Abstract
Topics include bendamustine (Treanda) for chronic lymphocytic leukemia, hepatitis B immune globulin (HepaGam B) to prevent hepatitis B infection following liver transplantation, and a fibrin sealant (Artiss) used in skin graft surgery for burn patients.
Bendamustine HCl (Treanda for Injection)
Manufacturer: Cephalon, Inc., Frazer, Pa.
Indication: Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Its efficacy relative to first-line therapies other than chlorambucil (Leukeran, GlaxoSmithKline) has not been established.
Drug Class: Bendamustine is an alkylating agent with a nitrogen mustard groupand a purine-like benzimidazol group.
Uniqueness of Drug: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activating DNA-damage stress response and apoptosis (cell death), inhibiting mitotic checkpoints, and inducing mitotic catastrophe, which disrupts cell division. Unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.
DNA replication stress develops in preneoplastic cells downstream of the activation of oncogenic growth-signaling pathways and contributes to oncogene-induced senescence.
Warnings and Precautions:
Myelosuppression: Patients receiving bendamustine are likely to experience myelosuppression. In a randomized CLL clinical study, treated patients experienced grade 3 or 4 neutropenia (24%) and febrile neutropenia (3%); 20% needed red blood cell transfusions, and fewer than 1% needed platelet transfusions. If treatment-related myelosuppression occurs, leukocytes, platelets, hemoglobin (Hb), and neutrophils should be closely monitored. In the study, hemoglobin and the white blood cell differential counts were monitored weekly and platelet counts were monitored during each cycle.
Based on data from this study, hematological nadirs should be expected in the third week of therapy and dose delays may be necessary if the recommended values have not recovered by day 28. Before the next cycle of therapy begins, the absolute neutrophil count should be one times 109/L or higher, and the platelet count should be 75 times 109/L or greater.
Infection: Infections, including pneumonia and sepsis, have been reported in patients in clinical trials and in postmarketing reports. Infection has been associated with hospitalization, septic shock, and death. Patients who have myelosuppression after treatment with bendamustine are more susceptible to infections, and they should be advised to contact a physician if they have symptoms or signs of infection.
Infusion reactions and anaphylaxis: Infusion reactions to bendamustine have been common in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Patients should be monitored, and the medication should be discontinued if reactions are severe. Patients should be asked about symptoms that suggest infusion reactions after the first cycle of therapy. In the CLL study, patients who experienced grade 3 or worse allergic-type reactions were not usually re-challenged.
Measures to prevent severe reactions, including antihistamines, antipyretic agents, and corticosteroids, should be considered in subsequent cycles for patients who have previously experienced grade 1 or 2 infusion reactions. Discontinuation of bendamustine should be considered in patients with grade 3 or 4 infusion reactions.
Tumor lysis syndrome: Bendamustine-associated tumor lysis syndrome has been reported. The onset tends to be within the first treatment cycle. Without intervention, the syndrome can lead to acute renal failure and death. Preventive measures include maintaining adequate volume status; close monitoring of blood chemistry, particularly potassium and uric acid levels; and the use of allopurinol (Zyloprim, Prometheus) during the first one to two weeks of bendamustine therapy in patients at high risk.
Skin reactions: Rash, bullous exanthema, and toxic skin reactions have been reported. Because some adverse drug events occurred when bendamustine was given along with other anticancer agents, the precise relationship of these events to bendamustine is uncertain. If skin reactions occur, they may be progressive and may increase in severity with further treatment. If skin reactions are severe or progressive, bendamustine should be withheld or discontinued.
Use in pregnancy: Bendamustine can cause fetal harm when given to pregnant women. Single intraperitoneal doses administered during organogenesis caused an increase in resorption, skeletal and visceral malformations, and decreased fetal body weights in mice and rats.
Dosage and Administration: Bendamustine HCl is available in a single-use vial containing 100 mg of lyophilized powder. The powder must be reconstituted and diluted further before it is infused. The dosing schedule is 100 mg/m2 infused intravenously over 30 minutes on days one and two of a 28-day cycle, up to six cycles.
For grade 2 non-hematologic toxicity or higher and for grade 4 toxicity, treatment should be delayed.
For grade 3 or greater toxicity, the dose should be reduced to 50 mg/m2 on the first and second days. If grade 3 or greater toxicity recurs, the dose should be lowered to 25 mg/m2 on days one and two.
