Caryn Domenici Belisle, RPh

The FDA approved Egrifta (tesamorelin) to treat lipodystrophy in HIV-infected patients. 

	Egrifta (tesamorelin) from Theratechnologies Inc was approved by the FDA on November 10, 2010, to treat lipodystrophy in patients also diagnosed with HIV.

	Lipodystrophy is a condition associated with some antiretroviral medications commonly prescribed to HIV patients.

 Lipodystrophy causes excessive adipose tissue to develop in certain areas of the body.

	Egrifta, an analog of growth hormone— releasing factor, binds to and stimulates growth hormone–releasing factor receptors. 

It does this with a potency comparable to that of endogenous growth hormone—releasing factor.

 In the same way that endogenous growth hormonereleasing factor acts on the pituitary cells to synthesize and release growth hormone, Egrifta stimulates the secretion of growth hormone.

	Egrifta is prescribed as a once-daily subcutaneous (sc) injection of 2 mg.

 The injection should be given in the abdomen daily and injection sites should be rotated to lessen injection site reactions.

 It is also important not to inject Egrifta in the navel or areas that are compromised by scar tissue or bruising.

	There were 2 multicenter studies done with HIV-infected patients who had lipodystrophy for a 26-week intervention phase followed by a 26-week safety extension. A total of 806 HIV patients treated with antiretroviral therapy with excess abdominal fat were randomized to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc once daily.

	At week 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P group, n = 135) for an additional 26 weeks, and patients on placebo were switched to tesamorelin (P-T group, n = 197).

	Visceral adipose tissue (VAT) was measured by computed tomography scan at the end of week 26 in the tesamorelin-treated patients; the VAT decreased significantly (—24 ± 41 cm2 vs 2 ± 35 cm2, tesamorelin vs placebo, P <0.001; treatment effect, –15.4%). At week 52, decreases in VAT [–35 ± 50 cm2 (–17.5 ± 23.3%)] and other measures, such as waist circumference, cholesterol, triglycerides, and nondensity lipoproteins (all P <0.001 vs original baseline), were maintained in the T-T group.

	Common side effects of patients taking Egrifta include injection site reactions, nausea, vomiting, fluid retention, and stomach, muscle, and joint pain.

 A decline in control over blood sugar has been noted in some patients while taking Egrifta.

 The safety and efficacy of Egrifta in pediatric and geriatric populations has not been confirmed.

 The safe and efficacious use of Egrifta in patients with limited renal and hepatic function has not been validated.

 Egrifta should not be given to women who are pregnant or nursing.

	Egrifta should not be used in patients with pituitary gland tumors or other related health conditions, or those who have recently undergone pituitary gland surgery.

 Egrifta is contraindicated in patients with any active malignancy, and treatment should be thoroughly evaluated in patients with history of cancer.

 Patients with a history of hypersensitivity reactions to either tesamorelin or mannitol should not be treated with Egrifta.

	Patients with elevated levels of insulin-like growth factor I (IGF-I) should be closely monitored. If elevated levels of IGF-I persist, treatment with Egrifta should be discontinued. 

 As glucose intolerance may develop, patients should be monitored for variations in their glucose metabolism and the use of Egrifta in those with diabetes should be evaluated and closely monitored.

	Cocomittant administration of Egrifta and drugs metabolized through the cytochrome P450 pathway may result in changed clearance rates of these drugs and should be monitored.

Caryn Belisle, RPh, Alka Patel, PharmD, and Amanda Slowinski, PharmD Candidate Egrifta, an analog of growth hormone— releasing factor, binds to and stimulates growth hormone– releasing factor receptors. Both Ms. Belisle and Dr. Patel are pharmacists at Brigham & Women’s Hospital, Boston, Massachusetts. Ms. Slowinski is a third-year pharmacy student at Northeastern University, Boston, Massachusetts. 

Articles

Theratechnologies Inc's Egrifta

The FDA approved Labopharm's Oleptro (trazodone hydrochloride) extended-release tablets for treatment of major depressive disorder in adults.

