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Pharmacy Times |
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| SECTION 1 Introduction SECTION 2 Balsalazide Disodium (Colazal) Cetrorelix Acetate (Cetrotide) Gemtuzumab Ozogamicin (Mylotarg) Insulin Aspart Recombinant (NovoLog) Lopinavir & Ritonavir (Kaletra) Pantoprazole Sodium (Protonix) Rivastigmine Tartrate (Exelon) Triptorelin Pamoate (Trelstar Depot) Unoprostone Isopropyl (Rescula) SECTION 4
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New Drugs of 2000
Michael A. Mancano, PharmDDr. Mancano is Associate Professor of Clinical Pharmacy at Temple University School of Pharmacy, Philadelphia, PA.
IntroductionDuring 2000, the FDA approved many important medications. This continuing education program will review, in depth, 23 new drug approvals of 2000. New treatments were approved for human immunodeficiency virus (HIV)-1 infection, diabetes mellitus, Alzheimer’s disease, epilepsy, and advanced prostate cancer, to name just a few.
The drug reviews contained in this program are comprised of the current dosing guidelines, common adverse effects, contraindications to therapy, and the current FDA-approved indications. This review focuses on the new molecular entities that pharmacists will most likely come in contact with in their practice.
Table 1 provides a complete list of the new molecular entities approved by the FDA during 2000.
Table 2 contains a list of the new formulation approvals—new dosage forms or new formulations of active ingredients already on the market—for 2000.
Table 3 contains a list of new combination approvals—drugs that contain two or more compounds, the combination of which has not been marketed together in a product—for 2000.
Table 4 contains the new derivative approvals. The new derivative approvals are a chemical derived from an active ingredient already marketed, “a parent drug.”
Alosetron tablets were indicated for the treatment of irritable bowel syndrome in women whose predominant bowel symptom is diarrhea. The FDA approved alosetron on February 9, 2000, however, by November 10, 2000, the FDA had received numerous reports of serious adverse events. The reported adverse events included 70 cases of ischemic colitis, severely obstructed or ruptured bowel, and death. After discussions between the FDA and Glaxo Wellcome, the company chose to voluntarily withdraw alosetron tablets from the market. At this time, the FDA and Glaxo Wellcome are working to develop risk management plans to ensure appropriate patient access to this medically important and effective drug.
Argatroban
(Acova) Argatroban is a direct thrombin inhibitor, derived from L-arginine, which reversibly binds to the thrombin active site. Argatroban does not require the cofactor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or thrombin-induced reactions (ie, fibrin formation, activation of coagulation factors V, VIII, and XIII, protein C, and platelet aggregation). Argatroban is capable of inhibiting the action of both free- and clot-associated thrombin. Argatroban does not interact with heparin-induced antibodies. Argatroban is indicated for use as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Before argatroban is administered, health care professionals should discontinue heparin therapy and obtain a baseline activated partial thromboplastin time (aPTT). The recommended initial dose of argatroban for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion. In patients with hepatic impairment, an initial dose of 0.5 mcg/kg/min is recommended. In general, argatroban therapy is monitored using the aPTT. Anticoagulant effects typically attain steady state within 1 to 3 hours following initiation of argatroban. After the initial dose of argatroban, the dose can be adjusted as clinically indicated, however not to exceed 10 mcg/ kg/min, until steady state aPTT is 1.5 to 3 times the initial baseline value, not to exceed 100 seconds. Argatroban is contraindicated in patients with overt major bleeding. Argatroban is intended for intravenous administration. All parenteral anticoagulants should be discontinued before administration of argatroban. Hemorrhage can occur at any site in the body in patients receiving argatroban. Hemorrhagic adverse events occurring with the use of argatroban have included a decrease in hemoglobin, hematocrit, and hemoptysis. A hemorrhagic event should be considered if the following occur: an unexplained fall in hematocrit, a fall in blood pressure, or any unexplained symptom. Argatroban should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. Nonhemorrhagic adverse events associated with argatroban therapy are hypotension, fever, diarrhea, nausea, vomiting, and abdominal pain. Concomitant use of argatroban and antiplatelet drugs, thrombolytics, and other anticoagulants may increase the risk of bleeding. A pharmacokinetic drug interaction between argatroban and warfarin has not been demonstrated; however, the concomitant use of argatroban and warfarin results in a prolongation of the prothrombin time and international normalized ratio (INR). The combination of warfarin and argatroban does not cause any further reduction in the vitamin K–dependent factor Xa activity than that seen with warfarin alone. Argatroban is supplied as a concentrated drug that must be diluted 100-fold prior to infusion. Argatroban should not be mixed with other drugs prior to dilution in a suitable intravenous fluid. Argatroban is supplied as 100-mg/mL solution in 2.5-mL single-use vials in packages of 1 or 10 vials. Each vial contains 250 mg of argatroban.
