A question worth discussing was posed in the January 14, 2013, edition of 

: Are generics really the same as branded drugs?

 To many of you, the quick answer is “yes.” If the generic medication was determined by the FDA to be an Approved Drug Product with Therapeutic Equivalence,

 then it is appropriate to substitute the brand name prescription for a generic product when the prescriber or institutional policy has allowed for this. It is also apparent to all of us that generic medications are used frequently, comprising about 80% of all dispensed prescriptions in 2012.

A smaller group of people, albeit a growing one, will answer the question with a resounding “no.” These people usually have direct patient experience with someone who had difficulty when going from the branded product to a generic substitution. The expressed issues might be a different side effect not previously observed or a blunted therapeutic response from what was previously achieved with a different manufacturer’s product.

 was written by Katherine Eban, an investigative journalist. She discusses the FDA reversal of a medication it had previously granted bioequivalence. Bupropion XL, the generic made by Teva Pharmaceuticals, is the medication that was highlighted. The situation started when numerous individuals were calling the radio program “The People’s Pharmacy” to describe their concerns with generic medications. As discussed in Joe and Terry Graedon’s book, “Top Screwups Doctors Make and How to Avoid Them," a study was initiated to test the bioequivalence of the Teva Pharmaceuticals product.

Results demonstrated that the generic bupropion, on average, achieved 75% of the expected concentration within the blood compared with the standard. In addition, since this generic had a different time-release method, it dissolved 4 times faster within the first 2 hours than the standard. It is presumed that these differences led to the patient concerns that were expressed on the radio show. This product is not on the market.

Currently, bioequivalence is determined by detecting between 80% and 125% of the active ingredient within the blood.

 This is true for both the max concentration and the area under the curve. There is no required evaluation for time to peak concentration, but it could be reviewed as a part of the bioequivalence process.

With all of these known bioequivalence issues and concerns, should hospital pharmacy and therapeutics committees or pharmacy department purchasers approach the selection of products differently? How about group purchasing organizations? Many times, the decision process stops if the products are all AB-rated generics. After that, the cheapest one will be selected. With the move to bar-coded medication administration, some organizations limit their purchases to the same manufacturers or those that are bar-code ready.

However, as a clinical profession, are we comfortable with a bioequivalence range of 80% to 125%? Shouldn’t health care professionals expect a smaller range of variation? Should pharmacy departments review the bioequivalence information as a part of the purchasing selection of a medication as opposed to just accepting the FDA review? Do our patients deserve more individual product scrutiny before switching to a different manufacturer? Should the profession pressure the FDA for tighter standards?

While there are many steps that go into selecting and purchasing a medication to be used in the hospital setting, we probably should also consider bioequivalence in addition to all of the other safety measures. Our patients deserve no less.

Stephen F. Eckel, PharmD, MHA, BCPS, FASHP, FAPhA, is assistant director of pharmacy, University of North Carolina Hospitals and clinical assistant professor, University of North Carolina Eshelman School of Pharmacy.

		Eban K. Are generics really the same as branded drugs? 

		Approved Drug Products with Therapeutic Equivalence Evaluations. http://en.wikipedia.org/wiki/Approved_Drug_Products_with_Therapeutic_Equivalence_Evaluations. Accessed March 29, 2013.

		Bioequivalence. http://en.wikipedia.org/wiki/Bioequivalence. Accessed March 29, 2013.

Articles

Editor’s Note

Questions have arisen regarding the standards for determining whether a generic medication is bioequivalent to the branded version.

The Generic Conundrum

Eculizumab (Soliris) is FDA-approved for the treatment of atypical hemolytic uremic syndrome (aHUS) in adult and pediatric patients to inhibit complement-mediated thrombotic microangiopathy (TMA) and also for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab is not indicated for the treatment of patients with Shiga toxin E coli—related hemolytic uremic syndrome (STEC-HUS).