For clinically significant grade 3 or greater non-hematological toxicity, the dose should be reduced to 50 mg/m2 on days one and two of each cycle. Dose re-escalation may be considered.
Commentary: CLL is a slowly progressing disease of the blood and bone marrow. The American Cancer Society estimates that more than 15,000 new cases of this rare disease will be diagnosed in the U.S. in 2008. Patients with CLL often have normal lives for many years because of treatments that control the disease over the long term. Granted orphan drug status by the FDA, bendamustine is an option that offers a delay in disease progression, an important goal for patients with CLL.
Bendamustine damages the DNA in cancer cells. Bendamustine-treated patients had a significantly longer progression-free survival at 18 months vs. six months (hazard ratio = 0.27; P < 0.0001) with no worsening of disease for a significant period of time. The duration of response to bendamustine lasted longer for treated patients (19 months) than in patients who received chlorambucil (seven months). Common adverse events in the trial were myelosuppression, fever, nausea, and vomiting.
Sources: www.cephalon.com; www.fda.gov/cder/foi/label/2008/022249lbl.pdf
Hepatitis B Immune Globulin Intravenous, Human (HepaGam B)
Manufacturer: Cangene, Winnipeg, Manitoba, Canada, and Apotex, Weston, Fla.
Indication: HepaGam B has been approved to prevent the recurrence of hepatitis B infection following liver transplantation in hepatitis B surface antigen (HBsAg)–positive patients. It was previously licensed to prevent hepatitis B virus (HBV) infection after acute exposure to blood or certain body fluids containing HBV; after perinatal exposure of infants to mothers exposed to HBV; after sexual exposure to persons exposed to HBV; and after household exposure to persons with acute HBV infection.
Drug Class: HepaGam B is a solvent/detergent–treated sterile solution of purified gamma globulin containing anti-HBs. It is prepared from plasma donated by healthy, screened donors with high titers of anti-HBs. It is purified by anion-exchange column chromatography.
Uniqueness of Drug: This purified antibody targets the hepatitis B virus. Patients who undergo liver transplantation because of HBV infection need long-term post-transplant therapy with hepatitis B immune globulin. In clinical trials, the product was highly effective in preventing recurrences of hepatitis B, and the dosing regimen used consistently yielded anti-HBsAg concentrations that exceeded target therapeutic levels.
Warnings and Precautions:
General: HepaGam B is made from human plasma. Products made from human plasma may contain infectious entities, such as viruses and, theoretically, the Creutzfeldt–Jakob disease agent. The risk of transmitting an infectious agent has been reduced by screening plasma donors for exposure to certain viruses, by testing for the presence of current viral infections, and by inactivating or removing certain viruses.
The manufacturing process includes a step using a solvent/detergent, tri-n-butyl phosphate/Triton X-100 (Union Carbide), which inactivates enveloped viruses such as HBV, HCV, and HIV. A Planova 20N Virus Filter is used to reduce the levels of some enveloped and non-enveloped viruses. These two processes are designed to increase product safety.
Despite these measures, plasma products still have the potential to transmit disease, and unknown infectious agents may be present in plasma products. Physicians and health care providers should notify Cangene Corporation about any infections suspected to have been transmitted by HepaGam B. The risks and benefits of this product should be discussed with the patient.
Anaphylactic precautions: Although allergic reactions have not been reported, the product should be given only where appropriate equipment and personnel trained in the management of acute anaphylaxis are available. If hypotension or anaphylaxis occurs, therapy should be discontinued immediately and supportive care given as needed.
Interference with blood glucose testing: The maltose contained in HepaGam B can interfere with some types of blood glucose–monitoring systems based on the glucose dehydrogenase–pyrroloquinequinone (GDH–PQQ) method. This can result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, thereby leading to life-threatening hypoglycemia. Cases of true hypoglycemia may remain untreated if the hypoglycemic state is masked by falsely elevated results.
Monitoring of serum anti-HBs antibody levels: A quantitative assay should be used to monitor liver transplant patients at regular intervals for serum anti-HBs antibody levels.
Infusion reactions: Certain adverse drug reactions may be related to the rate of infusion. The recommended infusion rate (2 mL/minute) must be closely followed. Patients must be monitored and carefully observed for any symptoms throughout the infusion period and immediately afterward.
