drug events, Knowlton noted that pharmacy benefit managers (PBMs) are partially to blame as well, since most PBMs only allow 2 drugs per class, based solely on costs and not metabolic pathways. Moreover, he noted that the payment models in the pharmacy space and existing software tools are out of date.

The better use of medication and pharmacy-patient consultations could help change the cost story. In an analysis of 200,000 patients in a CMS project, medication risk score (MRS), generated by a Tabula Rasa software solution, was found to correlate with average total cost and aligned closely with hospitalization. The software tool utilizes pharmacogenomic data to indicate which enzymes are present, while also showing information on the effectiveness of treatment, based on genomics, and other therapies being used.

An MRS of 10 correlated with a hospitalization risk of 26%, while a score of 20 or 30 had hospitalization rates of 44% and 64%, respectively. Moreover, CMS reported there was a cost savings that exceeded the 2% threshold established by CMS.

The CMS project now has 2 years of outcomes information showing consistent savings with the decision support tool, which is being marketed under the name MedWise by Tabula Rasa. The software is not currently covered by CMS, but that could change as more data become available. It can be found on the athenahealth Marketplace.

This article was updated on October 28, 2019.

Knowlton C. New Ways to Identify and Mitigate Adverse Drug Events and Get Paid for It. Presented at: NCPA 2019 Annual Convention & Expo; October 26, 2019; San Diego, CA.

Utilizing many of the skills learned in pharmacy school could help to personalize care and enhance medication delivery for patients, potentially leading to reductions in adverse drug events and health care costs,

New Approaches Could Cut Adverse Drug Events

The addition of the immunotherapy pembrolizumab (Keytruda) to standard presurgical chemotherapy improved pathological complete response (pCR) rates for patients with triple-negative breast cancer (TNBC). Moreover, the continuation of pembrolizumab following surgery also showed early signs of improvement in event-free survival compared with placebo, according to findings from the KEYNOTE-522 study presented at the ESMO Congress 2019. 

“The data suggest that the improved pathological complete response with pembrolizumab translates into fewer recurrences,” lead study author Peter Schmid, MD, PhD, from the Barts Cancer Institute, Queen Mary University, said in a statement.

The KEYNOTE-522 trial randomized patients with TNBC in a 2:1 ratio to receive pembrolizumab at 200 mg every 3 weeks (n = 784) or placebo (n = 390). All patients received 4 cycles of carboplatin plus paclitaxel followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. Following surgery, adjuvant pembrolizumab was continued for 9 cycles or until disease recurrence or unacceptable toxicity. EFS and pCR were dual primary endpoints for the study.

"Triple-negative breast cancer is a very difficult disease. Until now, we've struggled to have targeted therapies. Most of the treatments include chemotherapy," said Schmid. "It is well established that if you give chemotherapy before surgery for early triple-negative breast cancer that those patients where the cancer disappears, what we call a pathological complete response, those patients have a long-term benefit."

The pCR rate was 64.8% with pembrolizumab plus standard neoadjuvant chemotherapy compared with 51.2% for chemotherapy alone, showing a statistically significant improvement with the PD-1 inhibitor (

 = .00055). In the PD-L1—positive group (CPS ≥1), the pCR rate was 68.9% compared with 54.9%, for pembrolizumab and placebo, respectively. This was equivalent to a 14.2 percentage point increase (CI, 5.3-23.1). In PD-L1–negative patients, the pCR rate was 45.3% with pembrolizumab versus 30.3% for placebo, a 18.3 percentage point increase (CI, -3.3 to 36.8).

After a median of 15.2 months of follow-up, an early benefit in event-free survival (EFS) had also emerged. For the early EFS analysis, 7.4% of events had occurred in the pembrolizumab arm compared with 11.8% in the placebo group. In the pembrolizumab group, the EFS rate was 91.3% compared with 85.3% with placebo; however, this benefit was not yet statistically significant (HR, 0.63; 95% CI, 0.43-0.93).

"There's already a difference between the two curves. We will have subsequent event-free survival analyses coming out soon,” said Schmid.

At least 1 treatment-related adverse event (AE) of any grade was experienced by patients in both arms during the presurgical phase. Grade 3 to 5 treatment-related AEs occurred at similar frequencies in the 2 groups, with 76.8% in the pembrolizumab arm compared with 72.2% in the placebo group. AEs led to discontinuation of any drug for 24.5% of patients in the pembrolizumab group compared with 13.1% for the placebo arm.

The most common treatment-related AEs for pembrolizumab and placebo, respectively, during the presurgical phase were nausea (62.7% vs 63.2%), alopecia (60.3% vs 56.6%), anemia (55.1% vs 55.3%), neutropenia (46.7% vs 47.0%), fatigue (41.1% vs 37.8%), diarrhea (29.4% vs 23.7%), ALT increase (25.5% vs 24.7%), vomiting (25.5% vs 21.9%), asthenia (24.5% vs 25.4%), constipation (23.7% vs 21.1%), neutrophil count decrease (23.7% vs 28.8%), rash (21.8% vs 15.2%), and peripheral neuropathy (19.7% vs 21.1%).