Arsenic Trioxide
(Trisenox) Arsenic trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t (15;17) translocation or promyelocytic leukemia/retinoic acid receptor (PML/RAR)-alpha gene expression. The mechanism of action of arsenic trioxide is not completely understood. Arsenic trioxide causes morphological changes in DNA fragmentation characteristics of apoptosis in NB4 human promyelocytic leukemia cells. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. For induction treatment, arsenic trioxide should be administered intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Arsenic trioxide should be administered intravenously over 1 to 2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. The total induction dose regimen should not exceed 60 doses. The consolidation treatment schedule for arsenic trioxide should begin 3 to 6 weeks after completion of induction therapy. Arsenic trioxide should be administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks. The patient’s electrolyte, hematologic, and coagulation profiles should be monitored at least twice weekly (more frequently for clinically unstable patients during the induction phase and at least twice weekly during the consolidation phase). Electrocardiograms should be obtained weekly (more frequently for clinically unstable patients) during induction and consolidation. Most patients receiving arsenic trioxide experienced some drug-related toxicity (ie, leukocytosis, nausea, vomiting, diarrhea, abdominal pain, fatigue, edema, hyperglycemia, dyspnea, cough, rash, itching, headaches, and dizziness). Serious adverse events are also common in patients receiving arsenic trioxide (ie, APL differentiation syndrome, hyperleukocytosis, a QTc interval Ž500 ms, atrial dysrhythmias, and hyperglycemia). APL differentiation syndrome can be fatal; it is characterized by fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions, with or without leukocytosis. At the first signs of APL differentiation syndrome, high-dose steroids should be immediately initiated—irrespective of the leukocyte count—and continued for at least 3 days or until signs and symptoms have abated. The majority of patients do not require termination of arsenic trioxide therapy during treatment of the APL differentiation syndrome. Arsenic trioxide can cause QT-interval prolongation and complete atrioventricular block; QT prolongation can lead to a torsade de pointes–type ventricular arrhythmia, which can be fatal. Arsenic trioxide is supplied as a 10-mg/10-mL sterile injection in single-use ampules in packages of 10 ampules.
Balsalazide Disodium
(Colazal) Balsalazide disodium is a prodrug that is enzymatically cleaved in the colon by bacterial azoreduction to produce mesalamine, 5-aminosalicylic acid—an anti-inflammatory drug. Balsalazide disodium is indicated for the treatment of mildly to moderately active ulcerative colitis. The usual dose of balsalazide disodium for the treatment of active ulcerative colitis in adults is three 750-mg capsules to be taken three times daily for a total daily dose of 6.75 g for the duration of 8 weeks. Each 6.75-g daily dose of balsalazide disodium is equivalent to 2.4 g of mesalamine. The safety and efficacy of balsalazide disodium beyond 12 weeks have not been established, however, some patients in clinical trials have been treated for up to 12 weeks. Formal drug interaction studies have not been conducted with balsalazide disodium, however, the use of orally administered antibiotics can, theoretically, interfere with the release of mesalamine in the colon. In controlled clinical trials, the most frequently reported adverse effects are headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, arthralgia, rhinitis, insomnia, fatigue, rectal bleeding, and flatulence. Balsalazide disodium is contraindicated in patients with hypersensitivity to salicylates. Balsalazide disodium is supplied as capsules containing 750 mg of balsalazide disodium in bottles of 280.
Bivalirudin
(Angiomax) Bivalirudin is a specific and reversible direct thrombin inhibitor. Bivalirudin is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Bivalirudin is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. The recommended dosage of bivalirudin is an intravenous bolus dose of 1 mg/kg followed by a 4-hour intravenous infusion at a rate of 2.5 mg/kg/hour. After completion of the initial 4-hour infusion, an additional intravenous infusion of bivalirudin may be initiated at a rate of 0.2 mg/kg/hour for up to 20 hours, if needed. Bivalirudin should be administered with 300 to 325 mg of aspirin. Treatment with bivalirudin should be initiated prior to PTCA. The dose of bivalirudin may need to be reduced, and anticoagulation status monitored, in patients with renal impairment. The safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin, such as glycoprotein IIb/IIIa inhibitors. Drug interaction studies have been conducted with an adenosine diphosphate antagonist, ticlopidine, abciximab, and with low-molecular-weight heparin. Although data are limited regarding the efficacy and safety in combination with these agents, the results do not suggest pharmacodynamic interactions. In patients treated with low-molecular-weight heparin, low-molecular-weight heparin was discontinued at least 8 hours prior to the procedure and administration of bivalirudin. The most frequent adverse reactions associated with bivalirudin therapy are back pain, pain, nausea, headache, hypotension, and injection site pain. Bivalirudin is contraindicated in patients with active major bleeding or a hypersensitivity to bivalirudin or any of its components. Clinical trials have provided limited information for use of bivalirudin in patients with heparin-induced thrombocytopenia/heparin-induced thrombocytopenia-thrombosis syndrome (HIT/HITTS). A small number of patients with a history of HIT/HITTS have received bivalirudin in an emergency treatment program; bivalirudin appeared to provide adequate anticoagulation in these patients without platelet aggregation response. Bivalirudin is not intended for intramuscular administration. Although most bleeding associated with the use of bivalirudin occurs at the site of arterial puncture, hemorrhage can occur at any site. A hemorrhagic event should be considered if an unexplained fall in blood pressure or hematocrit or any unexplained symptoms occur; if a hemorrhagic event is suspected, bivalirudin administration should be stopped. Bivalirudin is supplied as a sterile, lyophilized product in single-use, glass vials. After reconstitution each vial delivers 250 mg of bivalirudin. Bivalirudin should be stored under refrigeration.
