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Pharmaceutical Approval Update August 2011

Marvin M. Goldenberg PhD, RPh, MS

Belatacept (Nulojix)

Manufacturer: Bristol-Myers Squibb, Princeton, N.J.

Indication: Belatacept is indicated for the prophylaxis of organ rejection in adults who have received a kidney transplant. It is to be used in combination with basiliximab (Simulect, Novartis) induction, mycophenolate mofetil (Cell-Cept, Roche), and corticosteroids. This drug should be used only in patients who are seropositive for Epstein–Barr virus (EBV) infection. The use of belatacept for preventing the rejection of transplanted organs other than the kidney has not been established.

Drug Class: Belatacept is a selective T-cell (lymphocyte) costimulation blocker.

Uniqueness of Drug: Belatacept binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28-mediated costimulation of T lymphocytes. In vitro, the drug inhibits T-lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-α, interleukin-4 (IL-4), and tumor necrosis factor alpha (TNF-α). Activated T lymphocytes are the predominant mediators of immunologic rejection. In non-human primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased the production of anti-donor antibodies when compared with the vehicle.

Boxed Warning. There is an increased risk of post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to EBV are at a particularly high risk; therefore, belatacept should be used only in EBV-seropositive patients. It should not be used in transplant recipients who are EBV-seronegative or in patients whose EBV serostatus is unknown.

Only physicians experienced in immunosuppressive therapy and in treating kidney transplant recipients should prescribe belatacept. Patients should be treated in facilities equipped with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have all information needed for patient follow-up. Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression.

The use of belatacept in liver transplantation is not recommended because of an increased risk of graft loss and death.

Warnings and Precautions:

Post-transplant lymphoproliferative disorder. Belatacept-treated patients have an increased risk of PTLD, primarily involving the CNS, compared with patients receiving a cyclosporine-based regimen. Because the total burden of immunosuppression is a risk factor for PTLD, patients should not receive any doses higher than those recommended, more frequent dosing of belatacept, or higher than the recommended doses of concomitant immunosuppressive agents. Physicians should consider a diagnosis of PTLD in patients who report new or worsening neurological, cognitive, or behavioral signs or symptoms.

EBV serostatus. The risk of PTLD is higher in EBV-seronegative patients than in EBV-seropositive patients, who are defined as having evidence of acquired immunity, as shown by the presence of immunoglobulin (IgG) antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). EBV serological status should be obtained before patients start belatacept, and only patients who are EBV-seropositive should receive this medication. Transplant recipients who are EBV-seronegative or whose serostatus is unknown are not candidates for belatacept.

Other risk factors for PTLD include the use of T-cell–depleting therapy and cytomegalovirus (CMV) infection. Caution should be used when T-cell–depleting therapies are prescribed for preventing acute organ rejection. CMV prophylaxis should be given for at least three months after transplantation.

Patients who are EBV-seropositive and CMV-seronegative may be at an increased risk of PTLD compared with patients who are EBV-seropositive and CMV-seropositive. Because CMV-seronegative patients have an increased risk of CMV infection (a risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined. However, these findings should be considered when belatacept is prescribed.

Immunosuppression. Only physicians experienced in using systemic immunosuppressant therapy in transplantation should prescribe belatacept. Patients should be treated in facilities equipped with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have all information necessary for patient follow-up.

Other malignancies. Patients receiving immunosuppressants, including belatacept, have an increased risk of malignancy, including skin cancer. Patients should limit their exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor.

Progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC (John Cunningham) virus, a human polyoma virus. In clinical trials, two cases of PML were reported in patients who received belatacept at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil and corticosteroids. One patient was a kidney transplant recipient, and the other patient was a liver transplant recipient. Because PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of belatacept and concomitant immunosuppressive agents, including mycophenolate mofetil, should not be exceeded.

Other infections. Patients receiving immunosuppressants, including belatacept, are at an increased risk of bacterial, viral (CMV and herpes), fungal, and protozoal infections, as well as opportunistic infections, which can lead to serious or fatal outcomes. Prophylaxis for CMV infection is recommended for at least three months after transplantation.

Tuberculosis. In clinical trials, tuberculosis was observed more frequently in patients receiving belatacept than in those receiving cyclosporine. Patients should be evaluated for tuberculosis and tested for latent infection before they start belatacept.