Coagulation disorders: For postexposure prophylaxis indications, HepaGam B is intended for intramuscular (IM) use only. In patients who have severe thrombocytopenia or a coagulation disorder that would contraindicate IM injections, HepaGam B should be given only if the expected benefits outweigh the potential risks.
Nonclinical toxicology: Nonclinical pharmacology studies in animals have not been performed with HepaGam B, because there is broad experience in humans with IV and IM administration of immune globulin products. Because of HepaGam B’s human origin, immunogenicity is expected when this product is administered to animals.
Toxicology studies have not been performed with Hepa-Gam B because it has been formulated with ingredients that are known to be nontoxic at levels present in the final product.
Special Populations:
Pregnancy Category C: Studies of reproduction in animals have not been conducted with HepaGam B, and it is not known whether the product causes fetal harm when given to pregnant women or whether it affects reproductive capacity. The product should be given to pregnant women only if it is clearly indicated.
Nursing Mothers: It is not known whether HepaGam B is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when the product is given to nursing mothers.
Dosage and Administration: Any vials of HepaGam B that have been entered should be used promptly and should not be reused or saved for future use. The product contains no preservatives; therefore, partially used vials should be discarded immediately.
To prevent hepatitis B recurrence after liver transplantation in HBsAg–positive patients, clinicians should administer Hepa-Gam B intravenously according to a set dosing regimen designed to attain serum levels of antibodies to anti-HBs above 500 IU/L. On the basis of the clinical trial, patients should receive 20,000 IU per dose. The volume of each 20,000 IU dose should be calculated from the measured potency of the particular lot, as stamped on the vial label.
The first dose should be administered concurrently with the grafting of the transplanted liver (the anhepatic phase) with subsequent dosing (Table 1). Dose adjustments may be necessary if patients do not achieve anti-HBs levels of 500 IU/L within the first week after transplantation. Patients who experience surgical bleeding or abdominal fluid drainage (more than 500 mL) or patients who undergo plasmapheresis are particularly susceptible to extensive loss of circulated anti-HBs. In these cases, the dosing regimen should be increased to a half-dose (10,000 IU calculated from the measured potency, as stamped on the vial label) intravenously every six hours until the target anti-HBs antibody levels are achieved.
Table 1.
Dosing Regimen for Intravenous (Human) Hepatitis B Immune Globulin (HepaGam B)*
| Anhepatic Phase | Week 1 Postoperatively | Weeks 2 to 12 Postoperatively | Month 4 Onward |
|---|---|---|---|
| First dose | Daily from days 1 to 7 | Every two weeks from day 14 | Monthly |
Each dose should contain 20,000 IU calculated from the measured potency, as stamped on the vial label.
HepaGam B is most effective when patients have no or low levels of HBV replication at the time of transplantation. Regular monitoring of serum HBsAg and anti-HBs antibody levels should be performed before the infusion in order to track patients’ responses to therapy and to allow for adjustments in treatment.
The product should be prepared under aseptic conditions and should be given through a separate IV line via an infusion pump. The rate of administration should be set at 2 mL/minute and should be decreased to 1 mL/minute or more slowly if the patient experiences discomfort or infusion-related adverse events or if the speed of infusion is a concern.
Commentary: Hepatitis is contagious and is caused by HAV, HBV, or HCV. HBV (serum hepatitis) spreads through infected body fluids, such as blood, saliva, semen, vaginal fluids, tears, and urine. Approximately 8,500 new cases of hepatitis B are reported annually in the U.S. Exposure to HBV can lead to acute (short-lived) or chronic (long-term) infection. About 1% of acute hepatitis B (fulminant hepatitis) patients die of liver damage in this early stage, and 10% of hepatitis B patients develop chronic, life-long infection. Patients with chronic hepatitis B might not have symptoms, but they can become carriers and can spread the disease. This infection increases the chance of permanent liver damage, including cirrhosis and liver cancer.
Patients with HBV infection who undergo liver transplantation require long-term therapy with hepatitis B immune globulin after the procedure. In a clinical trial, HepaGam B was effective in preventing recurrences and the dosing regimen used consistently yielded anti-HBsAg levels that exceeded target therapeutic levels.
In 2005, about 6,500 liver transplant procedures were performed in the U.S. The number of liver transplants performed per year has been increasing steadily for more than 15 years. Approximately 17,000 Americans are currently on a waiting list for a liver transplant. The most common reason for needing a liver in adults is cirrhosis.