Cetrorelix Acetate
(Cetrotide) Cetrorelix acetate is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. Cetrorelix acetate for injection is indicated for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation. Ovarian stimulation therapy with gonadotropins (ie, follicle-stimulating hormone [FSH], human menopausal gonadotropin) is started on cycle day 2 or 3. The dose of gonadotropins should be adjusted according to individual response. Cetrorelix acetate may be administered subcutaneously either once daily (0.25-mg dose) or once (3-mg dose) during the early- to mid-follicular phase. In the single-dose regimen, 3 mg of cetrorelix acetate is administered when the serum estradiol level is indicative of an appropriate stimulation response, usually on stimulation day 7. If human chorionic gonadotropin (HCG) has not been administered within 4 days after injection of cetrorelix acetate 3 mg, cetrorelix acetate 0.25 mg should be administered once daily until the day of HCG administration. In the multiple-dose regimen, 0.25 mg of cetrorelix acetate is administered on either stimulation day 5 (morning or evening) or day 6 (morning) and continued daily until the day of HCG administration. When assessment by ultrasound shows a sufficient number of follicles of adequate size, HCG is administered to induce ovulation and final maturation of the oocytes. To reduce the chance of developing ovarian hyperstimulation syndrome, no HCG should be administered if the ovaries show an excessive response to the treatment with gonadotropins. Prior to therapy with cetrorelix acetate, patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. Caution is advised in patients with hypersensitivity to GnRH. These patients should be carefully monitored after the first injection. In a study for an indication unrelated to infertility, a severe anaphylactic reaction associated with cough, rash, and hypotension was observed in one patient after 7 months of treatment with cetrorelix acetate (10 mg daily). Mild and short-lasting reactions (ie, reddening, itching, and swelling) may occur at the injection site. Nausea and headache have also been reported. Cetrorelix acetate is contraindicated in patients hypersensitive to GnRH or any other GnRH analogs and patients with known or suspected pregnancy and lactation. Cetrorelix acetate for injection is available in glass vials containing 0.25 or 3 mg in a carton of one packaged tray. Each packaged tray contains one glass vial of cetrorelix acetate, one prefilled glass syringe with 1 or 3 mL of Sterile Water for Injection, one 20-gauge needle, one 27-gauge needle, and two alcohol swabs. Cetrorelix acetate 0.25 mg is also available in a carton of seven packaged trays. Cetrorelix acetate 3 mg should be stored at controlled room temperature and cetrorelix acetate 0.25 mg should be stored under refrigeration.
Cevimeline HCl
(Evoxac) Cevimeline is a cholinergic agonist that binds to muscarinic receptors and is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s syndrome. The recommended dose of cevimeline is 30 mg taken three times daily. Currently, there is insufficient evidence to support doses greater than 30 mg three times daily of cevimeline. Cevimeline is primarily metabolized by CYP2D6 and CYP3A4, and should be administered with caution with medications that may inhibit these isoenzymes. Cevimeline should also be administered with caution in patients receiving beta blockers, because of the possibility of conduction disturbances. Also, drugs that have parasympathomimetic effects may produce additive effects when administered with cevimeline. Patients should be informed that cevimeline may cause visual disturbances, especially at night, that could impair their ability to drive safely. Since dehydration may develop while taking cevimeline, patients should also be advised to drink extra water if they sweat excessively. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. Therefore, cevimeline should be used with caution in patients with a history of angina or myocardial infarction. Cevimeline should also be used with caution in patients with a history of nephrolithiasis or cholelithiasis. Contractions of the gallbladder or biliary smooth muscle could precipitate complications such as cholecystitis, cholangitis, and biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis. Cevimeline is contraindicated in patients with uncontrolled asthma because of its potential to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. It is also contraindicated in patients in whom miosis is undesirable (ie, patients with narrow-angle glaucoma or acute iritis).
