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Pharmaceutical Approval Update August 2014
Manufacturer: Takeda Pharmaceuticals America, Deerfield, Illinois
Date of Approval: May 20, 2014
Indication: Vedolizumab injection is indicated for the treatment of adult patients with moderate-to-severe ulcerative colitis and adult patients with moderate-to-severe Crohn’s disease. It is approved to treat those conditions when one or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor blockers) have not resulted in an adequate therapeutic response.
Biological Class: Vedolizumab, a monoclonal antibody, is an integrin receptor antagonist. Integrin receptors—proteins expressed on the surface of certain cells—function as bridges for cell–cell interactions. Vedolizumab binds to integrin alpha-4 beta-7, which results in selective anti-inflammatory activity in the gut.
Uniqueness of Biologic: By blocking the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), vedolizumab blocks the migration of those circulating inflammatory cells across those blood vessels and into already-inflamed areas of the intestine.
Warnings and Precautions:
Infusion and serious allergic reactions. These reactions can occur while patients are receiving the infusion or several hours afterward. Patients should receive medical help right away if they experience any of these symptoms during or after an infusion of vedolizumab: rash; itching; swelling of the lips, tongue, throat, or face; shortness of breath, trouble breathing, or wheezing; dizziness; feeling hot; or palpitations.
Infections. Vedolizumab may increase the risk of serious infections. Patients should be advised to tell their health care provider, before receiving the infusion or at any time during treatment, if they think they have an infection or if they have symptoms of an infection, such as fever, chills, muscle aches, cough, shortness of breath, runny nose, sore throat, red or painful skin, sores, tiredness, or pain during urination.
Progressive multifocal leukoencephalopathy (PML). Although PML has not been reported with vedolizumab, it may be possible for a person to get this rare, serious brain infection caused by a virus. People with weakened immune systems can be vulnerable to PML, which can result in death or severe disability. There is no known treatment, prevention, or cure. Symptoms may include confusion or difficulty thinking, loss of balance, changes in gait or speech, decreased strength, weakness on one side of the body, blurred vision, or loss of vision.
Liver problems. People who receive vedolizumab can experience liver problems.
Dosage and Administration: Vedolizumab is an intravenous (IV) infusion administered over approximately 30 minutes at zero, two, and six weeks and every eight weeks thereafter. Patients should be observed during and until completion of the infusion, as hypersensitivity reactions, including anaphylaxis, have occurred.
Commentary: Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal (GI) bleeding, and diarrhea. Crohn’s disease is a chronic condition that causes inflammation of any part of the GI tract. More than half a million Americans have been diagnosed with Crohn’s disease.
These two debilitating diseases affect the quality of life of those who have them. Although there is no cure for these conditions, the approval of this biologic provides an important new treatment option for patients who have had an inadequate response to conventional therapy to help control their symptoms. Somewhat greater benefits were seen in the clinical trials for ulcerative colitis than for Crohn’s disease. The Food and Drug Administration (FDA) has advised health care professionals to monitor patients closely on vedolizumab for new or worsening neurological symptoms, noting that it plans post-marketing surveillance and adverse event reporting.
Another integrin receptor antagonist, natalizumab (Tysabri, Biogen Idec), has been associated with PML, a brain infection caused by the JC virus that usually results in death or severe disability. In clinical trials of vedolizumab, no cases of this rare opportunistic infection occurred, but uncertainty remains regarding the risk, according to the FDA. Natalizumab is rarely prescribed because it increases the risk of PML.
Dalbavancin for Injection (Dalvance)
Manufacturer: Durata Therapeutics, Chicago, Illinois
Date of Approval: May 23, 2014
Indication: Dalbavancin is intended to treat acute bacterial skin and skin structure infections (ABSSSIs) in adults caused by certain susceptible gram-positive bacteria, such as Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius, and S. constellatus).
Drug Class: Dalbavancin for injection is a lipoglycopeptide synthesized from a fermentation product of the Nonomuraea species. It is a mixture of five closely related active homologs (A0, A1, B0, B1, and B2); B0 is the major component of dalbavancin. The homologues share the same core structure and differ in the fatty acid side chain of the N-acylaminoglucuronic acid moiety (R1) structure and/or the presence of an additional methyl group (R2) on the terminal amino group.
Uniqueness of Drug: This once-weekly, two-dose anti biotic belongs to the same class as vancomycin, the most widely used antibacterial and one of the few treatments available to patients infected with methicillin-resistant Staphylococcus aureus (MRSA). Dalbavancin was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin. It possesses in vitro activity against a variety of gram-positive pathogens, including MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE).
Warnings and Precautions:
Hypersensitivity reactions. Serious hypersensitivity and skin reactions have been reported in patients treated with dalbavancin. If an allergic reaction occurs, treatment with dalbavancin should be discontinued. Before using dalbavancin, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy.
Infusion-related reactions. Dalbavancin is administered via IV infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid IV infusions of dalbavancin can cause reactions that include flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.
