Pamela Sardo, PharmD, BS

The National Institutes of Health report that pain is the most common reason for seeking medical care.

 Data from 2012 estimated that 126.1 million adults in the United States suffer from pain,

 which can be nociceptive (from tissue injury), neuropathic (from nerve injury), or nociplastic (from a sensitized nervous system). There is also overlap in the different types of pain.

Multimodal therapy to treat pain isdefined by the International Association for the Study of Pain as the concurrent use of separate therapeutic agents with different mechanisms of action. This combination of agents is aimed to address different pain mechanisms.

 Co-crystal formulations can be considered a multimodal therapy.

The FDA defines co-crystals as crystalline materials composed of 2 or more different molecules in the same lattice.

 Combining tramadol and celecoxib into a co-crystal of celecoxib-tramadol (CTC) provides peripherally and centrally mediated analgesia.

CTC (Seglentis; Kowa Pharmaceuticals America, Inc) is an FDA-approved Schedule IV controlled substance. It is indicated for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

The mode of action of tramadol is not completely understood. It is believed to be due to binding to mu-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via cyclooxygenase-2 (COX-2).

CTC contains celecoxib 56 mg and tramadol hydrochloride 44 mg. Initiate treatment with 2 tablets every 12 hours as needed for pain relief. When starting treatment with this celecoxib-tramadol tablet formulation, consider the pain severity, patient response, prior analgesic treatment, and risk factors for addiction, abuse, and misuse.

The full prescribing information recommends to discuss availability of naloxone with the patient. CTC should be used for the shortest duration aligned with patient treatment goals.

The efficacy and safety of CTC was evaluated in a randomized, double-blind, parallel group study comparing CTC to tramadol, celecoxib, and placebo for acute pain after bunionectomy with osteotomy (bone cutting procedure). The study enrolled patients ≥18 years of age with acute postoperative pain (rated >5 and <9 on a 0-10 Numeric Pain Rating Scale [NPRS]). Patients had a mean baseline pain intensity of 6.7 on the NPRS.

The primary efficacy endpoint was time-weighted summed pain intensity difference over 48 hours (SPID48). Researchers reported patients in the CTC group had statistically significantly better mean SPID48 scores than any of the other groups after bunionectomy.

Negative differences in the score corresponded to an amelioration of pain. The total scale ranged from -480 (best) to +480 (worst). A higher negative value of SPID indicated greater pain relief (Table 1).

The most common AEs with incidence greater than 5% in adults taking CTC are nausea, vomiting, dizziness, headache, and somnolence. There is a boxed warning in the FDA-approved label that describes the risks of addiction, abuse, and misuse. The celecoxib-tramadol tablet is available under the Opioid Analgesic REMS (Risk Evaluation and Mitigation Strategy) program.

The boxed warning also includes cardiovascular thrombotic events and risk factors for life-threatening respiratory depression in children. It also describes gastrointestinal bleeding, ulceration, and perforation.

Cytochrome P450 interactions and risk with concomitant CNS depressants are also explained. Due to the large volume of information in the boxed warning, pharmacists should refer to the full prescribing information for comprehensive details.

CTC is contraindicated in ages <12 years of age and during postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. It should not be used in CABG surgery or in individuals with acute or severe bronchial asthma.

CTC is contraindicated with gastrointestinal obstruction and with monoamine oxidase inhibitors (MAOIs) within the past 14 days. It should not be used in individuals with urticaria or other allergic reactions after taking aspirin or other nonsteroidal anti-inflammatory agents. Additional warnings include serotonin syndrome, risk of seizure, risk of suicide, adrenal insufficiency, renal and hepatotoxicity.

There is a risk of fetal harm with CTC in pregnant women. Breastfeeding is not recommended. The safety and efficacy of CTC in pediatrics has not been established. Elderly individuals taking nonsteroidal anti-inflammatory agents are determined to be at greater risk for serious AEs so individuals taking CTC should be monitored.