Colesevelam HCl
(Welchol) Colesevelam is a nonabsorbed, polymeric, bile-acid binding, lipid-lowering agent intended for oral administration. Colesevelam is indicated to be administered alone or in combination with a hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, as adjunctive therapy to diet and exercise for the reduction of elevated low-density lipoprotein cholesterol levels in patients with primary hypercholesterolemia. The recommended dose of colesevelam as monotherapy is three tablets taken twice daily with meals or six tablets once daily with a meal. The colesevelam dose may be increased to seven tablets depending on the desired therapeutic effect. Patients should be directed to take colesevelam with a liquid and a meal, and to adhere to their recommended lipid-lowering diet. When utilized as combination therapy with an HMG-CoA reductase inhibitor, the dose of colesevelam is four to six tablets per day. For maximal therapeutic effect in combination with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily with a meal. In nonclinical, 1-year safety studies, colesevelam did not induce any clinically significant reduction in the absorption of vitamins A, D, E, or K. However, caution should be exercised when treating patients with susceptibilities to vitamin K deficiencies or The most frequent adverse effects of therapy with colesevelam were primarily gastrointestinal (GI) in nature (ie, constipation, dyspepsia, flatulence). Colesevelam is contraindicated in patients with bowel obstruction. Patients with triglyceride levels greater than 300 mg/dL were not included in colesevelam clinical trials and caution should be exercised when treating patients with triglyceride levels greater than 300 mg/dL. The safety and efficacy of colesevelam have not been established in patients with dysphagia, swallowing disorders, severe GI motility disorders, or major GI tract surgery. Consequently, caution should be exercised when colesevelam is used in patients with these GI disorders. Colesevelam is supplied as 625-mg tablets in bottles of 180.
Gemtuzumab Ozogamicin
(Mylotarg) Gemtuzumab ozogamicin is an injectable chemotherapy agent indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. Gemtuzumab ozogamicin is composed of a recombinant humanized IgG4, kappa antibody conjugated with a cytotoxic antitumor antibiotic (calicheamicin) isolated from fermentation of a bacterium (Micromonospora echinospora species Calichensis). The antibody portion of gemtuzumab ozogamicin binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of leukemic blast cells in more than 80% of patients with acute myeloid leukemia. CD33 is also expressed on normal and leukemia myeloid colony-forming cells, including leukemic clonogenic precursors, but it is not expressed on pluripotent hematopoietic stem cells or on nonhematopoietic cells. Binding of the anti-CD33 antibody portion of gemtuzumab ozogamicin with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivatives bind to the DNA in the minor groove resulting in DNA double strand breaks and cell death. The recommended dose of gemtuzumab ozogamicin is 9 mg/m2, administered as a 2-hour intravenous infusion. Patients should receive diphenhydramine 50 mg orally and acetaminophen 650 to 1,000 mg orally approximately 1 hour prior to gemtuzumab ozogamicin infusion. Because gemtuzumab ozogamicin can produce a postinfusion symptom complex of fever and chills, two additional doses of acetaminophen 650 to 1,000 mg orally, every 4 hours as needed, is recommended. Vital signs should be monitored during the infusion and for 4 hours following the infusion. The recommended treatment course with gemtuzumab ozogamicin is a total of two doses with 14 days between the doses. It is important to note that patients with hepatic or renal impairment were not included in the clinical studies of gemtuzumab ozogamicin. Full recovery from hematologic toxicities is not a requirement for administration of the second dose. Gemtuzumab ozogamicin may be administered on an outpatient basis. Severe myelosuppression, grade 3 or 4 neutropenia, will occur in all patients given the recommended dose of gemtuzumab ozogamicin. Careful hematologic monitoring is required. Patients may also experience anemia, thrombocytopenia, infection, bleeding, mucositis, nonspecific rash, and hepatotoxicity. Gemtuzumab ozogamicin is supplied as a single-vial package with an amber 20-mL glass vial containing 5 mg of gemtuzumab ozogamicin lyophilized powder. After reconstitution gemtuzumab ozogamicin should be refrigerated and protected from light. Gemtuzumab ozogamicin is light sensitive and must be protected from light during the preparation and administration of the infusion.
Insulin Aspart Recombinant
(NovoLog) Insulin aspart is a human insulin analog that is a rapid-acting, parenteral blood glucose-lowering agent. Insulin aspart is very similar to regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in the position B28; also, it is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker’s yeast) as the production organism. Insulin aspart has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection. The dosage of insulin aspart should be individualized and determined based on the needs of the patient. The total daily, individual insulin requirement is usually between 0.5 and 1 units/kg/day. In a meal-related treatment regimen, 50% to 70% of this requirement may be provided by insulin aspart and the remainder by an intermediate- or long-acting insulin. Patients may require more basal insulin in relation to bolus insulin and more total insulin when using insulin aspart compared to regular human insulin to prevent premeal hyperglycemia. Additional basal insulin injections may be necessary. Mixing insulin aspart with neutral protamine Hagedorn (NPH) human insulin immediately before injection produced some attenuation in the peak concentration of insulin aspart, but the time to peak and total bioavailability of insulin aspart were not significantly affected. If insulin aspart is mixed with NPH human insulin, insulin aspart should be drawn into the syringe first. The injection should be made immediately after mixing. The effects of mixing insulin aspart with insulins of animal sources, insulin preparations produced by other manufacturers, and crystalline zinc insulin preparations have not been studied. Hypoglycemia is the most common adverse effect of insulin, including insulin aspart. As with all insulins, the timing of hypoglycemia may differ among various formulations. Glucose monitoring is recommended for all patients with diabetes. Any change in insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, species, or method of manufacture may result in the need for a change in dose. Insulin aspart is supplied as a clear, colorless aqueous solution containing 100 units of insulin aspart per milliliter. Insulin aspart is available as 10-mL vials and 3-mL PenFill cartridges for use with the NovoPen 3 Insulin Delivery Devices and NovoFine disposable needles. Insulin aspart should be refrigerated. Cartridges and vials in use may be kept at ambient temperatures below 86o F for up to 28 days, but should not be exposed to excessive heat or sunlight.
