Sara L. Tolliday, PharmD, RPh

Larotrectinib (Vitrakvi) is a tyrosine kinase receptor (TRK) inhibitor indicated for the treatment of metastatic or unresectable neurotrophic receptor tyrosine kinase (NTRK) gene fusion-positive solid tumors in adults and children.

 NTRK gene fusion is an actionable oncogenic driver, a gene variation that promotes initiation and continuation of tumor growth.

Patients are eligible for treatment based on history of unsatisfactory prior treatment and presence of NTRK (1, 2, or 3) gene fusion in tumor samplings.

Larotrectinib is available as a 25 mg capsule, 100 mg capsule, and a 20 mg/ml oral solution. Adults and children with body surface area (BSA) ≥1m

 should take 100 mg twice daily until disease progression or adverse effect (AE) intolerability. Pediatric patients with BSA ≤1m

Larotrectinib is the first drug to receive accelerated FDA approval (November 26, 2018) for patients of all ages based on a common molecular marker, independent of tissue origin for targeted therapy.

The approval of larotrectinib was based on data from 3 trials, 2 of which were cohorts conducted in 2018 (N=55 in primary group and N=67 in secondary).

The total response rate was 81% (63% partial response, 17% complete response) over 24 different types of NTRK fusion-positive tumors. Most patients (75%) in the primary group stayed disease-free for 1 year after treatment.

) studies mentioned above found larotrectinib to be safe and tolerable, with only 1 of the 122 patients discontinuing treatment due to AEs.

 The most common AEs noted were fatigue, anemia, elevated liver enzymes, weight gain, and neutropenia. Only 8 (15%) of the 55 patients in the initial group had their doses reduced due to elevated liver enzymes.

Clinicians should monitor liver tests (ALT and AST) every 2 weeks during the first month of treatment then monthly thereafter. Patients with existing moderate to severe hepatotoxicity should begin therapy at half of the typical starting dose.

Patients should avoid strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice) while taking larotrectinib or a clinician must reduce the dose by 50% to prevent toxicity. CYP3A4 inducers (e.g., carbamazepine, St. John’s Wort) can reduce the efficacy of larotrectinib. Clinicians should increase the larotrectinib dose by 50% if these drugs cannot be avoided.

Larotrectinib can cause fetal harm and should not be taken during pregnancy. Females of reproductive age should use effective contraception during treatment and for 1 week after last dose. Clinicians should advise women not to breastfeed during therapy and for 1 week after last larotrectinib dose.

Larotrectinib is a highly tolerable and effective NTRK-gene fusion positive targeting agent that treats a vast variety of solid tumors among adults and children.

Sara L. Tolliday, PharmD, RPh, is a full-time clinical pharmacist in the Outpatient Pharmacy at Wentworth-Douglass Hospital in Dover, NH.

1. VITRAKVI (larotrectinib) – Official Healthcare Provider Site. Last updated May 2021. Accessed October 17, 2021. 

2. Drilon, A. TRK inhibitors in TRK fusion-positive cancers. 

. 2019;30(8):viii24-viii30. doi:10.1093/annonc/mdz282.

3. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. 

. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448.

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Articles

Larotrectinib was the first drug to receive accelerated FDA approval for patients of all ages based on a common molecular marker, independent of tissue origin for targeted therapy.

Larotrectinib Treats NTRK Gene Fusion-Positive Cancers Successfully With Low Rates of Adverse Effects

Olaparib (Lynparza) is an oral poly (ADP-ribose) polymerase (PARP) inhibitor. PARP enzymes are responsible for repairing single-strand DNA breaks.

 Enzyme inhibition results in double-strand DNA breaks normally repaired by homologous recombination.

However, BRCA-mutant cells are defective and this homologous recombination defect (HRD) causes double-strand DNA breaks to accumulate, resulting in cell death. Approximately 15%-21% of ovarian cancers hold BRCA mutations and half could be HRD-positive and, therefore, responsive to PARP inhibitors.

Olaparib is available in 100 mg and 150 mg tablets and is dosed as 300 mg twice daily, with or without food.

Treatment should be continued until disease progression, intolerability, or at the 2-year mark. Patients who experience complete response at 2 years should stop treatment unless the clinician can obtain benefit from continuous treatment.

Olaparib was the first PARP inhibitor to be developed (2005) and hence the most studied.

It was approved by the FDA on December 19, 2018, as monotherapy for the first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer.

The FDA extended the approval to first-line maintenance of HRD-positive advanced ovarian cancer in combination with bevacizumab on May 8, 2020.