In summary, despite the availability of multiple pharmacotherapies, many individuals

continue to suffer in pain. Because pain can involve multiple mechanisms, combining products with different mechanisms of action, or in the form of a co-crystal formulation, may be a therapeutic option.

Pain. National Institutes for Health. National Center for Complementary and Integrative Health. Updated June 3, 2022. Accessed June 3, 2022. 

Nahin R. Estimates of pain prevalence and severity in adults: United States, 2012. 

. 2015;16(8):769-780. doi:10.1016/j.jpain.2015.05.002

Cohen S., Vase L., Hooten W. Chronic pain: an update on burden, best practices and new advances. 

2021;397(10289):2082-2097. doi: 10.1016/S0140-6736(21)00393-7

Almansa C, Frampton C, Vela J, Whitelock S, Plata-Salamán C. Co-crystals as a new approach to multimodal analgesia and the treatment of pain. 

Raffa R, Pergolizzi J Jr., Tallarida R. Analgesic combinations. 

.2010;11(8):701–709. doi:10.1016/j.jpain.2009.12.010

Regulatory classification of pharmaceutical co-crystals guidance for the industry. US Food and Drug Administration. February 2018. Accessed 6/3/2022. 

Seglentis. Prescribing information. Kowa Pharmaceuticals America, Inc.; 2021. Accessed June 1, 2022. 

https://www.kowapharma.com/documents/SEGLENTIS_Prescribing_Information.pdf

Seglentis. Efficacy demonstrated in the phase 3 clinical trial. Kowa Pharmaceuticals America, Inc. May 2022. Accessed June 1, 2022. 

https://www.seglentis.com/clinical-data/efficacy

Articles

Combining tramadol and celecoxib into a co-crystal of celecoxib-tramadol provides peripherally and centrally mediated analgesia.

Clinical Overview: Exploring the Impact of Co-Crystal Celecoxib and Tramadol Combination

The American Cancer Society has published good news that more than 3.1 million men in the United States who have been previously diagnosed with prostate cancer are alive.

 The FDA has approved multiple agents for prostate cancer; however, unmet medical need remains.

Approximately 1 in 8 men will be diagnosed with prostate cancer during their lifetime. Individuals 65 years of age or older and non-Hispanic Black men are more likely to be diagnosed with prostate cancer.

 In addition, castration-resistant prostate cancer (CRPC) may develop in 10% to 20% of patients within 5 years of diagnosis.

 (Verzenio; Eli Lilly and Company) is an FDA-approved kinase inhibitor being investigated for new indications in individuals with hormone-sensitive prostate cancer or CRPC.

 The cyclin-dependent kinases 4 and 6 (CDK4/6 proteins) control how quickly cells grow and divide.

These kinases are activated upon binding to D-cyclins.

 CDK4/6 inhibitors selectively target CDK4 and CDK6 and lead to the suppression of phosphorylation and subsequent inhibition of G1-S cell cycle progression.

The starting and maintenance dose for individuals in clinical trials with hormone-sensitive and CRPC taking abemaciclib has not yet been reported. Abemaciclib is currently available in 50 mg, 100 mg, 150 mg, and 200 mg tablets for other indications and can be taken orally with or without food.

Prostate cancer studies will determine whether dosing interruption and/or dose reductions may be required, among other requirements.

Two late-stage phase 3 abemaciclib clinical trials for individuals with prostate cancer are listed on ClinicalTrials.gov. In the CYCLONE 2 study, researchers are investigating abiraterone acetate for its antiandrogenic effect.

 The primary outcome being evaluated is radiographic progression-free survival (rPFS) from baseline to radiographic disease progression or death from any cause within an estimated timeframe of up to 21 months.

An additional trial, titled CYCLONE 3, is investigating rPFS from randomization to radiographic progression or death from any cause within approximately 48 months.