Polyoma virus nephropathy. In addition to cases of JC virus–related PML, polyoma virus–associated nephropathy (PVAN), caused primarily by BK virus infection, has been reported. PVAN is associated with deteriorating renal function and kidney graft loss. Patient monitoring may help to detect patients at risk for PVAN. Reducing immunosuppressive agents should be considered for patients with evidence of PVAN.

Liver transplantation. Belatacept is not recommended for liver transplant recipients. In a clinical trial, the use of regimens that involved more frequent administration of belatacept than any of the other regimens studied in kidney transplantation, along with mycophenolate mofetil and corticosteroids, was associated with a higher rate of graft loss and death compared with patients in control arms who received tacrolimus (Prograf, Astellas/Fujisawa).

Dosage and Administration: Belatacept is indicated for intravenous infusion only and is available as a 250-mg lyophilized powder. Patients do not require premedication prior to administration. The total infusion dose should be based on the patient’s actual body weight at the time of transplantation and should not be modified during the course of therapy unless there is a change in body weight of greater than 10%. The prescribed dose must be evenly divisible by 12.5 mg in order for it to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100.

Commentary: Belatacept is the first selective T-cell co-stimulation blocker indicated for preventing organ rejection in adults receiving a kidney transplant. It is used with basiliximab induction, mycophenolate mofetil, and corticosteroids. Only patients who are EBV-seropositive should receive this medication. The use of belatacept for preventing rejection of organs other than the kidney has not been established.


Vandetanib (Caprelsa)

Manufacturer: Astra-Zeneca, Wilmington, Del.

Indication: Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. The use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease should be carefully considered because of the treatment-related risks.

Drug Class: Vandetanib is an orally available receptor tyrosine kinase (RTK) inhibitor, which blocks both vascular endothelial growth factor (VEGF) RTK and epidermal growth factor (EGF) RTK. Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine.

Uniqueness of Drug: Blockade of the VEGF receptors limits the growth of new blood vessels, which support the growth of tumors. Without sufficient blood supply, tumor cells become starved for nutrients, and their growth is consequently halted or slowed.

Boxed Warning: Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. Patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome should not receive this drug. Hypocalcemia, hypokalemia, and hypomagnesemia must be corrected before vandetanib is taken, and patients should be monitored periodically.

Medications that prolong the QT interval should be avoided. If a drug that is known to prolong the QT interval must be administered, more frequent monitoring with electrocardiograms (ECGs) is recommended. Given the drug’s half-life of 19 days, ECGs should be obtained to monitor the QT interval at baseline, at two to four weeks, at eight to 12 weeks after starting treatment with vandetanib, and every three months thereafter. Following any dose reduction for QT prolongation, or any dose interruption lasting longer than two weeks, the QT interval should be assessed. Because of the drug’s 19-day half-life, adverse reactions, including a prolonged QT interval, may not resolve quickly.

Only prescribers and pharmacies certified through the company’s Risk and Evaluation and Mitigation Strategy (REMS) education program may prescribe and dispense vandetanib.

Warnings and Precautions:

QT prolongation and torsades de pointes. Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia, and sudden death have occurred with vandetanib therapy. Patients whose corrected (Fridericia) QTcf interval is greater than 450 msec and who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmia, or uncompensated heart failure should not receive this drug. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

Renal impairment: Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate-to-severe renal impairment, and the QT interval should be monitored closely.

Skin reactions and Stevens–Johnson syndrome. Severe skin reactions (including Stevens–Johnson syndrome), some fatal, have been reported with vandetanib. Treatment of severe skin reactions has sometimes consisted of systemic corticosteroids and permanent discontinuation of vandetanib. Mild-to-moderate skin reactions may manifest as rash, acne, dry skin, dermatitis, and pruritus.

Interstitial lung disease. Interstitial lung disease or pneumonitis has been observed with vandetanib, and deaths have been reported.

Ischemic cerebrovascular events. Vandetanib has been associated with ischemic cerebrovascular events, and some patients have died. In the randomized medullary thyroid cancer study, ischemic cerebrovascular events were observed more frequently with vandetanib than with placebo (1.3% vs. 0%). No deaths were reported.

