Pralatrexate (Folotyn)
Manufacturer: Allos Therapeutics, Westminster, Colo.
Indication: Pralatrexate for intravenous (IV) injection is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Benefits such as improvement in progression-free survival and overall survival have not been demonstrated.
Drug Class: Pralatrexate is an antineoplastic folate analogue. Its chemical name is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. Pralatrexate is a 1:1 racemic mixture of S- and R-diastereomers at the C10 position. The molecular formula is C23H23N7O5, and the molecular weight is 477.48.
Uniqueness of Drug: Pralatrexate competitively blocks dihydrofolate reductase and is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules, the synthesis of which depends on single carbon transfer.
Warnings and Precautions:
Bone marrow suppression. Pralatrexate can suppress bone marrow function, resulting in manifestations of thrombocytopenia, neutropenia, and anemia. Dose modifications are based on the absolute neutrophil and platelet counts before each dose is given.
Mucositis. Treatment with pralatrexate may cause mucositis. If grade 2 or higher mucositis is observed, the dose should be modified.
Folic acid and vitamin B12 supplementation. Patients should be instructed to take folic acid, and they should receive vitamin B12 to reduce potential treatment-related hematological toxicities and mucositis.
Pregnancy Category D. Pralatrexate can cause fetal harm in pregnant women, and it is embryotoxic and fetotoxic in rats and rabbits. If the drug is used during pregnancy or if the patient becomes pregnant while taking it, she should be apprised of the potential hazard to the fetus.
Decreased renal function. Although pralatrexate has not been formally tested in patients with renal impairment, caution is advised for patients with moderate-to-severe impairment. Patients should be monitored for renal function and systemic toxicity as a result of increased drug exposure.
Elevated liver enzymes. Liver function test (LFT) abnormalities have been observed after pralatrexate administration. Persistent LFT abnormalities may be indicators of liver toxicity, and dose modifications may be required. Patients should be monitored for liver function.
Dosage and Administration: Pralatrexate should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Peripheral T-cell lymphoma. The recommended dose is 30 mg/m2, administered as an IV push over three to five minutes via the side port of a free-flowing 0.9% sodium chloride injection, USP IV line once weekly for six weeks in seven-week cycles. Therapy should continue until progressive disease or unacceptable toxicity ensues.
Vitamin supplementation. Patients should take low-dose oral folic acid (1–1.25 mg) on a daily basis, starting during the 10-day period preceding the first dose of pralatrexate and continuing during the full course of therapy and for 30 days after the last dose. Patients should also receive a 1-mg vitamin B12 intramuscular injection no more than 10 weeks before the first dose of pralatrexate and every 8 to 10 weeks thereafter. Subsequent vitamin B12 injections may be given on the same day as treatment with pralatrexate.
Commentary: Pralatrexate injection was approved as an orphan drug and was the first single agent for patients with relapsed or refractory PTCL. The relatively rare and often aggressive type of non-Hodgkin’s lymphoma occurs in fewer than 9,500 patients annually in the U.S. The FDA’s action was based on a priority review of data from an open-label, non-randomized, uncontrolled, single-group, multicenter international clinical trial (PROPEL). Results showed that 27% of the evaluable patients demonstrated a reduction in tumor size, and most responders (66%) achieved this effect within the first cycle of therapy. Additional studies are necessary to verify tumor shrinkage.
Source: www.folotyn.com
Telavancin (Vibativ)
Manufacturer: Theravance, South San Francisco, Calif./Astellas Pharma US, Deerfield, Ill.
Indication: Telavancin for injection is indicated for adults with complicated skin and skin-structure infections (cSSSIs) caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, and S. constellatus), or Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be indicated if the pathogens include gram-negative organisms.
Drug Class: Telavancin HCl, a lipoglycopeptide antibacterial agent, is a synthetic derivative of vancomycin. The chemical name is vancomycin, N3″-[2-(decylamino)ethyl]-29-[[(phosphonomethyl)-amino]-methyl]-HCl. The final product is a sterile, preservative-free, white to slightly colored lyophilized powder containing telavancin HCl (equivalent to either 250 mg or 750 mg of telavancin as the free base) for IV use along with inactive ingredients.
Uniqueness of Drug: Telavancin inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan. It binds to the bacterial membrane and disrupts membrane barrier function.
Boxed Warning:
Fetal risk. Women of childbearing age should have a serum pregnancy test before receiving telavancin. This product should be avoided during pregnancy unless the potential benefits to the patient outweigh the potential risks to the fetus. In three animal species, adverse developmental outcomes observed at clinically relevant doses raise concerns about possible adverse outcomes in humans.
Warnings and Precautions:
Pregnancy. If a woman of childbearing age is not yet pregnant, she should use effective contraception during treatment. Pregnant women should avoid taking this drug unless the potential benefits outweigh the potential risks to the fetus.
Nephrotoxicity. Increases in serum creatinine to 1.5 times baseline occurred more frequently among telavancin-treated patients with normal baseline serum creatinine levels (15%) compared with vancomycin-treated patients with normal baseline serum creatinine levels (7%).
Decreased efficacy with moderate-to-severe baseline renal impairment. In a subgroup analysis of pooled cSSSI studies, clinical cure rates in telavancin-treated patients were lower in patients with a baseline creatinine clearance (CrCl) of 50 mL/minute or less than in those with a CrCl above 50 mL/minute. A decrease of this magnitude was not observed in vancomycin-treated patients. These data should be considered when one is selecting antibacterial therapy for patients with baseline moderate-to-severe renal impairment.