Researchers have not reported specific AE details for abemaciclib in individuals with prostate cancer. For other indications, the most common abemaciclib AEs (incidence ≥20%) are diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

Drug metabolism and the cytochrome P450 enzyme system are important considerations in oncology. The current FDA-approved prescribing information for other indications warns that ketoconazole, a strong CYP3A inhibitor, can increase abemaciclib’s area under the concentration curve (AUC) up to 16-fold.

Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of abemaciclib decreased unbound AUC

 of abemaciclib plus its active metabolites by approximately 70% in healthy subjects. 

Researchers have not studied abemaciclib’s effects of on fertility in humans. Abemaciclib may impair fertility in males.

In animals dosed with abemaciclib, cardiovascular and skeletal malformations have been identified. The abemaciclib monarchE breast cancer study required males to use an acceptable method of birth control and not donate sperm during the study and for at least 12 weeks following the last dose of abemaciclib.

In summary, researchers investigating abemaciclib for prostate cancer are striving to broaden the armamentarium for patients. Pipeline awareness enables pharmacists to be well positioned for health care team discussions.

Awareness of prostate cancer treatment advances, complex treatment regimens, and protocols contributes to enhancing the range of services provided and successful clinical decision-making. The pharmacist’s role as patient advocate and educator is critical as concerned oncology patients request discussion of therapeutic options for personized approach to care.

Pamela Sardo, PharmD, BS, is a licensed pharmacist and a freelance medical writer at Sardo Solutions

Key statistics for prostate cancer. American Cancer Society. Updated January 12, 2022. Accessed May 10, 2022. 

www.cancer.org/cancer/prostate-cancer/about/key-statistics.html

Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. 

 2017;71(4):630-42. doi: 10.1016/j.eururo.2016.08.002

Eight studies for abemaciclib and prostate cancer. ClinicalTrials.gov. Updated April 19, 2022. Accessed May 10,2022. 

https://clinicaltrials.gov/ct2/results?cond=Prostate+Cancer&term=abemaciclib&cntry=&state=&city=&dist=

Verzenio. Prescribing information. Eli Lilly and Company; 2022. Accessed May 4, 2022. 

https://uspl.lilly.com/verzenio/verzenio.html#pi

Wu C, Peng S, Pilie P, et al. PARP and CDK4/6 inhibitor combination therapy induces apoptosis and suppresses neuroendocrine differentiation in prostate cancer. 

 2021;20(9): 1680–1691. doi:10.1158/1535-7163.MCT-20-0848

Zytiga. Prescribing information. Janssen; 2021. Accessed May 10,2022. 

https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ZYTIGA-pi.pdf

A study of abiraterone acetate plus prednisone with or without abemaciclib(LY2835219) in participants with prostate cancer (CYCLONE 2). ClinicalTrials.gov. Updated April 19, 2022. Accessed May 6, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03706365?term=cyclone+2&cond=Prostate+Cancer&draw=2&rank=1

Abemaciclib CDK4 & 6 Inhibitor Flashcards. Eli Lilly and Company; 2022. Accessed May 10, 2022. 

https://www.lillyloxooncologypipeline.com/flashcards/cdk_flash_card_off_cycle_feb_2022.pdf

A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3). ClinicalTrials.gov. Updated April 26, 2022. Accessed May 6, 2022.

https://clinicaltrials.gov/ct2/show/NCT05288166?term=CYCLONE+3&cond=Prostate+Cancer&draw=2&rank=1

VERZENIO® (abemaciclib): Use in Pregnancy and Lactation and Effect on Fertility. Eli Lilly and Company; 2022. Accessed May 6, 2022.

https://www.lillymedical.eu/en-gb/answers/verzenios-abemaciclib-use-in-pregnancy-and-lactation-and-effect-on-fertility-91378

Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). 

Abemaciclib (Verzenio; Eli Lilly and Company) is an FDA-approved kinase inhibitor being investigated for new indications in individuals with hormone-sensitive prostate cancer and castration-resistant prostate cancer.