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Pharmaceutical Approval Update January 2011

Marvin M. Goldenberg PhD, RPh, MS

Eribulin Mesylate (Halaven for Injection)

Manufacturer: Eisai, Woodcliff Lake, N.J.

Indication: Eribulin mesylate is a microtubule inhibitor intended for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Biological Class: This non-taxane, microtubule dynamics inhibitor is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The empirical formula is C40H59NO11 • CH4O3S. The molecular weight is 826.0 (729.9 for free base).

Uniqueness of Product: Eribulin inhibits the growth phase of microtubules without affecting the shortening phase, and it sequesters tubulin into nonproductive aggregates. The drug exerts its effects via a tubulin-based antimitotic mechanism, leading to blocking of the G2/M cell cycle, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic inhibition.

Warnings and Precautions:


In one study, severe neutropenia (an absolute neutrophil count of below 500/mm3) lasting more than one week occurred in 62 of 503 of patients (12%) and led to discontinuation in fewer than 1% of patients. Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels more than three times the upper limit of normal (ULN) experienced a higher incidence of grade 4 neutropenia and febrile neutropenia compared with patients having normal aminotransferase levels. Patients with bilirubin levels exceeding 1.5 times the ULN also had a higher incidence of grade 4 neutropenia and febrile neutropenia.

Peripheral neuropathy

In study 1, grade 3 peripheral neuropathy occurred in 40 of the 503 patients (8%), and grade 4 affected two patients (0.4%). Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin in 24 of these patients (5%). Neuropathy lasting more than one year occurred in 26 patients (5%), and 109 patients (22%) experienced a new or worsening neuropathy that had not responded within a median follow-up duration of 269 days (range, 25–662 days).

Embryofetal toxicity

No adequate or well-controlled studies of eribulin have been conducted in pregnant women. Because this agent is a microtubule inhibitor, it is expected to cause fetal harm when administered to pregnant women.

QT prolongation

In an uncontrolled open-label electrocardiographic (ECG) study of 26 patients, prolongation of the QT interval was observed on day 8, independent of the eribulin concentration; no QT prolongation had been observed on day 1. ECG monitoring is recommended if patients who begin taking this drug have congestive heart failure, bradyarrhythmias, and electrolyte abnormalities and are taking another agent that prolongs the QT interval (including Class Ia and III antiarrhythmics).

Dosage and Administration: The recommended dose of eribulin is 1.4 mg/m2, administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. For patients with mild hepatic impairment (Child–Pugh class A), the recommended dose, for the same duration and cycle, is reduced to 1.1 mg/m2; for those with moderate hepatic impairment (Child–Pugh B), 0.7 mg/m2; and for those with moderate renal impairment (a creatinine clearance [CrCl] of 30–50 mL/minute), 1.1 mg/m2. Eribulin was not studied in patients with severe hepatic impairment (Child–Pugh C).

Commentary: Breast cancer is the second leading cause of cancer-related deaths among women, according to the National Cancer Institute. In 2010, it was estimated that 207,090 cases would be diagnosed and almost 40,000 women would die from the disease.

The FDA approved eribulin after its safety and effectiveness were established in a single study of 762 women with metastatic breast cancer who had received at least two prior chemotherapy regimens for late-stage disease. Patients were randomly assigned to receive either eribulin or a different single agent therapy chosen by their oncologist. The study was designed to measure the length of time from the start of treatment to a patient’s death (overall survival). The median overall survival rate was 13.1 months with eribulin and 10.6 months with a single-agent therapy.

Other FDA-approved therapies for late-stage breast cancer include capecitabine (Xeloda, Roche) for patients with breast cancer refractory to paclitaxel and anthracycline-containing chemotherapy; ixabepilone (Ixempra, Bristol-Myers Squibb) for patients with late-stage disease after failure with an anthracycline, taxane, and capecitabine regimen; and ixabepilone plus capecitabine for late-stage disease after failure of anthracycline- and taxane-based chemotherapy.

Common adverse drug effects of eribulin have included neutropenia, anemia, leukopenia, hair loss, fatigue, nausea, weakness, peripheral neuropathy, and constipation.

Treatment options are limited for women with aggressive forms of late-stage breast cancer who have already received other therapies. Overall, eribulin produced a clear survival benefit.


Denosumab for Subcutaneous Injection (Xgeva)

Manufacturer: Amgen, Thousand Oaks, Calif.

Indication: Denosumab is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Biological Class: This human immunoglobulin G (IgG2) monoclonal antibody binds to human receptor activator of nuclear factor–κβ ligand (RANKL). Denosumab is produced in genetically engineered Chinese hamster ovary cells. Its approximate molecular weight is 147 kDa. Each single-use vial of the product contains 120 mg of denosumab, 4.6% sorbitol, 18 mM acetate, water for injection (USP), and sodium hydroxide to a pH of 5.2.