Eculizumab is a monoclonal antibody that binds with high affinity to complement protein C5 and prevents the generation of the terminal complement complex C5b-9. In patients with PNH, eculizumab inhibits terminal complement—mediated intravascular hemolysis and in patients with aHUS, eculizumab inhibits complement-mediated TMA.

 Minimal eculizumab is excreted in urine with small quantities of immunoglobulin found in bile. The elimination half-life for PNH patients is 8 to 15 days and for aHUS patients, the elimination half-life is approximately 12 days.

Eculizumab dosing for adults with PNH is 600 mg IV every 7 days for the first 4 weeks, then 900 mg IV for the fifth dose 7 days later, then 900 mg every 14 days thereafter. Eculizumab dosing for adults with aHUS is 900 mg IV every 7 days for the first 4 weeks, then 1200 mg IV for the fifth dose 7 days later, then 1200 mg IV every 14 days thereafter. Pediatric dosing is based on body weight, with doses ranging from 300 mg to 900 mg.

 Eculizumab should be administered by IV infusion over 35 minutes via an infusion pump; it should not be administered as an IV push or bolus injection. Eculizumab should be diluted to a final concentration of 5 mg/mL by adding appropriate amounts of 0.9% sodium chloride (NaCl), 0.45% NaCl, 5% dextrose in water (D5W), or Ringer’s injection. The final infusion volume is 60 mL for 300-mg doses, 120 mL for 600-mg doses, 180 mL for 900-mg doses, and 240 mL for 1200-mg doses.

In clinical trials of eculizumab in PNH patients, significant reductions in lactate dehydrogenase (LDH) levels were achieved within the first week of treatment, with near-normal levels achieved at week 2 and maintained up to 36 months in certain patients. Eculizumab achieved rapid and sustained efficacy, regardless of baseline LDH levels or platelet counts.

 In adults with PNH, eculizumab treatment for 26 weeks achieved stabilization of hemoglobin levels in significantly more patients than placebo treatment, and reduced the need for packed red cell transfusions to a significantly greater extent than placebo. Eculizumab was also associated with significant improvements in fatigue and health-related quality-of-life scores in several trials.

There are limited published studies available on eculizumab in aHUS patients; however, reduction in terminal complement activity has been observed in patients receiving eculizumab. Additionally, eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks.

Eculizumab therapy increases the risk of serious meningococcal infections, which can be fatal if not treated early. Patients must have received a meningococcal vaccine at least 2 weeks before the first dose of eculizumab unless already immunized; however, a booster dose may be required. Common adverse effects occurring in ≥30% of adult patients include hypertension, upper respiratory tract infection, headache, and diarrhea.

Product Availability and Cost Considerations

Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) and is supplied as 300-mg single-use vials containing 30 mL of 10 mg/ mL sterile, preservative-free solution per vial. Vials must be stored in the original carton until time of use under refrigerated conditions at 2° to 8° C (36o to 46° F) and protected from light. The vials should not be frozen, shaken or used beyond the expiration date stamped on the carton. The acquisition cost of Soliris is $6830 per 300-mg vial; the cost per dose would range between $6830 and $27,320, depending on dose and indication. Complete prescribing information is available at www.soliris.com.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She is currently the pharmacy and therapeutics secretary at UNCH and manages the day-to-day operations of the Drug Information Center and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy.

		Soliris [package insert]. Cheshire, CT: Alexion Pharmaceuticals, Inc; December 2012.

Eculizumab. In: DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Updated periodically.

McKeage K. Eculizumab: a review of its use in paroxysmal nocturnal haemoglobinuria. 

Formulary Drug Review

This monoclonal antibody is approved to treat atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

Eculizumab (Soliris)

It is no secret that obesity has become a significant health concern in the United States, now affecting approximately 30% of the population.

 Obesity is associated with an increased risk of many medical conditions such as hypertension, hyperlipidemia, diabetes, stroke, and heart disease and is also responsible for increased health care costs.

 As of 2008, obesity was the second-leading cause of preventable death in the United States.

