Jola Mehmeti is a 2018 PharmD graduate from the UConn School of Pharmacy. She is a PGY1 Clinical Research Pharmacy Resident at Michigan Medicine. Connect with her on LinkedIn or send a message to contact@jolamehmeti.com.

Jola Mehmeti, PharmD, MBA

First-in-class drug palbociclib (Ibrance, Pfizer) works by inhibiting cyclin-dependent kinases (CDK) 4 and 6 to inhibit downstream signaling pathways.

This, coupled with G1 phase cell cycle arrest, prevents progression to the S phase responsible for DNA replication and diminishes cellular proliferation.

The oral capsule is approved for treatment of HR-positive and HER2-negative advanced or metastatic breast cancer in 2 settings: in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in combination with fulvestrant in women with disease progression following endocrine therapy.

The above indications were based on the PALOMA clinical trials.

PALOMA-1 was a 1:1, randomized, open-label, Phase 2 trial that compared palbociclib + letrozole (n=84) to letrozole alone (n=81). The primary endpoint was progression-free survival. Median progression-free survival in the combination group was 20.2 months, nearly double the median progression-free survival of the letrozole alone group at 10.2 months. The findings from this trial prompted the FDA to grant accelerated approval of this first CDK4/6 inhibitor.

PALOMA-2 was a 2:1, randomized, double-blind, Phase 3 trial with 444 patients randomized to palbociclib plus letrozole and 222 patients randomized to placebo plus letrozole. Median progression-free survival was 24.8 months in the palbociclib-letrozole group and 14.5 months in the placebo-letrozole group.

PALOMA-3 was a 2:1, multicenter, randomized, double-blind, Phase 3 trial that compared palbociclib and fulvestrant to placebo and fulvestrant. Median progression-free survival was 9.5 months in the palbociclib-fulvestrant group and 4.6 months in the placebo-fulvestrant group.

All of the above trials used a 125-mg dose of palbociclib given once daily for 3 weeks, which was followed by an off week.

The most frequently reported adverse reaction in PALOMA-2 and PALOMA-3 was neutropenia, with 80% or higher occurrence of all grades of neutropenia in each trial. 2.5% of patients in PALOMA-2 and 0.9% of patients in PALOMA-3 experienced febrile neutropenia (1.8% across both studies). Other adverse reactions of all grades with an incidence of 10% or greater included alopecia, anemia, diarrhea, fatigue, leukopenia, nausea, rash, stomatitis, thrombocytopenia, and vomiting.

Palbociclib is administered as 3 weeks (21 days) on 1 week (7 days) off therapy. These 4 weeks constitute 1 cycle. The drug is available in 75-, 100-, and 125-mg oral capsules. They must be swallowed whole and taken with food to minimize variability in absorption.  

Moderate and strong CYP3A inducers can decrease palbociclib exposure by as much as 85%. If unable to avoid strong inhibitors, reduce the palbociclib dose. Because of these drug interactions, it is important that patients alert providers if they are starting or stopping any medications or herbal products.

Because of the above-mentioned myelosuppression, providers must obtain a baseline complete blood count (CBC) prior to initiating palbociclib therapy. Monitor the CBC again on Day 15 of the first 2 cycles and as clinically indicated. No dose adjustment or holding of therapy is required, unless the patient develops Grade 3 or 4 toxicities, irrespective of whether these toxicities are hematologic or non-hematologic. When resuming therapy after toxicity, palbociclib should be re-initiated at the next available lower dose. For example, if the patient was previously taking 125 mg daily, they should be re-started on the 100-mg capsule.

As a result of the CYP3A activity, pharmacists should counsel patients to avoid grapefruit products. Patients should be instructed on how to monitor their body temperature at home and the gravity of presenting for emergency care if their temperature reaches 100.4 F or greater. Additionally, patients should be educated on the importance of not becoming pregnant while taking palbociclib and to use reliable contraception for at least 2 weeks after the end of treatment. In case of a missed dose, patients should not double up and should take their next dose as scheduled.

1. De Groot AF, Kuijpers CJ, Kroep JR. CDK4/6 inhibition in early and metastatic breast cancer: A review. 

2017;60:130-138. doi: 10.1016/j.ctrv.2017.09.003. 

2. Ibrance [prescribing information]. New York, NY: Pfizer, Inc; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf. Accessed July 12, 2018.

3. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. 

. 2015;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. 

4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. 

5. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. 

. 2016;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. 

Articles

Approvals and indications of this drug were based on 3 main clinical trials.

A Quick Overview of CDK4/6 Inhibitor Palbociclib

Whether you’re a 2018 PharmD graduate or a currently practicing pharmacist looking to get licensed in a different state, knowing where to start studying for the Multistate Pharmacy Jurisprudence Examination (MPJE) can be a challenge.

Before you read anything else, read the MPJE competency statements, commonly referred to as the exam’s 'blueprint,' that are posted on the NABP Candidate Application Bulletin. This document is an excellent guide on what to study for the exam, as it will list topics that you may otherwise overlook. There are 3 competency areas: pharmacy practice; licensure, registration, certification, and operational requirements; and general regulatory processes.

In addition to the bulletin, check the websites of your state’s Board of Pharmacy (BoP), pharmacy associations, and its rules and regulations. They may have some guidance or suggested study materials. If you can, reach out to pharmacy programs and attend review sessions if any are offered.

Personally, I purchased 1 federal resource, 1 state resource, and a state question bank. My federal resource was the 9th edition of 

 by Reiss and Hall. This book supplemented my studying as it familiarized me with the main federal acts that are relevant to pharmacy practice (e.g., Controlled Substances Act). My state resource was a book sold by the pharmacy association in my residency program’s state, recommended to the incoming class by current residents.