Hepatic effects. Among subjects who had normal baseline transaminase levels in phase 2 and 3 clinical trials, more people treated with dalbavancin than with comparators had a post-baseline alanine aminotransferase (ALT) elevation greater than three times the upper limit of normal. Overall, abnormalities in liver tests (ALT, aspartate aminotransferase, bilirubin) were reported with similar frequency in the dalbavancin and comparator arms.
Clostridium difficile-associated diarrhea (CDAD). In users of nearly all systemic antibacterial drugs, including dalbavancin, CDAD has been reported with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile, which produces toxins A and B that contribute to CDAD development. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Taking a careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of drug-resistant bacteria. Prescribing dalbavancin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Dosage and Administration: For treatment of adults with ABSSSI, the recommended two-dose regimen of dalbavancin is 1,000 mg followed one week later by 500 mg. Dalbavancin should be administered over 30 minutes by IV infusion.
In patients with renal impairment whose known creatinine clearance is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended two-dose regimen of dalbavancin is 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and dalbavancin can be administered without regard to the timing of hemodialysis.
Commentary: Dalbavancin is the first drug designated as a qualified infectious disease product (QIDP) to receive FDA approval. It received a QIDP designation because it is an antibacterial drug intended to treat serious or life-threatening infections. The FDA also gave dalbavancin an expedited review, and Durata will receive an extra five years of exclusive marketing rights for the drug.
Durata has yet to set a price for Dalvance, but it is likely to charge a substantial premium over its chief competitor, generic vancomycin, which is the treatment of choice for ABSSSI. Convincing hospitals to put a premium-priced drug on their formularies in a fixed-payment environment could be a challenge. Clinical trials showed dalbavancin to be as effective as, but not better than, vancomycin for ABSSSI treatment.
However, dalbavancin has advantages that might appeal to hospitals. Described as a long-acting antibiotic, dalbavancin has the potential to reduce the length of stay for hospitalized patients with ABSSSI and perhaps help them avoid hospitalization altogether. Since vancomycin is administered via IV solution for ABSSSI treatment, it is generally given on an inpatient basis. Cellulitis, for example, which represents more than half of ABSSSI cases, is treated with vancomycin delivered via a peripherally inserted central catheter line in the hospital once or twice daily over 14 days. About 183,000 Medicare patients with cellulitis were admitted to hospitals in 2012—primarily to receive IV vancomycin.
Antihemophilic Factor (Recombinant) (Eloctate)
Manufacturer: Biogen Idec, Cambridge, Massachusetts
Date of Approval: June 6, 2014
Indication: Eloctate is indicated for use in adults and children who have hemophilia A.
Drug Class: Eloctate is an Fc fusion protein and consists of the coagulation factor VIII molecule (historically known as antihemophilic factor) linked to a protein fragment, Fc, that is found in antibodies. This makes the product last longer in the patient’s blood.
Uniqueness of Drug: Eloctate is developed by fusing B-domain deleted factor VIII to the Fc portion of immunoglobulin G subclass 1, or IgG1 (a protein commonly found in the body). This was designed to enable Eloctate to use a naturally occurring pathway to prolong the time therapy remains in the body. Eloctate is the first hemophilia A treatment designed to require less frequent injections when used to prevent or reduce the frequency of bleeding.
Warnings and Precautions:
Hypersensitivity reaction. Anaphylaxis and other reactions are possible with Eloctate. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
Neutralizing antibodies. The formation of inhibitors to factor VIII can occur following administration of Eloctate. Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the plasma factor VIII level fails to increase as expected or if bleeding is not controlled after Eloctate administration, suspect the presence of an inhibitor (neutralizing antibody).
Monitoring laboratory tests. Monitor plasma factor VIII activity by performing a validated test (such as a one-stage clotting assay) to confirm that adequate factor VIII levels have been achieved and maintained. Monitor for the development of factor VIII inhibitors as well. Perform a Bethesda inhibitor assay if expected factor VIII plasma levels are not attained, or if bleeding is not controlled with the expected dose of Eloctate. Use Bethesda Units to report inhibitor levels.
Dose and Administration: Eloctate is available in 250-IU, 500-IU, 750-IU, 1,000-IU, 1,500-IU, 2,000-IU, and 3,000-IU vials with supplies.
Commentary: Hemophilia A is an inherited, sex-linked, genetic blood-clotting disorder that primarily affects males and is caused by defects in the factor VIII coagulation protein. Hemophilia A affects one in every 5,000 males born in the United States. People with hemophilia A can experience repeated episodes of serious bleeding, mainly into the joints, which can be severely damaged by the bleeding. Eloctate received an orphan drug designation for this use from the FDA, which described it as the first drug for this condition. Currently, hemophilia A is treated with recombinant factor VIII or concentrates derived from blood donations.
Eloctate is approved to help control and prevent bleeding episodes, to manage bleeding during surgical procedures, and to prevent or reduce the frequency of bleeding episodes (prophylaxis). The approval of this product provides an additional therapeutic option for use in the care of patients with hemophilia A.