 Olaparib is the only PARP inhibitor approved for first-line maintenance of germline BRCAm (gBRCAm) ovarian cancer.

 Olaparib can also be used for recurrent ovarian cancers after response to platinum-based chemotherapy.

Olaparib is also indicated for a certain type of BRCA gene, human epidermal growth factor receptor 2-negative breast cancer that has metastasized. These patients should have first received chemotherapy either before or after cancer spread.

In addition, olaparib can be used as first-line maintenance treatment of gBRCAm metastatic pancreatic cancer and homologous recombination repair gene-mutatedmetastatic castration-resistant prostate cancer.

Adverse Effects (AE), Management, and Monitoring

Olaparib’s most common AEs are fatigue, nausea, vomiting, and anemia.

 A 2018 study found anemia as the most common serious AE, occurring in 7% of patients in the olaparib group and zero patients in the placebo group. No AEs during or up to 30 days after this trial resulted in death.

Clinicians should monitor patient fatigue using a 0-10 scale, with 10 being the most severe.

Nonpharmacologic interventions include energy conversation methods such as prioritizing tasks, avoiding multitasking, and timing activities when energy is highest. Other interventions include exercise, massage therapy, and cognitive behavioral therapy.

Occasional breaks in olaparib therapy can help fatigue return to baseline.1 The olaparib dose can be reduced to 200 mg twice daily in more severe cases. Methylphenidate can improve fatigue; however, clinicians should first rule out depression or sleep disturbances before initiation.

Gastrointestinal upset may subside within 1 to 2 months of treatment initation.

Antiemetics may help relieve nausea and vomiting.

Olaparib requires weekly complete blood counts with differential during the first month of treatment and once monthly thereafter. Clinicians should also obtain a complete metabolic panel at baseline and then periodically.

Olaparib can cause fetal harm, therefore, females should use effective contraception during treatment and for 6 months after the last dose.

Males should not donate sperm during treatment and should use effective contraception until 3 months after the last dose. Clinicians should advise lactating women not to breastfeed during treatment and for 1 month after last dose due to lack of studies and the possibility of serious AEs.

, is a full-time clinical pharmacist in the Outpatient Pharmacy at Wentworth-Douglass Hospital in Dover, NH.

1. Moore KN, Monk BJ. Patient Counseling and Management of Symptoms During Olaparib Therapy for Recurrent Ovarian Cancer. 

. 2016;21(8):954-963. doi:10.1634/theoncologist. 2015-0268.

2. AstraZeneca. Lynparza (olaparib) HCP site – Physician info and Resources. Last updated April 2021. Accessed October 13, 2021. 

3. Taylor KN, Scott M. PARP inhibitors: Choosing what to use in epithelial ovarian cancer. 

4. Arora S, Balasubramaniam S, Zhang H, et al. FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer. 

. 2021;26(1):e164-e172. doi:10.1002/onco.13551

5. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. 

. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

6. Lynparza (olaparib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; March 2021.

Olaparib was the first PARP inhibitor to be developed and has been the most studied.

Olaparib: The First PARP Inhibitor With 7 Indications Across 4 Tumor Types

Regorafenib (Stivarga) is an oral multikinase inhibitor approved for metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-oxaliplatin and irinotecan-based chemotherapy, second line use in metastatic or unresectable gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.

In 2012, CRC was one of the most common diagnosed cancers worldwide, estimated at 1.36 million new cases and 694,000 fatalities.

 Treatment, management, and overall survival (OS) of patients with mCRC has improved in recent years.

Regorafenib is available in 40 mg tablets, dosed as 160 mg (four, 40 mg tablets) once daily for 3 weeks, followed by a 1-week treatment break.

Patients should take regorafenib whole with water after a low-fat meal (<600 calories and <30% fat) at the same time daily.

They should avoid grapefruit juice and St. John’s Wort, as they may increase or decrease blood levels of regorafenib, respectively. Regorafenib does not require renal dosing adjustments.

The FDA approved regorafenib for chemorefractory mCRC and GIST on September 27, 2012.

 The CORRECT trial randomized 760 patients to receive regorafenib or placebo and median OS was 6.4 months in the regorafenib group versus 5 months in the placebo group.

 The GRID trial employed regorafenib in patients with progressive metastatic or unresectable GIST despite standard treatment.

 Results showed considerable improvement in progression-free survival in the regorafenib group versus placebo.

The FDA expanded its approval for HCC in patients previously treated with sorafenib on April 27, 2017—the first drug approved for liver cancer in almost 10 years.

