The recommended adult initial dosage of Megace ES (megestrol acetate) oral suspension is 625 mg/day (5 mL/day or one teaspoon daily). The equicaletn Megace dose it 800 mg and requires 20 ml. Megace ES 625 mg/5 mL and megestrol acetate oral suspension 800 mg/20 mL are bioequivalent in a fed state.
A bioavailability study directly comparing the rate and extent of absorption of Megace ES and megestrol acetate oral suspension revealed that the Cmax** level with the original formulation was 1,364 ng/mL in fed patients and 187 ng/mL in unfed patients. In contrast, the Cmax level with Megace ES was 1,517 ng/mL in fed patients and 1,041 ng/mL in unfed patients. Further, in unfed patients Megace ES achieved 5 times greater peak plasma levels than megestrol acetate oral suspension. Additionally, the study demonstrated that a lower volume of Megace ES achieved maximum blood concentration more rapidly than the currently available oral suspension products.

However, the two products were nto directly compared in regard to clinical effectiveness and it is not known if this pharmacokinetic advantages translate into any clinical advantage.

Jamie H. Von Roenn, MD; Donald Armstrong, MD; Donald P. Kotler, MD; David L. Cohn, MD; Nancy G. Klimas, MD; N. S. Tchekmedyian, MD; Lawrence Cone, MD; Patrick J. Brennan, MD; and Sigmund A. Weitzman, MD, Megestrol Acetate in Patients with AIDS-related Cachexia , Ann Intern Med. 15 September 1994;121(6):393-399

Michelle H. Oster, PhD, RD; Sheila R. Enders, BS; Steven J. Samuels, PhD; Lawrence A. Cone, MD; Thomas M. Hooton, MD; Henry P. Browder, PhD; and Neil M. Flynn, MD
Megestrol Acetate in Patients with AIDS and Cachexia Ann Intern Med. 15 September 1994;121(6):400-408

Food Effect Working Group of the Biopharmaceutics Coordinating Committee, Office of Pharmaceutical Science. Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Food and Drug Administration, Center for Drug Evaluation and Research Web site. http://www.fda.gov/cder/guidance/5194fnl.pdf. Published December 2002

MegaceES, Prescribing Information, 2013

Food and Drug Administration, Center for Drug Evaluation and Research. Electronic Orange Book: Approved Drug Products With Therapeutic Equivalence Evaluations. 28th ed. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research; 2008.

For Lay version see here

Marinol for cachexia

Thalidmide for cachexia

Because of its expense (greater than $100/dose), for many years it was only used for patients undergoing cancer chemotherapy or after surgical procedures. As the cost dropped (now under a $1 a dose), it is came to be used in many hospital and outpatient settings. A growing area of use is empiric use in nursing homes. The drug is so effective, that some physicians consider using it as needed less morbid that performing a workup to determine the etiology of nausea in these patients.

This strategy needs more data to be considered well supported. Zofran is not a completely innocuous drug.  The U.S. Food and Drug Administration (FDA) recently informed healthcare professionals and the public that preliminary results from a recently completed clinical study suggest that a 32 mg single intravenous dose of ondansetron (Zofran, ondansetron hydrochloride, and generics) may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as Torsades de Pointes. Consequenlty, GlaxoSmithKline (GSK) has announced changes to the Zofran drug label to remove the 32 mg single intravenous dose. While the 8 mg dose is presumably free of this complication, one remains uncomfortable about empiric use of Zofran in  any clinical situation and such a strategy needs to be validated with clinical trials.

Several other uses have been preliminarily explored. During the past decade ondansetron has been increasingly used in the United States for Nausea and Vomiting of Pregnancy (NVP), owing to the lack of a drug indicated by the FDA for this condition; some concern had been voiced about potential increased incidence of cleft palate in the offspring of mothers who took Zofran during pregnancy.  A 2006 double-blind, randomized controlled trial indicated that ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. Another, albeit small, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia. Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson’s disease. Hewlett and others performed an open label study that suggested that it can decrease symptoms of OCD. Zofran appears to decrease the craving for alcohol, especially in early-onset alcoholics. Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions. Ondansetron has been useful in irritable bowel syndrome with diarrhea (IBS-D). Two small, placebo-controlled trials showed that ondansetron was found to be as effective as pethidine (meperidine, Demerol) to decrease post-anethsia shivering, when given prior to anesthesia.

In early January of 2012, the Food and Drug Administration approved the first generic versions of Zofran (Ondansetron) Tablets, Orally Disintegrating Tablets and Oral Solution which are indicated to prevent nausea and vomiting associated with surgery, radiotherapy and cancer chemotehrapy. This si a part of the FDA initiative to reduce drug costs by expediting approvals of generics. The indication is narrower than that of brand Zofran, which also includes  postoperative nausea.