The National Institutes of Health defines normal weight as a body mass index (BMI) of 18.5 to 24.9 kg/m

, obese as a BMI greater than or equal to 30 kg/m

, and extreme obesity as a BMI of greater than or equal to 40 kg/m

 Optimal management of obese patients includes a combination of behavioral interventions targeted at improving diet and increasing physical activity.

 According to the US Food and Drug Administration (FDA), pharmacologic treatment should be considered for patients with a BMI at or above 30 kg/m

 if a weight-related comorbidity is present.

Despite these recommendations, orlistat was the only FDA-approved agent for long-term management of obesity prior to 2012. Phentermine and diethyl-propion are also available, but are only approved for short-term use.

 These medications were preceded by numerous agents, including sibutramine, dexfenfluramine, and fenfluramine, which were removed from the market due to significant safety concerns.

 Left with few options, safe and effective medications for the treatment of obesity have been in high demand. To guide the development of new agents, the FDA released the following criteria. In order for a new agent to be proved effective, at least 1 of the following must be met:

		“The difference in mean weight loss between the active-product and placebo-treated groups is at least 5% and the difference is statistically significant.”

		“The proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.

This article will assist pharmacists with evaluating pharmacotherapy options for chronic weight management by highlighting 2 new agents that were recently approved—lorcaserin (Belviq) and phentermine and topiramate extended-release (PHN/TPM, Qsymia).

Lorcaserin received FDA approval in June 2012 for chronic weight management in combination with a reduced-calorie diet and increased physical activity in adults with either a BMI greater than or equal to 30 kg/m

 if at least 1 weight-related comorbidity is present.

 agonist that is believed to activate receptors in the hypothalamus, leading to decreased food intake and satiety.

 receptor, is thought to minimize the risk of cardiac valvulopathy that is associated with previous non-selective 5-HT

 agonists such as fenfluramine and dexfenfluramine.

 The recommended dosing for lorcaserin is 10 mg by mouth twice daily. Although specific dose adjustments are not recommended, lorcaserin should be used with caution in patients with moderate renal impairment and avoided in end-stage renal disease. No dosage reductions are recommended for patients with mild to moderate hepatic impairment and its use has not been evaluated in severe hepatic dysfunction.

Three randomized, placebo-controlled trials were conducted to evaluate the efficacy of lorcaserin. A total of 4292 subjects were enrolled in the active-product arms, which included male and female adults with a BMI of at least 30 kg/m

 with a weight-related comorbidity. After 1 to 2 years of treatment, lorcaserin achieved significant weight loss in all patients as well as improvements in other parameters such as glycated hemoglobin (HbA1C) in patients with diabetes. Lorcaserin met the first FDA criterion because 37.5% to 47.5% of subjects achieved greater than or equal to 5% of baseline weight loss across all 3 trials. However, it failed to achieve the first of the 2 FDA criteria listed above (see Table 1 for more detailed results).

 Based on these results, the package insert recommends discontinuing lorcaserin if at least 5% of baseline weight loss is not achieved within the first 12 weeks of use.

The most common side effects associated with lorcaserin include hypoglycemia in patients with diabetes (29.3%), headache (16.8%), dizziness (8.5%), nausea (8.3%), fatigue (7.2%), constipation (5.8%), dry mouth (5.3%), and vomiting (3.8%).

 The use of lorcaserin is only contraindicated in patients who are pregnant; however, caution should be used in several patient populations, including, but not limited to, those with valvular heart disease, psychiatric disorders, and cognitive impairment. Lorcaserin is also associated with precautions related to a risk of priapism, heart rate decreases, hematological changes, and prolactin elevations. Concomitant use of other serotonin-modulating medications can increase the risk of serotonin syndrome or neuroleptic malignant syndrome.

 Although initial concerns for the risk of cardiac valvulopathy were alleviated by low rates in the active product and placebo groups in clinical trials, the FDA is requiring the completion of 6 post-marketing studies to evaluate long-term cardiac outcomes.