 The RESORCE trial found regorafenib improved OS, at 10.6 months in regorafenib group versus 7.8 months in the placebo group.

Clinicians should monitor liver function before and during therapy as severe hepatic injury occurred across all regorafenib clinical trials.

 Adjustments or discontinuation may be necessary in patients with repeatedly elevated liver function tests. Common notable AEs include hypertension, hand-foot skin reactions, infection, and diarrhea. Prescribers can reduce doses in 40 mg increments if these AEs become intolerable. The lowest effective dose is 80 mg daily.

Regorafenib can cause fetal harm and should not be taken during pregnancy. Females of childbearing age and their male partners should use effective contraception during and for 2 months after treatment.

Breastfeeding is not recommended while taking regorafenib and should be avoided for 2 weeks after the last dose.

is a full-time pharmacist at Wentworth-Douglass Hospital, Outpatient Pharmacy, Dover, NH.

1. Bayer Healthcare Pharmaceuticals Inc. STIVARGA® (regorafenib): Official Prescriber Site. Last updated June 2021. Accessed October 4, 2021. 

2. Dhillon S. Regorafenib: A Review in Metastatic Colorectal Cancer. 

. 2018;78(11):1133-1144. doi:10.1007/s40265-018-0938-y.

3. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 

. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X.

4. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 

. 2013;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1.

5. U.S. Food and Drug Administration (FDA). FDA expands approved use of Stivarga to treat liver cancer. April 27, 2017. Accessed October 6, 2021. 

www.fda.gov/news-events/press-announcements/fda-expands-approved-use-stivarga-treat-liver-cancer

6. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017 Jan 7;389(10064):36]. 

. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9.

The FDA initially approved regorafenib for chemorefractory metastatic colorectal cancer and unresectable gastrointestinal stromal tumor in 2012.

Oncology Overview: Regorafenib For Metastatic Colorectal Cancer, Gastrointestinal Stromal Tumor, Hepatocellular Carcinoma

Having a baby should be a happy time, so why are many mothers sad after delivery? The weeks following childbirth, often called the "fourth trimester" can be confusing, exhausting, and difficult.

 If this condition lasts more than 4 weeks, it may indicate postpartum depression.

 As childbearing's most common, debilitating complication, postpartum depression is often undertreated.

 Many mothers do not receive a diagnosis until 6 to 12 months after delivery but may experience symptoms earlier.

 Table 1 differentiates baby blues from postpartum depression.

Postpartum depression generally starts after delivery (50%) or within 4 months (40%).

 Its most common risk factor is a previous history of depression. The results of a prospective study of pregnant women (N = 1000) showed that the risk more than doubled in those with a history of depression.

 The results of another prospective study (N = 200) showed that the risk of postpartum depression was 5-fold greater in women depressed during pregnancy.

 Genetics and social factors, such as a history of abuse, lack of social support, or marital difficulties, also increased the risk of postpartum depression.

Symptoms of postpartum depression mimic those of nonperinatal depression and include agitation, fatigue, feelings of hopelessness, hypersomnia or insomnia, an inability to concentrate, lack of interest or pleasure in activities, significant weight change, and suicidal ideation.

Other symptoms are associated with the baby, such as anxiety, exhaustion, an obsession with the baby's well-being, and worries about causing harm.

Patient-specific treatment approaches to postpartum depression vary depending on access to care and disease severity. Table 2 indicates a combination of interventions that are sometimes necessary.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy when psychological interventions alone are inaccessible or ineffective.

 SSRIs are considered safe while breastfeeding, as less than 10% of the maternal dose passes into breast milk.

 Sertraline is preferred in new-onset postpartum depression. Citalopram and fluoxetine are also first-line choices. Mirtazapine or selective norepinephrine reuptake inhibitors can also be used with minimal passage into breast milk.

Bupropion is not preferred because of case reports of infant seizures. Monoamine oxidase inhibitors are rarely given because of their poor adverse effect profiles, and tricyclic agents should be avoided during lactation as they may pass into breast milk. Women should continue taking antidepressants for 6 months to 1 year or longer in patients who experience recurrent episodes, and these medications should be tapered over a period of 4 weeks to reduce the risk of withdrawal symptoms.

Adjunct drugs, such as antipsychotics or benzodiazepines, may help when patients are unresponsive to a single agent.

 Prescribers should consider lactation safety with all drugs before initiation.

The FDA approved brexanolone (Zulresso), a GABAA modulator, in March 2019 for the treatment of postpartum depression.