Several alternatives exist for opioid induced nausea(OINV). , although currently there are no drugs specifically approved for opioid induced nausea. They include the less expensive compazine and metocopropamide and others. A recent guidelines says that  the drug of choice for preventing OINV is droperidol.

Several alternatives exist, although currently there are no drugs specifically approved for opioid induced nausea(OINV). They include the less expensive compazine and metocopropamide and others. A recent guideline says that  the drug of choice for preventing OINV is droperidol.
Gómez-Arnau JI, Aguilar JL, Postoperative nausea and vomiting and opioid-induced nausea and vomiting: guidelines for prevention and treatment. Rev Esp Anestesiol Reanim. 2010 Oct;57(8):508-24.

Lohitnavy M, Chaijittiprasert K, Polnok S, Lohitnavy O, Taytiwat P. Bioequivalence study of ondansetron tablet in healthy Thai male volunteers. J Med Assoc Thai. 2002 Jul;85(7):808-13.

Frank Porreca, and Michael H. Ossipov, Nausea and Vomiting Side Effects with Opioid Analgesics during Treatment of Chronic Pain: Mechanisms, Implications, and Management Options PAIN MEDICINE Volume 10 • Number 4 • 2009

Salvucci AA, Squire B, Burdick M, et al. Ondansetron is safe and effective for prehospital treatment of nausea and vomiting by paramedics. Prehosp Emerg Care 15(1): 34-8, Jan 2011.

Chu LF, Liang DY, Li X, Sahbaie P, Dʼarcy N, Liao G, Peltz G, David Clark J (February 2009). “From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics”. Pharmacogenet. Genomics 19 (3): 193–205

Zofran, Prescribing Information, 2012

Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006). “Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study”. Schizophrenia Research 88 (1–3): 102–10. Zullino DF, Eap CB, Voirol P (2001). “Ondansetron for tardive dyskinesia”. Am J Psychiatry 158 (4): 657–8. .

Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD (2000). “Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia”. Am J Psychiatry 157 (2): 287–9.

Zoldan J, Friedberg G, Livneh M, Melamed E (1995). “Psychosis in advanced Parkinson’s disease: treatment with ondansetron, a 5-HT3 receptor antagonist”. Neurology 45 (7): 1305–8.

Hewlett WA, Schmid SP, Salomon RM (2003). “Pilot trial of ondansetron in the treatment of 8 patients with obsessive compulsive disorder”. J Clin Psychiatry 64 (9): 1025–30.

Corrêa Filho JM, Baltieri DA. A pilot study of full-dose ondansetron to treat heavy-drinking men withdrawing from alcohol in Brazil. Addict Behav. 2013 Apr;38(4):2044–2051

For Lay version see here

This trial raised more questions than it answers. It does not prove that Cymbalta is uniquely beneficial for oxaliplaitn induced neuropathy and toxicity was significant. It was a comparison against placebo, not another analgesic or anti-depressant. Clearly, comparative studies are needed before it can be considered standard of care.

 C. Teng, H. Teng, Y. Yang, C. Yen, T. Lin, J. Lin, W. Chen, C. Tzeng, W. Wang; Department of Medicine, National Yang-Ming University Hospital and Taipei Veterans General Hospital, Yilan, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, Taipei City Hospital Renai Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan  Use of duloxetine for oxaliplatin-induced neuropathic pain in patients with colorectal cancer: An open-label pilot study. Clin Oncol 29: 2011 (suppl; abstr e19644)

Ya-Hsu Yang, Jen-Kou Lin, Wei-Shone Chen, Tzu-Chen Lin, Shung-Haur Yang, Jeng-Kai Jiang, Shih-Ching Chang, Yuan-Tzu Lan, Chun-Chi Lin, Chueh-Chuan  Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study
Supportive Care in Cancer July 2012, Volume 20, Issue 7, pp 1491-1497 Ya-Hsu Yang, Jen-Kou Lin

Ellen M. Lavoie Smith, Herbert Pang, Constance Cirrincione, Stewart Barry Fleishman, Electra D. Paskett, Camilo E. Fadul, Chetaye Knox, Charles L. Shapiro, Paul Gilman, Cancer and Leukemia Group B; University of Michigan, Ann Arbor, MI; Duke University, Durham, NC; Alliance Statistical Center, Duke University, Durham, NC; Continuum Cancer Centers of New York, Beth Israel and St. Luke’s-Roosevelt, New York, NY; The Ohio State University Comprehensive Cancer Center, Columbus, OH; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Illinois Oncology Research Association, Peoria, IL; The Ohio State University, Columbus, OH; Main Line Hematology and Oncology Associates, Wynnewood, PA  CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN).  Citation:
J Clin Oncol 30, 2012 (suppl; abstr CRA9013)

For Lay version see here

Sancuso [package insert]. Bedminster, NJ: ProStrakan Inc.; 2008.