The interpretation of this advice should not be to purchase every text available or the exact resources that I used. The important thing is that you at least cover major federal acts (including a thorough understanding of the Controlled Substances Act of 1970), cover your state laws, and have a repetition method of some sort. For me, this repetition came in the form of the question bank at the end of the federal pharmacy book, and the separate question bank that I purchased to review the state laws. For others, this may have been recent and reliable Quizlet sets relevant to their specific MPJE. 

This is a good question to ask yourself as you study. The point of this test is to make sure that you can practice pharmacy according to federal regulations and the laws of the state in which you wish to practice, with a portion of the focus being on the community practice setting. This includes concentrations limits of substances, which drug schedules they belong to, and what type of storage is permitted for stock bottles, files, and other records, according to their drug schedules. Additionally, it’s important for pharmacists to know how to address patient requests for over-the-counter Schedule V substances, and how this information is logged. 

Careful reading and attention are required as you read the rules and regulations. One example of an easily missed distinction is the one between 'personal charge' and 'supervision.' Another is the distinction between 'delegation' and 'designation.' Paying attention to these words as you are reading will prevent mistakes on the exam.   

Do I get a calculator?                                                                      

According to the MPJE bulletin, a calculator is not necessary, and will not be provided by the Pearson testing center if requested.

This can be frustrating to hear when looking for MPJE advice, but it rings true: the most important thing that you can do is to study. When repeating some of the readings, and practice questions, I noticed nuances in rules and regulations, as well as important differences in 'must' or 'should' situations. In the end, using common sense, and imagining yourself in the situation that the question presents can be very helpful, and point you to the correct answer. For example, does it make sense that a pharmacist 'must' do what the answer option is suggestion?

Just as importantly, make sure that you have the appropriate identification documents prior to leaving for the testing center. The acceptable types of ID are available in the MPJE bulletin.

Studying for the MPJE can be daunting. Numerous online threads offer advice on where to start

Answers to Common Questions About Studying for the MPJE

As pharmacists experience expanding roles on the healthcare team, attention to hypersensitivities remains a key responsibility when directing drug therapy. While the active pharmaceutical ingredient is to blame for a lot of the time, patients can also experience reactions and intolerances to excipients present in drug formulations. Providers are typically concerned with drug allergies alone, but sometimes food allergies can also have a role in drug selection. A discussion with the healthcare team, alongside professional judgment, will determine the best course of action for each patient.

Drugs of interest: Heparin; the low molecular weight heparins dalteparin and enoxaparin

These drugs are contraindicated in hypersensitivity to pork products because they are derived from heparin in porcine intestinal mucosa.

Though peanut and soy allergies are different, the allergens that trigger hypersensitivity reactions are in the same Leguminosae and can be subject to IgE cross-reactivity binding. However, this does not always indicate clinical cross-reactions.

Drugs of interest: Dimercaprol injection, progesterone capsules, valproic acid capsules

Drugs of interest: Clevidipine, fat emulsions, propofol

Drug of interest: Atrovent and Combivent metered dose inhalers

Drugs of interest: Amphotericin B liposome, doxorubicin liposome

Drugs of interest: Yellow fever vaccine, influenza vaccine

The measles, mumps, and rubella (MMR), and rabies vaccines are incubated in chick embryo fibroblast cultures, and thus contain virtually no egg protein.

The yellow fever, and influenza vaccines may contain higher amounts of egg protein. Twenty-seven studies support the CDC’s Advisory Committee on Immunization Practices (ACIP) recommendation that persons who report having had even severe reactions to egg can still receive influenza vaccine formulations that are appropriate for their age and health status. However, if a severe reaction occurs in response to administration of an influenza

 then they should not receive further doses of any influenza vaccine formulations.

Allergen: Egg lecithin, egg phospholipids

Drugs of interest: Emulsions that include fat emulsions, clevidipine, and propofol; tablets of ibuprofen, diphenhydramine, and rosiglitazone

Drugs of interst: Protamine injection, NPH insulin

Protamine is generally used for two purposes: to reverse the effects of heparin, and to increase the duration of action for insulin. Though protamine is obtained from salmon testes, it appears unrelated to actual fish allergy. 

Dronabinol capsules; estradiol, progesterone, nandrolone, and testosterone injections; haloperidol decanoate and fluphenazine decanoate injections

Three other very common excipients for pharmacists to be aware of are gelatin, 

, and lactose. Though lactose in small amounts may be easily tolerated by many lactose intolerant patients, it stills behooves any pharmacist to ensure that patients are receiving safe therapy that is not negatively impacting their quality of life.

The above lists are not all comprehensive. For example, protamine is a specific allergen, and does not necessarily encompass all fish allergies. Clinicians should ensure they’re consulting the appropriate clinical resources as well as the package inserts of individual drugs.

Lovenox [package insert]. Bridgewater, NJ: Sanofi-aventis U.S. LLC; 2017.

Cabanillas B, Jappe U, Novak N. Allergy to Peanut, Soybean, and Other Legumes: Recent Advances in Allergen Characterization, Stability to Processing and IgE Cross-Reactivity. 

 2018 Jan;62(1). doi: 10.1002/mnfr.201700446. Epub 2017 Nov 3.

Al-Ahmed N. Aldoesifi D, Vadas P. Peanut allergy: an overview. 

. 2008 Dec 15;4(4):139-43. doi: 10.1186/1710-1492-4-4-139. Epub 2008 Dec 15.

Kelso JM. Potential food allergens in medications. 

. 2014 Jun;133(6):1509-18; quiz 1519-20. doi: 10.1016/j.jaci.2014.03.011.

Flu Vaccine and People with Egg Allergies. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/protect/vaccine/egg-allergies.htm. Accessed 26 Jun 2018.

Food allergens can be present in a variety of medications, but they don't always merit a switch in therapy.