 Administered in a hospital over 60 hours as a continuous intravenous drip, its benefits are a long duration (1 month) and speedy response. Brexanolone crosses into breast milk at levels less than 10 ng/mL and has an oral bioavailability of less than 5%, so infant exposure and the risk of adverse effects are low.

Brexanolone's drawbacks include the cost ($35,000) and the required hospital stay.

 Brexanolone also has Risk Evaluation and Mitigation Strategies to decrease the risk of serious harm from excessive sedation and sudden loss of consciousness during infusion.

Patients may be apprehensive about antidepressants, and pharmacists can ease their nerves with counseling and empathy. Nausea is common while beginning treatment but can be mitigated by starting at a low dose and slowly increasing it. Pharmacists should stress that patients may not respond fully for up to 4 weeks.

 Not only is sleep vital for functioning with a new baby, but it can also positively affect time to depression demission and treatment response.

 Patients often stop taking antidepressants without telling their prescribers. Pharmacists should advise patients that tapering over at least 4 weeks prevents withdrawal symptoms and rebound phenomena.

Early recognition of postpartum depression is key, as patients may respond to treatment slowly. Pharmacists should counsel patients beginning antidepressants about adverse effects, consequences of abrupt discontinuation, typical response time, and postpartum depression relapse. Postpartum depression is not a symbol of failure, but a common childbirth complication.

is a clinical pharmacist at Wentworth-Douglass Hospital in Dover, New Hampshire.

1. Recovering from delivery (postpartum recovery). Familydoctor.org. Updated August 28, 2020. Accessed September 16, 2021. https://familydoctor.org/recovering-from-delivery

2. Stewart DE, Vigod S. Postpartum depression. 

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3. Stewart DE, Vigod SN. Postpartum depression: pathophysiology, treatment, and emerging therapeutics. 

. 2019;70:183-196. doi:10.1146/annurev-med-041217-011106

4. The Lancet Psychiatry. Seeing the whole picture of postpartum depression. 

. 2019;6(7):547. doi:10.1016/S2215-0366(19)30226-3

5. Langan R, Goodbred AJ. Identification and management of peripartum depression. 

6. Gaillard A, Le Strat Y, Mandelbrot L, Keïta H, Dubertret C. Predictors of postpartum depression: prospective study of 264 women followed during pregnancy and postpartum. 

 2014;215(2):341-346. doi:10.1016/j.psychres.2013.10.003

7. Banti S, Mauri M, Oppo A, et al. From the third month of pregnancy to 1 year postpartum. Prevalence, incidence, recurrence, and new onset of depression. Results from the perinatal depression-research & screening unit study. 

 2011;52(4):343-351. doi:10.1016/j.comppsych.2010.08.003

8. Kettunen P, Koistinen E, Hintikka J. Is postpartum depression a homogenous disorder: time of onset, severity, symptoms and hopelessness in relation to the course of depression. 

. 2014;14:402. doi:10.1186/s12884-014-0402-2

9. Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant withdrawal and rebound phenomena. 

. 2019;116(20):355-361. doi:10.3238/arztebl.2019.0355

10. Cristea IA, Naudet F. US Food and Drug Administration approval of esketamine and brexanolone. 

. 2019;6(12):975-977. doi:10.1016/S2215-0366(19)30292-5

11. Postpartum depression is treatable. Sage Therapeutics, Inc. Accessed September 19, 2021. https://www.zulresso.com/

12. Arnedt JT, Swanson LM, Dopp RR, et al. Effects of restricted time in bed on antidepressant treatment response: a randomized controlled trial. 

. 2016;77(10):e1218-e1225. doi:10.4088/JCP.15m09879

13. Swanson LM, Huntley ED, Bertram H, et al. Insomnia as a moderator of response to time in bed restriction for augmenting antidepressant treatment: a preliminary investigation. 

. 2018;16(4):315-324. doi:10.1080/15402002.2016.1210149

Common and debilitating, the mental health condition is often underdiagnosed and undertreated.

Moms Are Not OK: Understand, Recognize, and Treat Postpartum Depression

The human body’s largest organ—the skin—serves as a first line of defense, and has essential immunological and biochemical roles. Aquaporins (AQPs), a group of membrane channels responsible for transmission of water and other small uncharged solutes, are heavily involved in the skin’s physiology. They are vital for skin hydration and wound healing. AQP dysfunction has been linked to melanoma and other skin disorders.

 in May 2021 suggests AQPs as potential drug targets for skin cancer. Recent innovations in melanoma biology indicate expression of 8 of the 13 AQP isoforms in melanoma cells. This review discusses current knowledge of AQP envelopment in skin’s function and pathology. Many studies outlined focus on AQP1 and AQP3 as possible melanoma drug targets.