McEvoy GK, ed. AHFS: Drug Information. Bethesda, MD: American Society
of Health-System Pharmacists; 2008: 2996-2998.

nccn, 2012

Read the Lay version here.

I reviewed the literature and performed a literature search. I identified two prospective open-label studies of modafinil(Provigil). One study showed positive effects on fatigue that had persisted for an average of 2 years following breast cancer treatment. For these patients, fatigue severity and other measures of quality of life were significantly improved following 1 month of treatment with modafinil. Another recent study of 30 patients with malignant and benign brain tumors who were treated with surgery, radiotherapy, and/or chemotherapy found that modafinil was associated with significant improvements in fatigue scores. The most commonly reported adverse effects of modafinil treatment were headache, infection, nausea, nervousness, anxiety, and insomnia, all of which were generally mild. Randomized clinical trials of modafinil are under way to investigate its effect on cancer related fatigue in patients receiving chemotherapy and those who have completed chemotherapy or radiation therapy.

A phase III trial was presented at the 2008 meeting of the American Society of Clinical Oncology in Chicago, May 30-June 2. It included 642 patients with cancer-related fatigue who were undergoing chemotherapy for a variety of cancers. Patients were randomized to receive Provigil (n=320) or placebo (n=322) and were evaluated for fatigue, sleepiness, and depression at two different time points. Patients with severe baseline fatigue had significant improvement on Provigil compared with placebo (p=0.017). However, patients with mild to moderate fatigue did not show improvement. All patients in the study appeared to have less “sleepiness” than in the control group (p=0.002). Provigil had no effect on depression. The authors concluded that Provigil could be of benefit in treating severe cancer-related fatigue.

The subject was favorably discussed at ASCO educational meeting in 2010. A 2009 review by Cooper et al found 2 prospective open-label studies, one randomized double-blind, dose-controlled trial with an open-label extension, and one Phase 3 randomized, placebo-controlled, double-blind trial. It concluded that the studies were too disparate to be able to provide definitive recommendations; however, if traditional therapies have failed or are intolerable, modafinil can be considered a treatment option.

Similarly, the 2013 Cochrane guideline says: “There is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results from this review.” More recent studies question whether such is the case. For example,  in a study presented at ASCO on June 8, 2013, 208 patients with lung cancer were randomly assigned in a 1:1 fashion to modafinil or placebo in a recent study. Enrollees were given modafinil at a dose of 100 mg for 14 days, followed by 200 mg for 14 days. At 28 days, those assigned to the modafinil group (104 patients) demonstrated a change of 5.28 points in fatigue score compared to 5.11 in the placebo group (104 patients; Fig. 1). Adverse events, including headache, nausea/vomiting, and anxiety—symptoms commonly associated with modafinil—were equal between groups.

K. Fife, A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue: Dose response and patient satisfaction data. J Clin Oncol 31, 2013 (suppl; abstr 9503)

Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010; :CD006704.

Morrow GR, Jean-Pierre P, Roscoe JA, et al. A phase III randomized, placebo-controlled, double-blind trial of a eugeroic agent in 642 cancer patients reporting fatigue during chemotherapy: a URCC CCOP Study. Journal of Clinical Oncology. 2008;26:abstract 9512

Kaleita TA, Wellisch DK, Graham CA et al. Pilot study of modafinil for treatment of neurobehavioral dysfunction and fatigue in adult patients with brain tumors. J Clin Oncol 2006 ASCO Meeting Abstract 1503.

Morrow GR, Gillies LJ, Hickok JT et al. The positive effect of the psycho-stimulant modafinil on fatigue from cancer that persists after treatment is completed. J Clin Oncol 2005 ASCO Meeting Abstract 8012.

Carr D, Goudas L, Lawrence D et al. Management of Cancer Symptoms: Pain, Depression, and Fatigue. Evidence Report/Technology Assessment No. 61. Prepared by the New England Center Evidence-Based Practice Center. Contract No. 290-97-0019. AHRQ Publication No. 02-E032. Rockville, MD: Agency for Healthcare Research and Quality, July 2002.

Maryann R Cooper, Heather M Bird, and Michael Steinberg Efficacy and Safety of Modafinil in the Treatment of Cancer-Related Fatigue
The Annals of Pharmacotherapy 2009; 43:721-725

Read the Layperson version here.