Infusion-related reactions. As a lipoglycopeptide antibacterial agent, telavancin should be administered over a period of 60 minutes to reduce the risk of infusion-related reactions. Rapid IV infusions of the glycopeptides can cause reactions resembling those of “red-man syndrome,” including flushing of the upper body, urticaria, pruritus, and rash. Stopping or slowing the infusion may result in cessation of these reactions.
Clostridium difficile–associated diarrhea. C. difficile–associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the flora of the colon and may permit overgrowth of C. difficile.
Development of drug-resistant bacteria. Prescribing telavancin in the absence of a proven or strongly suspected bacterial infection is unlikely to help the patient and increases the risk of the development of drug-resistant bacteria.
QTc prolongation. In a study involving healthy volunteers, doses of 7.5 and 15 mg/kg of telavancin prolonged the corrected QT (QTc) interval. Caution is warranted when patients are taking drugs that are known to prolong the QT interval.
Interference with coagulation testing. Although telavancin does not interfere with coagulation, it did affect the accuracy of some tests used to monitor coagulation when samples were drawn 0 to 18 hours after the drug was given once every 24 hours. Blood samples for these coagulation tests should be collected as close as possible to the time before the patient’s next dose. In clinical trials, no evidence of increased bleeding risk was noted. Telavancin has no effect on platelet aggregation.
Dosage and Administration: Telavancin is supplied in single-use vials containing either 250 or 750 mg as a sterile, lyophilized powder.
Complicated skin and skin-structure infections. The recommended dosing for telavancin is 10 mg/kg, given over a 60-minute period in patients 18 years of age or older, by IV infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient’s clinical and bacteriological progress.
Renal impairment. Because telavancin is eliminated primarily by the kidneys, a dosage adjustment is required for patients with a CrCl of 50 mL/minute or below. There is insufficient information to make specific dosage adjustment recommendations for patients with end-stage renal disease (those with a CrCl below 10 mL/minute), including patients undergoing hemodialysis.
Commentary: Telavancin for injection has demonstrated efficacy and safety in clinical trials for the treatment of gram-positive cSSSIs that included the largest cohort of patients with methicillin-resistant S. aureus (MRSA) studied to date. A retrospective analysis of clinical and microbiologic efficacy assessed at the test of cure (7 to 14 days after completing therapy) in 194 patients from two randomized, double-blind clinical trials comparing telavancin (10 mg/kg IV every 24 hours; n = 101) with vancomycin (1 g IV every 12 hours; n = 93) for the treatment of cSSSIs. Baseline characteristics were similar for both treatment groups. Clinical cure and microbiologic eradication rates demonstrated consistent trends favoring telavancin over vancomycin, although the differences were not statistically significant. The incidence of adverse events was generally similar between groups. Thus, the novel bactericidal lipoglycopeptide telavancin has an acceptable adverse-event profile and is non-inferior to standard use of vancomycin treatment of patients with cSSSIs. For more information, please see the work of Wilson et al. (Am J Surg 2009;197[6]:791–796).
Source: www.astellas.us
Bepotastine Besilate Ophthalmic Solution 1.5% (Bepreve)
Manufacturer: Ista Pharmaceuticals, Irvine, Calif. (licensed from Senju Pharmaceuticals, Japan)
Indication: This prescription eyedrop is a nonsedating, highly selective histamine H1-receptor antagonist intended for treating itching associated with signs and symptoms of allergic conjunctivitis in patients older than two years of age.
Drug Class: Bepotastine besilate is designated chemically as (+)-4-[[(S)-p-chloro-alpha2-pyridyl benzyl]oxy]-1-piperidine butyric acid monobenzene sulfonate. The molecular weight is 547.06. The product is supplied as a sterile, aqueous 1.5% solution with a pH of 6.8.
Uniqueness of Product: The solution, which inhibits the release of histamine from mast cells, also suppresses the migration of eosinophils into inflamed tissues.
Warnings and Precautions:
Contamination. To minimize the risk of contaminating the dropper tip and solution, care should be taken not to touch the eyelids or any surrounding areas with the dropper tip of the bottle. The bottle should be kept tightly closed when not in use.
Contact lens use. Patients should be advised not to wear contact lenses if the eye is red. The solution should not be used to treat contact lens–related irritation, and it should not be instilled while the patient is wearing contact lenses. The lenses should be removed before the product is instilled. The preservative in the solution, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted 10 minutes after the solution is instilled.
Contraindications: There are no contraindications to the use of this product.
Adverse Effects: The most common adverse reaction occurring in 25% of patients was a mild taste following instillation. Other events occurring in 2% to 5% of patients were eye irritation, headache, and nasopharyngitis.
Dosage and Administration: Bepotastine is indicated for topical ophthalmic use only. One drop at a concentration of 1.5% is instilled into the affected eye twice a day.
Commentary: Allergic conjunctivitis is a common disease, affecting 20% to 30% of the general population, or 60 to 90 million individuals in the U.S. The prevalence may be increasing, and patients of all ages are affected. Most patients use many different medications over time for a variety of reasons. Medications targeting multiple mechanisms of action against inflammatory mediators are more efficacious.
Bepotastine has a stabilizing effect on mast cells. In clinical studies, highly statistically significant reductions were noted in the primary endpoints of ocular itching. Results also showed a statistically significant effect on the rapidity of response and on additional signs or symptoms of ocular allergy, including improvement in nasal symptoms.
Sources: Medical News Today, September 9, 2009; Ista, www.istavision.com