Following surgery, there were far fewer treatment-related AEs noted. Grade 3 to 5 treatment-related AEs were experienced by 5.7% of those receiving pembrolizumab and for 1.9% of those in the placebo group. The most common treatment-related AEs between the pembrolizumab and placebo groups, respectively, were arthralgia (7.9% vs 6.7%), rash (4.9% vs 2.2%), and pruritus (4.2% vs 2.2%).

"The side effects are relatively comparable between the two arms. We haven't really had any completely new safety signals, we do see more rash with pembrolizumab but otherwise there's very little difference between the two groups on average," Schmid said. "Most of the side effects are side effects of chemotherapy. In the phase after surgery, where patients receive placebo alone or pembrolizumab alone, you can see that the rate of toxicity is very low and there's little difference between the two groups."

The FDA has granted a breakthrough therapy designation to pembrolizumab plus neoadjuvant chemotherapy, based on earlier findings for the combination in patients with high-risk, early-stage TNBC from the KEYNOTE-173 and the I-SPY 2 trials. Submission of a supplemental new drug application for pembrolizumab in TNBC is highly likely, based on the KEYNOTE-522 data.

Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage high-risk triple-negative breast cancer. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. Abstract LBA8_PR.

The addition of the immunotherapy pembrolizumab (Keytruda) to standard presurgical chemotherapy improved pathological complete response (pCR) rates for patients with triple-negative breast cancer (TNBC). 
 

Pembrolizumab Before/After Surgery Improves pCR, EFS for Early TNBC

A pharmacist and nurse led non-medical prescribing clinic that was focused on side effect management and survivorship support for patients with melanoma helped to improve common every-day pressure seen in a medical day unit (MDU) and improved overall patient experience, according to findings from two posters presented at the ESMO Congress 2019.

"When creating non-medical prescribing clinics, due to the skill mix and the multidisciplinary approach to care, pharmacists and nurses should work together," according to the authors of the study. "The clinic has helped improve MDU pressures, especially by removing patients requiring greater holistic support. The clinic in turn has sought out survivorship issues important to melanoma patients."

The treatment of cancer has evolved rapidly in the past 10 years, with the introduction of immunotherapy. One of the primary areas where immunotherapy had an impact was for the treatment of melanoma, where the first immune checkpoint inhibitor ipilimumab (Yervoy) was approved nearly a decade ago. Accommodation of these new therapies, and the vastly improved outcomes that come with them, has let to added pressures in the MDU related to patient education and discussions, according authors of the poster.

Overall, the study enrolled 36 patients (age range, 24-89 years). Of these, 33 participated in further involvement in the clinic. The primary reason for inclusion in the clinic was to discuss immunotherapy, followed by steroid weaning and chemotherapy. Of those included, 4 required a physician's input: 2 for inpatient admission due to immunotherapy toxicity, 1 for a biopsy of a new skin nodule, and 1 for new scan results.

Within the pharmacist and nurse led clinic, patients received initial survivorship support consultation that ranged from 15 to 45 minutes. The common education needs that emerged during these discussions were focused on the physical activity, anxiety on stopping immunotherapy, sun awareness, financial burden, and advice on complementary therapies.

Next steps from the clinic included referrals to other experts, including fitness instructors, psychological support, lymphedema education, tissue viability nurse, ophthalmologist, dermatologist, and surgeon. Additionally, within 3 months of stopping treatment, the clinic also initiated a discussion with patients on stopping care geared toward alleviating anxiety. This discussion occurred in 18 of the 33 patients.

Patient experience surveys consisting of 10 questions using the Likert scale were given to 10 participants. Five participants returned the survey, with 2 not responding and 3 passing away. Of those who did response, all felt comfortable being included in the clinic. Patients noted that they felt heard and that they had the opportunity to ask questions.

"I very much felt that I was a participant in the direction of my care," the poster at ESMO quoted one of the patients as saying. "Sharing responsibility and a sense of purpose helped me to foster a positive attitude in dealing with my disease."

Overall, all patients included in the clinic felt involved in the decision related to their care and felt empowered in the management of their disease. All patients said they would recommend this service to their friends or family, should the need arise.

"We are aware of the small patient numbers and another patient satisfaction survey is planned," the authors wrote. "However, this new model of care showcases that patients can be referred to a pharmacist/nurse led non-medical prescribing clinic."

The study was conducted at the Royal Marsden NHS Foundation Trust in London. Based on the findings, the authors noted that a new outpatient clinic has been creating, using the model developed for the study. Given the benefits, the authors recommended that similar units be considered in other hospitals.

Chauhan D, Larkin J, Turajlic S, Hughes P. Pharmacist and nurse led melanoma immunotherapy clinic. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. CN58.

Chauhan D, Larkin J, Turajlic S, Hughes P. Pharmacist and Nurse Led Melanoma Immunotherapy Clinic: Patient Experience Survey. Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. CN70.

A pharmacist and nurse led non-medical prescribing clinic that was focused on side effect management and survivorship support for patients with melanoma helped to improve common every-day pressure seen in a medical day unit and improved overall patient experience.