On February 3, 2010, the FDA approved Labopharm Inc’s Oleptro (trazodone hydrochloride) for treatment of major depressive disorder (MDD) in adults. MDD, a common mental illness affecting more than 14 million US adults, is often characterized by a combination of social and somatic symptoms. Oleptro is an extended-release form of trazodone given once daily.

Although the mechanism of action of Oleptro is not fully understood, it is thought to exert its effects by selectively inhibiting the neuronal reuptake of serotonin, and also by antagonizing the 5-HT 2A/2C serotonin receptors.

Oleptro is well absorbed after oral administration and is primarily metabolized in the liver by cytochrome P450 3A4 to an active metabolite. Oleptro is highly protein bound (85%-95% in vitro), andis predominantly excreted in the kidneys. The mean terminal half-life after a 300-mg single dose of Oleptro is 10 hours.

A double-blind study was conducted with 412 patients with MDD in which they were randomized 1:1 to receive Oleptro (150-375 mg) or placebo oncedaily. The doses were optimizedduring the first 2 weeks of therapy, and then continued for 6 weeks.

The mean maximum daily dose was 310 mg for the active group and 355 mg for the placebo group starting at the end of the 2-week optimization period and ending at the completion of the 6-week duration of therapy. Based on the primary endpoint, a changein the 17-Item Hamilton Depression Rating Scale (HAMD-17) from baseline to last study visit, there was a statistically significant difference between Oleptro and placebo on the mean HAMD-17 score (-11.4 vs -9.3; P = .012).3 The outcome was that the extended-release formulation of trazodone was more effective in treating patients with MDD than placebo. Headache and somnolence were the most commonly reported adverse effects for both the active and placebo groups.

Oleptro is available in 150- and 300-mg scored tablets. The recommended initial dose is 150 mg once daily. The dose may be increased to 75 mg per day every 3 days, with a maximum daily dose of 375 mg per day.

Oleptro should be taken at the same time every day, preferably at bedtime due to potential for drowsiness or dizziness. The tablets are not to be crushed or chewed, but broken at the scored line if a partial dose is needed.2 If therapy is to be discontinued, a gradual decrease in dose is recommended.

Oleptro should not be taken concomitantly with monoamine oxidase inhibitors (MAOIs). A 14-day period must pass after the MAOI is discontinued to start Oleptro therapy. Oleptroshould not be given to patients during the initial recovery from a myocardial infarction.

Oleptro can cause QT prolongation, orthostatic hypotension, serotonin syndrome, hyponatremia, and priapism. There is potential risk for bleeding when Oleptro is taken with aspirin, nonsteroidal antiinflammatory drugs, or other medications that may affect coagulation.

Oleptro is pregnancy category C and should be used with caution during breastfeeding.

As with all antidepressants, Oleptro therapy should be monitored closely in patients with MDD at risk for suicide or who have suicidal tendencies.

1. Labopharm Receives FDA Approval For Oleptro [Press Release]. www.prnewswire.com/news-releases/labopharm-receives-fda-approval-for-oleptrotm-83429037.html.

2. Oleptro Package Insert; Labopharm Europe Limited June 2010

3. Sheehan DV, Croft HA, Gossen ER, Levitt RJ, Brullé C, Bouchard S, Rozova A.; Extended-release Trazodone in Major Depressive Disorder: A Randomized, Double-blind, Placebo-controlled Study. Psychiatry (Edgmont). 2009 May;6(5):20-33.

Both Ms. Belisle and Dr. Patel are pharmacists at Brigham and Women’s Hospital, Boston, Massachusetts. 

Labopharm Inc's Oleptro

Somaxon Pharmaceuticals' Silenor (doxepin HCl) has been FDA approved to treat long- or short-term insomnia in patients who have difficulty maintaining sleep. 

On March 18, 2010, the FDA approved Silenor (doxepin HCl) to treat longor short-term insomnia in patients who have difficulty maintaining sleep.

 The new drug application approval was based on clinical trials in adults and elderly individuals diagnosed with chronic and transient insomnia. Although doxepin has been approved for depression, anxiety, and dermatologic treatment, these indications are not approved for Silenor. Doxepin exerts sedation by blocking histamine 1 receptors.

 It also possesses pharmacologic properties similar to tricyclic antidepressants.