Phentermine and Topiramate Extended-Release

A combination of phentermine and extended-release topiramate (PHM/ TPM) was approved by the FDA in July 2012 for chronic weight management. PHN/TPM is approved for use in the same adult population as lorcaserin and should also be utilized with lifestyle modifications.

 Phentermine, a sympathomimetic amine and anorectic agent originally approved for short-term treatment of obesity, likely promotes weight loss through the release of catecholamines leading to reductions in appetite.

Topiramate, a monosaccharide derivative initially approved for the treatment of epilepsy and for the prevention of migraine headaches, has been associated with appetite suppression and satiety enhancement through an unknown mechanism of action.

 (An online table contains specific dosage and titration instructions for this agent.) Patients with moderate to severe renal impairment or moderate hepatic impairment should not receive doses greater than PHN/TPM 7.5 mg/46 mg daily. Its use has not been evaluated in patients with end-stage renal disease on dialysis or with severe hepatic impairment. Patients should be instructed to take PHN/TPM once daily in the morning with or without food.

The efficacy of PHN/TPM for weight loss was studied in 3 randomized, placebo-controlled trials, which randomized a total of 2246 subjects in the active product arms.

 These trials included male and female adults with a baseline BMI of at least 27 kg/m

, with or without comorbidities. PHN/TPM demonstrated statistically significant weight reduction and improvement in cardiometabolic variables after 1-year and 2-year follow-up periods. PHN/TPM both of the FDA criteria that are used to assess the efficacy of weight-loss agents. Specifically, 62% to 79% of patients receiving PHN/TPM throughout all trials lost at least 5% of their baseline body weight. In addition, the difference between weight loss in the active product and placebo-treated groups was at least 5% for all patients receiving standard treatment doses (see Table 2 for more detailed results).

The most common adverse events associated with the use of PHN/TPM include paresthesia (17%), dry mouth (16.6%), constipation (15.1%), upper respiratory tract infection (13.5%), nasopharyngitis, (10%), and headache (9.8%).

 Use of PHN/TPM is contraindicated in patients with glaucoma, hyperthyroidism, known hypersensitivity to sympathomimetic amines, or monoamine oxidase inhibitor use within the past 14 days, and during pregnancy. The Risk Evaluation and Mitigation Strategy requires that PHN/TPM only be dispensed through pharmacies certified by the manufacturer. Females of child-bearing potential should have negative pregnancy tests prior to therapy with PHN/TPM and monthly throughout treatment. Additional warnings associated with its use include the potential for elevations in resting heart rate, emergence or worsening of depression, and impairment of cognitive function. PHN/TPM may have additive effects with CNS depressants, potentiate the potassium-wasting action of diuretics, and cause alterations in plasma concentrations of oral contraceptives.

 To further assess the long-term safety of this agent, 10 post-marketing studies are required.

Table 3: Phentermine and Topiramate Extended-Release Dosage and Titration Instructions

						Start patients on PHN/TPM 3.75 mg/23 mg once daily for 14 days, then increase to the recommended dose of PHN/TPM 7.5 mg/46 mg once daily

						Evaluate weight loss after 12 weeks of treatment with PHN/TPM 7.5 mg/46 mg. If weight loss is <3% of baseline weight, discontinue treatment or escalate dose to PHN/TPM 11.25 mg/69 mg once daily for 14 days

						After 14 days of treatment with PHN/TPM 11.25 mg/69 mg, increase to the recommended dose of PHN/TPM 15 mg/92 mg once daily

						Evaluate weight loss after 12 weeks of treatment with PHN/TPM 15 mg/69 mg. If weight loss is <5% of baseline weight, discontinue treatment

						Taper drug upon discontinuing by taking a dose every other day for at least a week before stopping treatment.

Prior to the approval of these 2 new agents, orlistat received FDA approval in 1999 for managing obesity and reducing the risk of regaining weight after prior weight loss when used in combination with a reduced-calorie diet.