Insulin Glargine
(Lantus) Insulin glargine is a recombinant insulin analog that is long acting (up 24 hours in duration). The longer duration of action of insulin glargine is directly related to its slower rate of absorption. Insulin glargine is produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Insulin glargine is indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require long-acting insulin for control of hyperglycemia. Hypoglycemia is the most common adverse effect of insulin, including insulin glargine. As with all insulins, the timing of hypoglycemia may differ among various formulations. Glucose monitoring is recommended for all patients with diabetes. Any change in insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, species, or method of manufacture may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted upon initiation or change of insulin. When initiating insulin glargine in a patient with type 2 diabetes who is insulin naive and has already been treated with oral antidiabetic agents, insulin glargine is started at an average dose of 10 units once daily and subsequently adjusted to the patient’s specific insulin needs. Insulin glargine should be administered subcutaneously once daily at bedtime. If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with insulin glargine, the amount and timing of short-acting insulin, fast-acting insulin analog, or the dose of any antidiabetic drug may need to be adjusted. In clinical studies, when patients were transferred from once-daily NPH human insulin or ultralente human insulin to once-daily insulin glargine, the initial dose was usually not changed. However, when patients were transferred from twice-daily NPH human insulin to insulin glargine once daily at bedtime, the initial dose was usually reduced by approximately 20% within the first week of treatment and then adjusted based on patient response; this was done to diminish the risk of hypoglycemia. Insulin glargine has been administered safely in patients as young as age 6, however pediatric patients younger than 6 years of age have not been studied. Insulin glargine is supplied as a clear and colorless solution in a concentration of 100 units per 1 mL. Insulin glargine is available in 5- and 10-mL vials and 3-mL OptiPen cartridges in packages of five cartridges. While insulin glargine is a clear solution, it is not intended for intravenous administration and should not to be diluted or mixed with any other insulins or solutions. Insulin glargine should be stored in a refrigerator; however, if refrigeration is not possible, the 10-mL vials and 3-mL cartridges may be kept unrefrigerated for up to 28 days. However, the 5-mL vials can only be kept unrefrigerated for up to 14 days.
Linezolid (Zyvox) Linezolid is a synthetic antibacterial agent of the oxazolidinone class. Linezolid is indicated for the treatment of adult patients with the following infections caused by susceptible strains of the designated microorganisms. Linezolid is indicated for the treatment of infections due to vancomycin-resistant Enterococcus faecium, including cases with concurrent bacteremia. Linezolid is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains) or Streptococcus pneumoniae (penicillin-susceptible strains only), complicated skin and skin structure infections cause by S aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid is indicated for the treatment of uncomplicated skin and skin structure infections due to S aureus (methicillin-susceptible strains only) and S pyogenes. And lastly, linezolid is indicated for the treatment of community-acquired pneumonia caused by S pneumoniae (penicillin-susceptible strains only) and S aureus (methicillin-susceptible strains only). Due to concerns about the inappropriate use of antibiotics leading to an increase in resistant organisms, prescribers should carefully consider alternatives before initiating treatment with linezolid in the outpatient setting. The recommended dosage for linezolid for the treatment of vancomycin-resistant E faecium infections is 600 mg intravenously or orally every 12 hours for 14 to 28 days. The recommended dosage of linezolid for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, and community-acquired pneumonia is 600 mg intravenously or orally every 12 hours for 10 to 14 days. Lastly, the recommended dose of linezolid for the treatment of uncomplicated skin and skin structure infections is 400 mg orally every 12 hours for 10 to 14 days. Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents. Patients should be instructed that, while taking linezolid, large quantities of foods or beverages with high tyramine content should be avoided. Additionally, a reversible enhancement of the pressor effect of pseudoephedrine or phenylpropanolamine is observed when linezolid is coadministered with either of these agents. Patients should also inform their physician or pharmacist if they are taking serotonin reuptake inhibitors or other antidepressants. Linezolid is supplied as 400- and 600-mg film-coated tablets in bottles of 20 and 100. Linezolid is also supplied as an oral suspension available as a dry powder for reconstitution in 150-mL bottles—providing the equivalent of 100-mg linezolid in each 5 mL of reconstituted oral suspension. It is important to note that only linezolid oral suspension contains phenylalanine, which is of concern in phenylketonuric patients. Linezolid is also supplied as an intravenous formulation in single-use, ready-to-use infusion bags containing 200 mg of linezolid in 100 mL of intravenous solution, 400 mg of linezolid in 200 mL of intravenous solution, and 600 mg of linezolid in 300 mL of intravenous solution.