The efficacy and safety of Silenor for sleep maintenance was evaluated in several randomized clinical trials enrolling men and women aged 18 to 93 years old.

The efficacy and safety of Silenor was evaluated in adults aged 18 to 64 years diagnosed with chronic insomnia (≥3 months), who were experiencing ≥60 minutes of wake-after-sleep-onset (WASO) and ≥20 minutes of latency to sleep onset, as confirmed by polysomnography. Subjects were randomized to receive nightly doses for 35 days: doxepin 3 mg (n=75), 6 mg (n=73), or matching placebo (n=72). The 3- and 6-mg arms demonstrated improved WASO on night 1 (P <.0001) and at night 29 (both, P = .0299 and P = .0012, respectively). Both doses also showed improvement in various end points.

Another randomized, double- blind, placebo-controlled study enrolled elderly subjects diagnosed with chronic insomnia using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text revision scale. This study evaluated the efficacy of doxepin 1 mg (n=77), 3 mg (n=82), and placebo (n=81) taken nightly for 3 months. The doxepin arms were superior in onset of sleep and maintenance of sleep and reduced the incidence of early awakenings.

A 6-mg doxepin dose was also evaluated in a 4-week treatment trial, which also included elderly subjects diagnosed with chronic insomnia. The subjects were randomized to receive once-nightly 6-mg doxepin (n=130) or matching placebo (n=125).

 The double-blind study resulted in improvement in sleep maintenance and sleep duration. The time to sleep onset was improved but not superior to the placebo group.

Silenor is available in 3- and 6-mg tablets. Silenor 6 mg in adults and 3 mg in the elderly is the recommended starting dose. A washout period of 2 weeks from monoamine oxidase inhibitors is recommended before treatment with Silenor begins. It had no effect on QT prolongation. Silenor is taken 30 minutes before bedtime without food.

The most common adverse events reported in the clinical studies were headache, sedation, nausea, and vomiting.

 Doxepin is metabolized mainly by the enzymes cytochrome P450 2C19 (CYP2C19) and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Therefore, patients who are poor metabolizers of these enzymes will have higher doxepin concentrations.

Doxepin carries the FDA warning of an increase in suicidal risk and is contraindicated in patients with glaucoma and urinary retention. Silenor is a pregnancy category C drug and is excreted in human milk. Patients should be counseled on complex behaviors associated with taking hypnotics, as outlined in the Silenor package insert.

		Silenor [package insert]. San Diego, CA: Somaxon 3/2010

www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_CPR/ProductList/ND_PR/Drugs/CS/BFC038/DUPLICATIONSHIELDSYNC/A2A6CF/ND_PG/PRIH/ND_B/HCS/SBK/1/ND_P/Drugs/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/2570/ContentSetId/31#secN13F6A

		Lankford A, Hull S, et al. Poster presentation: Efficacy and Safety of Doxepin 3 and 6 mg in Adults with Primary Insomnia.

		Roth T, Gotfried M, et al. Poster presentation: Long-term Efficacy and Safety of Doxepin 1 and 3 mg in Elderly Subjects with Chronic Primary Insomnia.

		Segal S, Lankford A, et al. Poster presentation: Efficacy and Safety of Doxepin 6 mg in a 4-Week Outpatient Trial of Elderly Subjects with Primary Insomnia.

Rx Product Profile: Somaxon Pharmaceuticals' Silenor

Ms. Belisle and Dr. Patel are pharmacists at Brigham and Women’s Hospital, Boston, Massachusetts. Craig Dooley is a sixth-year PharmD candidate from Northeastern University School of Pharmacy currently on clinical clerkship in the Investigational Drug Service at Brigham and Women’s Hospital.

On October 16, 2009, the FDA approved GlaxoSmithKline’s Cervarix (human papillomavirus [HPV] bivalent [types 16 and 18] vaccine, recombinant) for use in girls and women aged 10 to 25 for the prevention of cervical precancers and cervical cancer associated with oncogenic HPV types 16 and 18.

 Cervarix is formulated with the adjuvant system AS04, composed of monophosphoryl lipid A (MPL) and aluminum hydroxide. 

More than 100 genotypes of HPV have been identified.