 This agent is available as both a prescription (Xenical) and over-the-counter product (Alli). This triacylglycerol lipase inhibitor leads to weight loss by preventing the absorption of dietary fat; therefore, its efficacy requires the presence of dietary fat. The most common side effects include oily spotting, flatus with discharge, and fecal urgency.

 Orlistat is also associated with a potential for decreased absorption of many medications, which requires separation of administration of the interacting agents.

Several agents are undergoing active investigation for their potential role in chronic weight management. For example, a combination of bupropion extended-release and naltrexone (Contrave) has demonstrated statistically significant weight loss in several randomized controlled trials with an acceptable safety profile. In addition, liraglutide is a glucagon-like peptide-1 analogue currently approved for treating type 2 diabetes mellitus and has also shown clinically significant, dose-dependent weight loss in randomized controlled trials.

Pharmacists are frequently approached for recommendations regarding prescription, over-the-counter, and herbal weight-loss products. Hospital pharmacists are optimally positioned to educate patients and providers regarding the risks and benefits of the available options, identify significant drug interactions, and determine appropriate weight-loss medications for specific patients. Pharmacists can also ensure that treatment duration is limited if clinically meaningful weight loss does not occur within 12 weeks of using lorcaserin and PHN/TPM at appropriate doses.

The approval of lorcaserin and PHN/TPM provides much-needed therapy options alongside orlistat for chronic weight management in combination with continued lifestyle modifications. Clinical experience and ongoing post-marketing trials will be important for determining long-term safety and defining the role of each agent in therapy.

Chronic Care Focus

Two new medications have recently been approved to help patients lose weight: lorcaserin and phentermine and topiramate extended-release.

Chronic Weight Management: New Medications

With 76,690 new cases and 9480 deaths estimated in 2013, melanoma will be the fifth-and seventh-most common malignancy among men and women, respectively.

 The incidence rate of melanoma increased by approximately 2.8% per year between 2005 and 2009. When diagnosed early at a localized stage (84% of cases), it is generally a curable disease with surgical excision having a 5-year survival rate of 98%. The survival declines significantly to 62% for regional disease and to 15% for metastatic disease (Table 1).

The FDA approval of ipilimumab and vemurafenib in 2011 marked the most significant advances in the treatment of melanoma since the advent of dacarbazine and interleukin-2 (IL-2) in 1975 and 1998, respectively. Conventional chemotherapy treatment with dacarbazine or temozolomide led to unsatisfactory results (10% to 20% response rate), while responses to immunotherapy with IL-2, even though durable in certain cases, were low (16%).

 The lack of improvement in overall survival (OS) and the significant associated toxicities limit the use of IL-2 to patients with good performance status and preserved organ function.

On the other hand, ipilimumab and vemurafenib have proved to be quite active and have improved OS compared with traditional chemotherapy. These agents not only changed the way we currently treat metastatic melanoma, but also earned the category 1 recommendation by the National Comprehensive Cancer Network. Additional preferred options are a clinical trial and high-dose IL-2. Other active agents include dacarbazine, temozolomide, imatinib (for c-kit mutated tumors), paclitaxel alone or in combination with carboplatin, and dacarbazine- or temozolomide-based chemotherapy or biochemotherapy (Table 2).

Table 2. Systemic treatment options for disseminated unresectable metastatic melanoma (NCCN guidelines v2.2013)

				Dacarbazine- or temozolomide-based chemotherapy/biochemotherapy

Ipilimumab is a recombinant, human monoclonal antibody which upon binding to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) on the surface of T cells blocks the effects of the negative T-cell regulator CTLA-4. This causes an enhanced T-cell activation and proliferation which leads to increased T-cell-mediated activity against tumor cells (Figure).