Uniqueness of Product: Denosumab binds to RANKL, a transmembrane or soluble protein that is essential for the formation, function, and sur vival of osteoclasts, which are involved in bone resorption. Denosumab prevents RANKL from activating its receptor (RANK) on the surface of osteoclasts and their precursors. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases.

Warnings and Precautions:


Denosumab can cause severe hypocalcemia. Pre-existing hypocalcemia should be corrected before denosumab treatment is initiated. Calcium levels must be monitored, and calcium, magnesium, and vitamin D should be given as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can also lower calcium levels. Patients should be advised to contact their health care professional if symptoms of hypocalcemia occur.

Based on clinical trials that included a lower dose of denosumab, patients with a CrCl of less than 30 mL/minute or who are receiving dialysis are at greater risk for severe hypocalcemia than patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every four weeks has not been evaluated in patients whose CrCl is less than 30 mL/minute or who are receiving dialysis.

Osteonecrosis of the jaw

Jaw osteonecrosis (ONJ) can occur in patients receiving denosumab. ONJ is manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be a manifestation of ONJ.

An oral examination and appropriate preventive dentistry should be performed before and periodically during denosumab therapy. Patients should be advised about oral hygiene practices. Invasive dental procedures should be avoided while the patient is being treated with denosumab. Patients who are thought to have, or who develop, ONJ while receiving denosumab should be treated by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition in these patients.

Dosage and Administration: The recommended dose of denosumab is 120 mg, given as a subcutaneous (SQ) injection every four weeks in the upper arm, upper thigh, or abdomen. The product is sold in a 120-mg/1.7 mL (70-mg/mL) single-use vial.

Calcium and vitamin D should be prescribed as necessary to treat or prevent hypocalcemia.

Commentary: Denosumab is a monoclonal antibody that targets a protein involved in cancer-related bone destruction called human RANKL. Other FDA-approved drugs for similar conditions include zoledronic acid (Zometa, Novartis) and pamidronate disodium (Aredia, Novartis).

The FDA approved denosumab to help prevent skeletal-related events in patients with cancer that has metastasized and damaged the bone. Skeletal-related events include bone fractures from cancer and bone pain requiring radiation. Bone metastases represent a major cause of pain and can affect a patient’s quality of life.

Denosumab’s safety and effectiveness were confirmed in three randomized, double-blind clinical studies involving 5,723 patients comparing denosumab with zoledronic acid. The studies were designed to measure the time until occurrence of a fracture or spinal cord compression resulting from cancer or until patients needed radiation or surgery for control of bone pain. Although denosumab delayed the spread of prostate cancer to the bones, it did not prolong the lives of men in a clinical trial.

In patients with breast or prostate cancers, denosumab was superior to zoledronic acid in delaying skeletal-related events. In men with prostate cancer, the median time to an event was 21 months with denosumab and 17 months with zoledronic acid.

Denosumab was originally approved under the trade name of Prolia in June 2010. Prolia is indicated for postmenopausal women with osteoporosis who are at high risk for bone fractures. Xgeva is administered at a higher dose and is given more often than Prolia. The safety profile of denosumab differs in patients with osteoporosis and in those with cancer and bone metastases.

Sources:; The New York Times, December 13, 2010

Dextromethorphan Hydrobromide and Quinidine Sulfate (Nuedexta)

Manufacturer: Avanir Pharmaceuticals, Aliso Viejo, Calif.

Indication: Nuedexta capsules are approved to treat patients with pseudobulbar affect, which occurs secondary to unrelated neurological conditions. Patients may experience involuntary, sudden, and frequent episodes of laughing, crying, or both. Episodes typically occur out of proportion or incongruent to the patient’s underlying emotional state.

The drug has not been shown to be safe or effective in other types of emotional lability that can occur in Alzheimer’s disease or other dementias.

Drug Class: The capsule combines dextromethorphan hydrobromide USP (20 mg) and quinidine sulfate USP (10 mg) in a fixed-dose combination that acts on the central nervous system (CNS). It has a molecular weight of 370.32.

Quinidine sulfate, a specific inhibitor of cytochrome P450 (CYP 450) 2D6-dependent oxidative metabolism, is added to increase the systemic bioavailability of dextromethorphan. Quinidine sulfate’s molecular weight is 782.96.

Uniqueness of Drug: Dextromethorphan is a sigma-1 receptor agonist and an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. Quinidine sulfate increases plasma levels of dextromethorphan by competitively inhibiting CYP 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown.

Warnings and Precautions:

Thrombocytopenia and other hypersensitivity reactions

Quinidine can cause immune-mediated thrombocytopenia, which can be severe or fatal. Nonspecific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or may occur with thrombocytopenia. Nuedexta should be discontinued immediately if thrombocytopenia occurs unless the thrombocytopenia is definitely not drug-related; continued use can increase the risk of fatal hemorrhage.