Persistent infection with HPV types 16 and 18, transmitted by sexual activity, cause about 70% of cervical cancers.

The dosing of Cervarix requires 3 intramuscular injections given at months 0, 1, and 6, with the preferred site of injection of the deltoid region.

The most common adverse events were injection-site reactions, headache, and fatigue. It is recommended to observe patients for 15 minutes after injection for syncope.

Two double-blind, randomized controlled clinical studies studied the efficacy of Cervarix to prevent cervical intraepithelial neoplasia (CIN), grades 2 and 3, or adenocarcinoma in situ. These trials enrolled a total of 19,757 women aged 15 to 25. 

Study 1 was a phase 2 double-blind, multicenter, randomized, placebo-controlled trial with 1113 women who were seronegative for HPV-16 and HPV-18 at the time of vaccination.

 Participants were vaccinated at months 0, 1, and 6. The objective of the study was to evaluate the efficacy of the bivalent vaccine to prevent infection with HPV-16 and/or -18 between 6 and 18 months. For the study, 560 subjects were randomized to active vaccine and 553 were randomized to placebo. 

To evaluate long-term safety, efficacy, and immunogenicity, a total of 776 women were also eligible for enrollment into a follow-up study (study 1 extension).

Results from a combined analysis of the initial and follow-up phases indicated that the vaccine was 94.7% (3 cases in the vaccinated group vs 51 in the placebo group) and 88.5% (9 cases in the vaccinated group vs 51 in the placebo group) effective against incident infections in the per-protocol population, respectively (95% confidence interval [CI], 83.5%-98.9% and 77%-95%, respectively).

 Cervarix efficacy against HPV- 16 and HPV-18 at 6 months in the combined analysis was 96% and 100% at 12 months (1 case in the vaccinated group vs 23 cases in the placebo group; 95% CI, 75.2%-99.9%; and 0 cases in the vaccinated group vs 9 in the placebo group; 95% CI, 52.2%-100%), respectively.

Study 2 was a randomized trial that enrolled 18,644 women aged 15 to 25. The primary outcome of the study was to assess the efficacy of Cervarix against CIN grade 2+ associated with HPV type 16 or 18.

The study enrolled subjects regardless of their HPV status (DNA status, HPV serostatus, or baseline cytology). 

 Subjects were randomized to receive Cervarix or hepatitis A vaccine (control group) at months 0, 1, and 6.

Vaccine efficacy was shown to be 98.1% (96.1% CI, 88.4%-100%, P <.001) against HPV-16/18; 100% (91.0%-100%, P <.0001) against HPV-16; and 92.3% (45.7%-99.9%, P = .0009) against HPV-18. In addition, a high level of efficacy against persistent infection was noted. Vaccine efficacy was 93.8% (96.1% CI, 91.0%-95.9%, P <.0001) against 6-month persistence, and 91.2% (85.9%-94.8%, P <.0001) against 12-month persistence.

Cervarix provides immunity against HPV types 16 and 18, known to be 2 of the more common oncogenic types.

 Gardasil adds immunity against types 6 and 11—2 types known to commonly cause genital warts in both men and women.

The importance of the degree of immunogenicity is yet to be determined, and long-term studies evaluating duration of efficacy are necessary for both vaccines.

	1. FDA approves Cervarix, GlaxoSmithKline’s cervical cancer vaccine. Available at: http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10112.htm. Accessed on February 1, 2010.

	2. Cervarix [package insert]. London, UK: GlaxoSmithKline plc: 2009.

	3. Hutchinson DJ, Klein KC. Human papillomavirus disease and vaccines. Am J Health-Syst Pharm. 2008;65:2105-2112.

	4. Harper DM, Franco EL, Wheeler C et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection of human papillomavirus types 16 and 18 in young women: a randomized control trial. 

	5. Paavonen J, Naud P, Salmeron J et al. Efficacy of humanpapillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomized study in young women. 

	6. Einstein MH, Baron M, Levin MJ et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. 

Cervarix (human papillomavirus bivalent [types 16 and 18] vaccine, recombinant) was approved by the FDA for use in girls and women aged 10 to 25 for the prevention of cervical precancers and cervical cancer associated with oncogenic human papillomaviras types 16 and 18. 