Lopinavir & Ritonavir
(Kaletra) Lopinavir/ritonavir is a coformulation of lopinavir, an inhibitor of HIV protease (which is metabolized by CYP3A), and ritonavir, an inhibitor of the CYP3A-mediated metabolism of lopinavir. This combination thereby provides increased plasma levels of lopinavir. Lopinavir/ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV infection. Patients should be informed that lopinavir/ritonavir is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The recommended adult dose of lopinavir/ritonavir is 400/100 mg (three capsules or 5 mL of oral solution) taken twice daily with food. When administered concomitantly with efavirenz or nevirapine, a dose increase of lopinavir/ritonavir to 533/133 mg (four capsules or 6.5 mL of oral solution) taken twice daily with food should be considered in treatment-experienced patients where reduced susceptibility to lopinavir is clinically suspected. In children 6 months to 12 years of age, the recommended dose of lopinavir/ritonavir oral solution is 12/3 mg/kg for those children 7 to <15 kg and 10/2.5 mg/kg for those children 15 to 40 kg (approximately equivalent to 230/57.5 mg/m2). It is to be taken twice daily with food, for up to a maximum dose of 400/100 mg in children >40 kg (5 mL or three capsules). When administered concomitantly with efavirenz or nevirapine, a dose increase of lopinavir/ritonavir oral solution to 13/3.25 mg/kg for those 7 to <15 kg and 11/2.75 mg/kg for those 15 to 50 kg (approximately equivalent to 300/75 mg/m2). It should be taken twice daily with food. A maximum dose of 533/133 mg (four capsules or 6.5 mL of oral solution) in children > 50 kg should be considered in treatment-experienced children where reduced susceptibility to lopinavir is clinically suspected. Consult the package labeling for detailed information and dosing tables for children receiving lopinavir/ritonavir. Patients receiving lopinavir/ritonavir oral solution should not receive metronidazole or disulfiram (due to the potential of severe nausea and vomiting due to the presence of alcohol in the oral solution). In addition patients receiving didanosine should take their didanosine dose 1 hour before or 2 hours after their lopinavir/ritonavir doses. Coadministration of Kaletra is contraindicated with drugs that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated concentrations are associated with serious and/or life-threatening events. Kaletra is an inhibitor of cytochrome CYP3A metabolism and, therefore, should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. The following drugs should not be coadministered with Kaletra: astemizole, rifampin, midazolam, triazolam, flecainide, propafenone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, St. John’s wort, lovastatin, simvastatin, pimozide, and cisapride. The following agents can be coadministered with Kaletra, however, concentration monitoring (or INR monitoring for warfarin) is required for these agents: amiodarone, lidocaine (systemic), quinidine, warfarin, and tricyclic antidepressants. In patients receiving Kaletra and rifabutin, the rifabutin dose should be reduced by 75% of the recommended dose with increased monitoring for adverse events. Cholesterol-lowering agents (ie, atorvastatin, cerivastatin) may have their serum concentrations increased by Kaletra, possibly leading to an increase in their activity or toxicity. Lastly, sildenafil concentrations are expected to be substantially increased and the sildenafil prescribing information should be consulted for current dose-reduction information in patients receiving Kaletra. Other potentially significant drug interactions can be due to CYP3A4 induction. Anticonvulsants (ie, phenobarbital, phenytoin, carbamazepine) may decrease Kaletra concentrations due to enzyme induction. For a complete list of medications and recommended steps to prevent or monitor adverse effects, consult the package labeling for Kaletra. The most commonly reported adverse effects of moderate severity related to lopinavir/ritonavir therapy are abnormal stools, diarrhea, feeling weak or tired, headache, and nausea. Children taking lopinavir/ritonavir sometimes may experience a skin rash. Blood tests in patients receiving lopinavir/ritonavir may show possible signs of liver problems. Patients with hepatitis B or C may experience a worsening of their disease. Some patients receiving lopinavir/ritonavir can develop pancreatitis, which may be fatal. Patients may experience a large increase in triglycerides, cholesterol, and blood sugar. Additionally, patients receiving protease inhibitors may experience changes in body fat, which may include increased fat in the upper back, neck, breasts, and abdomen. Loss of fat from the face, legs, and arms may also occur.