Nuedexta should not be restarted in sensitized patients, because thrombocytopenia can develop more rapidly and can be more severe than it was in the original episode. The medication should not be used if immune-mediated thrombocytopenia from other structurally similar drugs (including quinine and mefloquine) is suspected, because cross-sensitivity can occur. Quinidine-associated thrombocytopenia usually resolves within a few days of discontinuation of the sensitizing drug. Quinidine has also been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive antinuclear antibody (ANA) test.


Hepatitis has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Fever may be a presenting symptom, and thrombocytopenia or other signs of hypersensitivity may also occur. Most cases resolve when quinidine is withdrawn.

Cardiac effects

Nuedexta causes dose-dependent prolongation of the corrected QT (QTc) interval, which can result in torsades de pointes–type ventricular tachycardia, and the risk increases as the degree of prolongation increases. When patients at risk of QT prolongation and torsades de pointes begin Nuedexta therapy, ECG evaluation of the QT interval should be conducted at baseline and three to four hours after the first dose. This recommendation applies to patients (1) who are concomitantly taking or beginning to take drugs that prolong the QT interval or that are strong or moderate CYP 3A4 inhibitors, (2) who have left ventricular hypertrophy, and (3) who have left ventricular dysfunction. These latter two conditions are more likely to be present in patients with chronic hypertension, coronary artery disease, or a history of stroke.

The ECG findings should be re-evaluated if risk factors for arrhythmia change during the course of therapy. Risk factors include the concomitant use of drugs associated with QT prolongation, electrolyte abnormalities (hypokalemia, hypomagnesemia), bradycardia, and a family history of a QT abnormality. If patients taking Nuedexta experience symptoms that could indicate cardiac arrhythmias (such as syncope and palpitations), Nuedexta should be discontinued and the patient should be evaluated further.

Concomitant use of CYP 2D6 substrates

The quinidine in Nuedexta inhibits CYP 2D6 in patients in whom CYP 2D6 is not otherwise genetically absent or in those in whom its activity is otherwise pharmacologically inhibited. Because of this effect on CYP 2D6, accumulation of the parent drug or failure of active metabolite formation may decrease the safety or efficacy of drugs used with Nuedexta that are metabolized by CYP 2D6.


Nuedexta may cause dizziness. Precautions should be taken to reduce the risk of falls.

Serotonin syndrome

When used with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac, Eli Lilly) or a tricyclic antidepressant such as clomipramine or imipramine (Anafranil and Tofranil, both made by Mallinckrodt), Nuedexta may cause serotonin syndrome; changes include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.

Anticholinergic effects of quinidine

Patients should be monitored for worsening clinical condition if they have myasthenia gravis and other conditions that might be adversely affected by anticholinergic properties.

Poor metabolizers of CYP 2D6

The quinidine component of Nuedexta is intended to inhibit CYP 2D6 so that higher exposure to dextromethorphan can be achieved than when dextromethorphan is given alone. From 7% to 10% of Caucasians and from 3% to 8% of African-Americans lack the capacity to metabolize CYP 2D6 substrates and are classified as poor metabolizers.

Contraindications: The medication is not intended for patients with a prolonged QT interval, heart failure, congenital long QT syndrome, or a history suggesting torsades de pointes. Nuedexta causes dose-dependent QTc prolongation. Patients with or at risk for complete atrioventricular block should not take this drug unless a pacemaker has been implanted.

Dosage and Administration: Nuedexta capsules contain dextromethorphan 20 mg/quinidine 10 mg. The recommended starting dose is one capsule daily orally for the initial seven days of therapy. On the eighth day and thereafter, the daily dose should consist of a total of two capsules per day, given as one capsule every 12 hours. The need for continued treatment should be reassessed periodically, because pseudobulbar affect can improve spontaneously in some patients.

Commentary: Pseudobulbar affect (sometimes called labile affect, emotional incontinence, or involuntary emotional expression disorder) occurs secondary to otherwise unrelated neurological conditions and is manifested by involuntary, sudden, and frequent episodes of laughing or crying or both. Episodes may occur out of proportion to the patient’s actual emotional state. The onset can be unpredictable. An outburst typically lasts 30 seconds to 4 minutes, and can occur as often as four to five times per day.

Studies were conducted in patients with amyotrophic lateral sclerosis and multiple sclerosis. Nuedexta has not been shown to be safe and effective in other types of emotional lability, such as Alzheimer’s disease and other dementias.

Nuedexta may cause serious side effects, including possible changes in heart rhythm, and patients with QT interval prolongation, congenital long QT syndrome, torsades de pointes, or heart failure should not take it.