 The approved dosing schedule is 3 mg/kg intravenously over 90 minutes every 3 weeks for 4 doses. Ipilimumab earned FDA approval following the results of 2 phase III trials. It was shown to prolong OS by approximately 3.6 months when given alone or in combination with a vaccine to patients with previously treated metastatic mela- noma.12 In a separate study, compared with dacarbazine and placebo, ipilimumab given in combination with dacarbazine increased OS by 2.1 months.

 The side effects associated with ipilimumab are a consequence of the immune system activation and they may affect the skin, gastrointestinal tract, liver, and the endocrine system (Table 3). Generally, these are responsive to dose interruption, discontinuation, or the use of corticosteroids or other immunosuppressants such as infliximab in more severe cases. Even though they may be reversible, these side effects are life threatening if not promptly addressed.17 Patients should be counseled to report any increased bowel movements (including incontinence), black, bloody, or clay stools, nausea, and vomiting causing inability to take fluids by mouth, abdominal pain, cramping, or bloating.

Although durable once achieved, the response to ipilimumab is usually delayed by approximately 13 weeks (mean time). This characteristic made it the preferred agent for patients with a lower tumor volume and who are less symptomatic. Also, instead of the traditional Response Evaluation Criteria in Solid Tumors, new immune-related response criteria were developed.

 These criteria would evaluate the total disease burden independently of the appearance of new lesions and allow it to increase up to 25% from baseline before being deemed disease progression.

Approximately 7% of all cancers and 45% of the patients diagnosed with metastatic melanoma carry a mutated BRAF.

 This intracellular kinase is part of the RAS-RAF-MEK-ERK MAP kinase signaling pathway which regulates cell survival, growth, and differentiation in response to growth signals (Figure). A mutated BRAF leads to constitutive activation of this pathway resulting in dysregulation of these processes and malignant transformation.

 The treatment with the BRAF inhibitor vemurafenib is based on the detection of the V600E mutation, which occurs in approximately 97% of mutated BRAF cases. This detection is performed with the aid of the Cobas 4800 BRAF V600 diagnostic test, which received FDA approval alongside the drug.

Vemurafenib was shown to improve median OS by 3.6 months in a phase III trial (BRIM3), which compared it with dacarbazine in previously untreated patients carrying the BRAF

 The FDA-approved dose is 960 mg orally twice daily, and it may be taken with or without a meal. No dose adjustments are required for mild and moderate renal or hepatic dysfunction. In severe impairment it should be used with caution. Arthralgia and dermatologic side effects were most commonly reported, and secondary skin cancers may also occur (Table 3). Liver function tests as well as baseline and regular electrocardiogram monitoring are recommended throughout therapy. Patients should be advised to avoid sun exposure as much as possible, as this could lead to skin burns. Concomitant use of narrow therapeutic drugs metabolized by CYP1A2, CYP3A4, and CYP2D6 is not recommended, as their levels may be significantly altered by vemurafenib. Moreover, since vemurafenib is a substrate of CYP3A4, strong CYP3A4 inducers or inhibitors should be used with caution. Close monitoring of INR is recommended when the patient is also receiving warfarin. 

Table 3. Adverse effects observed with ipilimumab and vemurafenib

 - transaminitis, right upper quadrant pain

 - hypopituitarism, adrenal insufficiency, hypothyroidism, fatigue

Unlike ipilimumab, the rapid response seen with vemurafenib made it the preferred choice for patients with a mutated BRAF, higher disease burden, and symptomatic disease. However, the response seen with vemurafenib does not last long due to the development of treatment resistance. The median time to progression is less than 7 months, with some patients progressing aggressively after the initial response. Fortunately, promising new agents and combination regimens are currently undergoing clinical trials or are waiting to be tested.

Clinical Care Focus

The approval of ipilimumab and vemurafenib in 2011 marked a significant advance in the treatment of melanoma, and a number of new investigational agents are in the pipeline.

May 2013

The Generic Conundrum

Eculizumab (Soliris)

Chronic Weight Management: New Medications

Melanoma: Therapy Update