Meloxicam (Mobic) Meloxicam is an oxicam derivative and a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic activity and its mechanism of action is like that of other NSAIDs—cyclooxygenase inhibition. Meloxicam is indicated for the relief of the signs and symptoms of osteoarthritis. The usual starting and maintenance dose of meloxicam is 7.5 mg once daily. The lowest dose of meloxicam should be sought for each patient. However, some patients may receive additional benefit by increasing the dose to 15 mg once daily, which is the maximum recommended dose of meloxicam. There is no need for dosage reduction in patients with mild-to-moderate renal dysfunction (creatinine clearance >15 mL/min). Patients with severe renal insufficiency have not been adequately studied concerning the use of meloxicam. Meloxicam can interact with the same medications that most NSAIDs can interact with. For example, meloxicam can decrease the natriuretic effect of furosemide, diminish the antihypertensive effect of angiotensin-converting enzyme inhibitors, and produce elevated lithium levels. Due to the risk of bleeding complications and the potential for alterations in INR, meloxicam should also be utilized with caution in patients receiving concomitant warfarin therapy. The most common adverse reactions associated with meloxicam therapy are abdominal pain, diarrhea, dyspepsia, edema, dizziness, and headache. Due to the risk of GI toxicity with NSAIDs, meloxicam should only be prescribed with extreme caution in those with a prior history of ulcer disease or GI bleeding. Meloxicam is supplied as 7.5-mg tablets in bottles containing 30 or 100.
Mifepristone
(Mifeprex) Mifepristone is a synthetic steroid with antiprogestational effects. Mifepristone is indicated for the medical termination of intrauterine pregnancy through 49 days of pregnancy. For purposes of this treatment, pregnancy is dated from the first day of the last menstrual period in a presumed 28-day cycle with ovulation occurring at midcycle. The duration of pregnancy may be determined from menstrual history and by clinical examination. Ultrasonographic scan should be used if the duration of pregnancy is uncertain or if ectopic pregnancy is suspected. The antiprogestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Mifepristone inhibits the activity of endogenous or exogenous progesterone, therefore termination of pregnancy results. During pregnancy, mifepristone sensitizes the myometrium to the contraction-inducing activity of prostaglandins. Treatment with mifepristone and misoprostol for the termination of pregnancy requires three office visits by the patient. On day 1, patients must read and sign the patient agreement and then three 200-mg tablets (600 mg) of mifepristone are taken in a single oral dose. Any intrauterine device (IUD) should be removed before treatment with mifepristone begins. On day 3, the patient returns to the health care provider 2 days after ingesting the mifepristone dose. Unless abortion has occurred and has been confirmed by clinical examination or ultrasonographic scan, the patient takes two 200-mcg tablets (400 mcg) of misoprostol orally. During the period immediately following the administration of misoprostol, the patient may need medication for cramps or GI symptoms. The patient should be given instructions on what to do if significant discomfort, excessive bleeding, or other adverse reactions occur and should be given a phone number to call if she has questions following the administration of the misoprostol. In addition, the name and address of a physician who will be handling emergencies should be provided to the patient. Patients will return for a follow-up visit approximately 14 days after the administration of mifepristone. This visit is very important to confirm—by clinical examination or ultrasonographic scan—that the complete termination of pregnancy has occurred. Pregnancy termination by surgery is recommended in cases when mifepristone and misoprostol fail to cause termination of intrauterine pregnancy. Mifepristone is metabolized by CYP3A4; therefore, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism—increasing mifepristone’s serum levels. Furthermore, rifampin, dexamethasone, St. John’s wort, phenytoin, carbamazepine, and phenobarbital may induce mifepristone metabolism thereby decreasing mifepristone’s serum levels. Additionally, based on mifepristone’s CYP3A4 inhibition data, mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP3A4 substrates and have a narrow therapeutic range, including agents used in general anesthesia. Vaginal bleeding occurs in almost all patients during the treatment procedure. Women should expect to experience bleeding or spotting for an average of 9 to 16 days, while up to 8% of all subjects might experience some type of bleeding for 30 days or more. Patients should understand that vaginal bleeding and uterine cramping probably would occur after mifepristone and misoprostol treatment. Patients should also be aware that prolonged or heavy vaginal bleeding is not proof of complete expulsion and that, if the treatment fails, there is a risk of fetal malformation. Another pregnancy can occur following termination of pregnancy and before resumption of normal menses. Contraception can be initiated as soon as the termination of the pregnancy has been confirmed, or before the women resumes sexual intercourse. Mifepristone treatment is contraindicated in women with the following conditions: confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass, IUD in place, chronic adrenal failure, concurrent long-term corticosteroid therapy, history of allergy to mifepristone, misoprostol, or other prostaglandin, hemorrhagic disorders, concurrent anticoagulant therapy, and inherited porphyrias. Mifepristone is supplied only to licensed physicians who sign and return a Prescriber’s Agreement. Distribution of mifepristone will be subject to specific requirements imposed by the distributor, including procedures for storage, dosage tracking, damaged product returns, and other matters. Mifepristone is a prescription drug, although it will not be available to the public through licensed pharmacies.