Sources: www.hepagamb.com; www.rxlist.com
Fibrin Sealant, Human (Artiss)
Manufacturer: Baxter Healthcare, Deerfield, Ill.
Indication: Artiss sealant is designed to facilitate the adherence of autologous skin grafts to surgically prepared wound beds resulting from burns in adults and children. It is not indicated for hemostasis.
Drug Class: Artiss is a biologically active sealant consisting of human fibrinogen and a low concentration human thrombin.
Uniqueness of Product: Essential for blood clotting, Artiss contains less thrombin compared with other fibrin sealants. The lower concentration allows surgeons more time to position skin grafts over burns before the graft begins to adhere to the skin. Artiss also contains aprotinin, a synthetic protein that delays the breakdown of blood clots.
Warnings and Precautions:
Hypersensitivity and allergic or anaphylactic reactions: Fewer than one in 10,000 cases of allergic reactions have been reported in postmarketing experience with Artiss sealant. These reactions have sometimes progressed to severe anaphylaxis and may be more likely to occur if the sealant is applied repeatedly over time or in the same setting, or if patients have previously received systemic aprotinin. Even if the first treatment was well tolerated, another administration of Artiss or systemic aprotinin does not exclude the possibility of an allergic reaction. Such reactions can also occur in patients receiving the sealant for the first time.
If a hypersensitivity reaction does occur, the application should be discontinued. The already applied polymerized product should be removed from the surgical field. Mild reactions can be managed with antihistamines. Patients experiencing severe hypotensive reactions require an immediate intervention that uses the current principles of shock therapy.
Risk of infection from human plasma: Artiss sealant is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent is reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses. Despite these measures, such products can still transmit disease. Made from human blood, Artiss carries a risk of transmitting infection (viruses, and theoretically, the Creutzfeldt–Jakob disease agent). All infections suspected to have been transmitted by this product should be reported to Baxter Healthcare.
Application Precautions: The sealant is applied as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and with wound healing. Clinicians must use caution when applying the sealant and while using pressurized gas. Any application of pressurized gas carries a potential risk of air embolism, tissue rupture, or gas entrapment with compression, which may be life-threatening. The sealer protein and thrombin solutions can be denatured by alcohol, iodine, or heavy metal ions. If any of these substances have been used to clean the wound, the area must be thoroughly rinsed before the sealant is applied, and the area should be made as dry as possible.
Adverse Events: The following adverse drug events reflect those reported in postmarketing experience with Baxter’s fibrin sealant, and they can reasonably be expected to occur with Artiss: anaphylactic responses, hypersensitivity, bradycardia, tachycardia, dyspnea, nausea, hives, flushing, impaired healing, edema, pyrexia, and seroma.
Dosage and Administration: This product is intended for topical use only and should not be injected. The required dose depends on the size of the surface to be covered (Table 2). The aerosolized sealant is applied to the wound in a painting motion from side to side to achieve a single thin layer. The wound bed glistens in the area to which fibrin sealant has been applied. Any areas not covered by fibrin sealant are clearly visible.
Table 2.
Surface Area Covered by Package Sizes of Fibrin Sealant (Artiss)
| Approximate Area Requiring Skin Graft Fixation | Required Package Size of Sealant |
|---|---|
| 100 cm2 | 2 mL |
| 200 cm2 | 4 mL |
| 500 cm2 | 10 mL |
The skin graft is attached to the wound bed immediately after the sealant has been sprayed. The surgeon has approximately 60 seconds to manipulate and position the graft prior to polymerization. To prevent adherence, the surgeon wets the gloves with normal saline before touching the sealant. After the graft is applied, it is held in the desired position by gentle compression for at least three minutes to ensure that the sealant sets properly and adheres firmly to the surrounding tissue. The solidified fibrin sealant reaches its final strength approximately two hours later.
Commentary: The approval of Artiss fibrin sealant can help surgeons to fine-tune graft placement on burn sites. The fibrinogen and thrombin proteins in the sealant are derived from human plasma that is collected from FDA-licensed plasma centers. Both proteins undergo purification and virus-inactivation treatments to reduce the risk of blood-transmissible infections. In clinical trials, this sealant was as good, within a statistical error, as using staples to attain complete wound closure.
Source: www.baxter.com