In a small study comprised of 78 melanoma patients, AQP1-expressing cutaneous melanoma cells were present in 52 subjects. Those at high risk had elevated AQP1 levels. Follow-up with these patients showed a reduced survival rate, correlating AQP1 over-expression with negative prognosis. These authors found the same inverse relationship with AQP1 expression and survival in patients with extracranial metastasis. This data suggests AQP1 is a likely prognostic indicator for human cutaneous melanoma.

Another study that focused on AQP1’s anti-angiogenic features showed melanoma-afflicted mice with 75% tumor volume reduction after 6 days when injected intratumorally with AQP1 siRNA. Subsequent injections revealed inhibition of tumor growth. The same authors treated a mouse’s melanoma with these injections for 10 days and results showed inhibition of lung nodule growth and twice the survival rate compared to control mice.

AQP-modulating agent discovery has proved challenging, but many powerful AQP3 permeating molecules have been identified. Auphen, a gold-based compound, showed AQP3 permeability inhibition, reducing spread by 50% in AQP3-expressing tumors.

Cuphen, a strong copper-based AQP3 inhibitor, tended to suppress cell growth with minimal toxicity when studied in mice with melanoma. These results indicate auphen and cuphen as possible treatments for melanoma and other solid tumors.

Present knowledge suggests AQPs as promising drug targets for melanoma and other skin ailments. Further research regarding the roles of AQPs in both the presence and absence of skin disease is crucial to understand how AQP modulators can be applied in clinical practice.

da Silva IV, Silva AG, Pimpão C, Soveral G. Skin aquaporins as druggable targets: Promoting health by addressing the disease [published online ahead of print, 2021 Jun 11]. 

. 2021;S0300-9084(21)00146-2. doi:10.1016/j.biochi.2021.05.019

AQP-modulating agent discovery has proved challenging, but many powerful AQP3 permeating molecules have been identified.

Druggable Targets for Melanoma: Skin Aquaporins

Skin cancer is diagnosed more each year than all cancers combined, making it the most common cancer in the United States. Ultraviolet (UV) radiation from the sun is responsible for 90% of diagnosed nonmelanoma skin cancer (NMSC). Skin cancer can be prevented by reducing sun exposure and has a 99% 5-year survival rate when detected early.

Pharmacists often provide counseling regarding photosensitivity, a common drug adverse effect and are well-versed in over-the-counter products that prevent and treat sunburn. Their position is ideal to educate the public on skin cancer prevention.

Journal of American Pharmacists Association

 outlines Skin Cancer Awareness Now! (SCAN!), a sun safety project led by community pharmacists and pharmacy students. This study proved community pharmacies are model settings for skin cancer prevention education in rural communities with insufficient access to health care services.

The study authors piloted SCAN! in the Appalachian region—a vast medically underserved area with high skin cancer mortality. This vulnerable population needs accessible melanoma prevention and screening.

SCAN! had 2 elements: training for pharmacists and pharmacy students, and a 5–10-minute face-to-face counseling session delivered by those who were trained. Trainers recruited potentially eligible participants or obtained consent from patients presenting to participating pharmacies for routine services.

Trainers started their counseling with the Environmental Protection Agency’s sun safety handout, underscoring the importance of protective clothing, sunscreen, hat, shade, and sunglasses. Trainers also discussed the American Academy of Dermatology’s ABCDE (asymmetry, border, color, diameter, evolving) skin cancer acronym, and challenges patients may face while seeking preventive care. Participants completed a short postintervention survey.

Survey results indicated strong acceptance of and willingness to follow counseling recommendations.

A study limitation was the small sample size (n=90). A larger scale study is warranted to emphasize the positive influence SCAN! can have in the community pharmacy setting.

Pharmacist intervention can positively impact skin cancer’s ever-growing morbidity and mortality by providing underserved populations with access to prevention and sun safety awareness.

 is a full-time pharmacist at Wentworth-Douglass Hospital, Outpatient Pharmacy, Dover, New Hampshire.

. The Skin Cancer Foundation. Accessed 6 Jul 2021. 

https://www.skincancer.org/skin-cancer-information/skin-cancer-facts/

Kelly KM, Dhumal T, Scott VG, et al. SCAN! A pharmacy-based, sun safety feasibility study

 (2003). 2021;61(1):e69-e79. doi: 10.1016/j.japh.2020.10.004.

A recent study proved community pharmacies are model settings for skin cancer prevention education in rural communities with insufficient access to health care services.