Hemorrhage and heart failure. Serious hemorrhagic events, as well as heart failure, have been observed with vandetanib and have sometimes resulted in fatalities.

Diarrhea. Diarrhea has been documented in patients who received vandetanib. Routine antidiarrheal agents are recommended.

Hypertension. Vandetanib has been associated with hypertension, including hypertensive crisis.

Reversible posterior leukoencephalopathy syndrome. Characterized by subcortical vasogenic edema, this syndrome has been observed with vandetanib therapy.

Dosage and Administration: The recommended daily dose is 300 mg taken orally. Vandetanib should be continued until patients are no longer benefiting from treatment or until unacceptable toxicity occurs.

Commentary: According to the FDA, medullary thyroid cancer accounts for 3% to 5% of approximately 45,000 new cases of thyroid cancer diagnosed in the U.S. each year. No other FDA-approved systemic treatments for the disease are available. The product was approved as a once-daily oral tablet for patients with thyroid cancer. As an orphan drug, this kinase inhibitor is indicated for patients with metastatic or locally advanced, inoperable medullary thyroid cancer.

In addition to a boxed warning noting the possibility of QT prolongation, torsades de pointes, and sudden death, other serious warnings and precautions are associated with vandetanib. Consequently, great care should be taken with the use of this drug.


Gabapentin Enacarbil Extended-Release Tablets (Horizant)

Manufacturer: Xenoport, Inc., Santa Clara, Calif./Glaxo-SmithKline, Research Triangle Park, N.C.

Indication: Horizant is intended for adults with moderate-to-severe primary restless legs syndrome (RLS), also known as Ekbom’s disease.

Drug Class: Gabapentin enacarbil is a prodrug of gabapentin. Its chemical formula is (1-{[({(1RS)-1-[(2-methyl-propanoyl)oxy]ethoxy}carbonyl)amino]methyl}cyclohexyl) acetic acid. The molecular formula is C16H27NO6, and the molecular weight is 329.39.

Uniqueness of Drug: The precise mechanism by which the medication is efficacious in RLS is unknown. Gabapentin is structurally related to the neurotransmitter gamma-amino-butyric acid (GABA), but it has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil and gabapentin have been tested in radioligand binding assays, and neither drug has exhibited affinity for a number of other common receptors, ion channels, or transporter proteins.

Warnings and Precautions:

Effects on driving. Horizant therapy may result in significant impairment during driving. Patients should not drive until they have gained sufficient experience to assess whether the medication is impairing their ability to drive.

Somnolence, sedation, and dizziness. Somnolence with sedation and dizziness may occur with therapy. Patients should be advised not to drive or operate other complex machinery until they have gained sufficient experience with the regimen to assess whether the medication has impaired their ability to perform these tasks.

Lack of interchangeability with gabapentin. Gabpentin enacarbil (Horizant) is not interchangeable with other gabapentin products because they have differing pharmacokinetic profiles. The same dose of Horizant results in plasma concentrations of gabapentin that differ when compared with the same dose of other gabapentin products.

Suicidal behavior and ideation. Gabapentin enacarbil is a prodrug of gabapentin, which is an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. As a prodrug, Horizant also increases this risk. Patients who are using an AED should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

Discontinuation of therapy. Patients receiving the recommended dose of 600 mg daily can stop taking the drug without tapering. If the recommended Horizant dose is exceeded, it should be reduced to 600 mg daily for one week before patients stop therapy in order to minimize the potential of withdrawal seizures.

Tumorigenic potential. In a study of oral carcinogenicity, Horizant increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats. The clinical significance of this finding is unknown.

Commentary: Gabapentin enacarbil ( Horizant) is the first medication in its class to be approved for patients with moderate-to-severe primary RLS. This chronic neurological condition is characterized by an urge to move caused by unpleasant sensations in the legs. Patients with moderate-to-severe primary RLS can experience a range of disruptive symptoms. RLS is underrecognized, and many patients remain untreated as a result.

The efficacy of this medication was demonstrated in two 12-week clinical trials. As a result of different pharmacokinetic profiles, this form of gabapentin is not interchangeable with other gabapentin products. The same dose of Horizant results in different plasma concentrations of gabapentin relative to the same dose of other gabapentin products.