Nateglinide
(Starlix) Nateglinide is an oral antidiabetic agent that is structurally unrelated to the oral sulfonylureas. Nateglinide is indicated as monotherapy to lower blood glucose in patients with type 2 diabetes whose hyperglycemia cannot be adequately controlled by diet and physical exercise and who have not been chronically treated with other antidiabetic agents. Nateglinide is to be administered with metformin in patients whose hyperglycemia is inadequately controlled with metformin. Nateglinide may be added to metformin therapy but not substituted for metformin. Patients whose hyperglycemia is not adequately controlled with glyburide, other sulfonylureas, or insulin secretagogues should not be switched to nateglinide, nor should nateglinide be added to their treatment regimen. Nateglinide is an amino acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent on functioning beta cells in the pancreatic islets. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide should be administered 1 to 30 minutes prior to meals. The recommended starting and maintenance dose of nateglinide alone or in combination with metformin is 120 mg three times daily before meals. Patients should be instructed to skip their scheduled dose of nateglinide if they skip a meal so that the risk of hypoglycemia is reduced. The 60-mg dose of nateglinide, either alone or in combination with metformin, may be used in patients who are near goal HbA1c when treatment is initiated. No dosage adjustment is necessary for geriatric patients, patients with mild-to-severe renal insufficiency or patients with mild hepatic insufficiency; however, due to a lack of clinical data, nateglinide should be used with caution in patients with moderate-to-severe hepatic insufficiency. Nateglinide is predominantly metabolized by CYP2C9 and, to a lesser extent, by CYP3A4. Nateglinide also is a potential CYP2C9 inhibitor. Nateglinide has been evaluated for pharmacokinetic drug interactions with glyburide, metformin, digoxin, diclofenac, and warfarin; no significant changes to the pharmacokinetics of the agents were demonstrated. Nateglinide is also highly bound to albumin (98%). Nateglinide was evaluated with a number of highly protein-bound medications without an effect on the extent of nateglinide protein binding. However, prudent evaluation of individual patient cases is warranted in the clinical setting. The pharmacokinetics of nateglinide were not affected by the ingestion of a high-fat meal, however, peak plasma levels of nateglinide were significantly reduced when nateglinide was administered 10 minutes prior to a liquid meal. Adverse reactions associated with nateglinide therapy are upper respiratory infection, flu symptoms, dizziness, arthropathy, and diarrhea. There were increases in mean uric acid levels in patients treated with nateglinide monotherapy, however, the clinical significance of this is unknown. Nateglinide is supplied as 60- and 120-mg tablets in bottles of 100 and 500.
Oxcarbazepine
(Trileptal) Oxcarbazepine is an antiepileptic drug whose pharmacologic activity is primarily mediated through its 10-monohydroxy metabolite (MHD). Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy. It is also indicated as adjunctive therapy in the treatment of partial seizures in children ages 4 to 16 with epilepsy. Oxcarbazepine should always be administered in a twice-daily dosage regimen without regard to the ingestion of food. In adults, if administered as adjunctive therapy, oxcarbazepine should be initiated with a dose of 300 mg twice daily. This dose may be titrated upward by 600 mg daily at weekly intervals up to the usual daily dose of 600 mg twice daily. Daily doses above 1,200 mg show somewhat greater effectiveness; however, most patients could not tolerate a dose of 2,400 mg daily due to excess central nervous system side effects. In adults not currently receiving antiepileptic therapy, oxcarbazepine can be initiated at 300 mg twice daily; the dose may be increased by 300 mg/day every third day to the usual daily dose of 600 mg twice daily. In pediatric patients ages 4 to 16, treatment with oxcarbazepine should be initiated at a daily dose of 8 to 10 mg/kg—generally not to exceed 600 mg/day. The target maintenance dose of oxcarbazepine, dependent on patient weight, should be achieved over 2 weeks. The target doses are as follows: 20 to 29 kg, 900 mg daily; 29.1 to 39 kg, 1,200 mg daily and >39 kg, 1,800 mg daily. The most common adverse reactions associated with oxcarbazepine therapy are dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait. Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4, with potentially important effects on the plasma concentrations of several drugs. Oxcarbazepine can decrease the plasma concentrations of several antiepileptic agents (ie, carbamazepine, phenobarbital, phenytoin, and valproic acid). Conversely, strong inducers of cytochrome P450 enzymes (ie, carbamazepine, phenytoin, phenobarbital) have been shown to decrease the plasma levels of oxcarbazepine’s primary metabolite, MHD. Oxcarbazepine can lower the plasma concentrations of hormonal contraceptives and, therefore, may render these agents less effective. Therefore, female patients should be advised that an additional form of nonhormonal contraception should be utilized when receiving oxcarbazepine. Oxcarbazepine has also been shown to decrease the plasma levels of dihydropyridine calcium channel blockers and verapamil. Patients who have experienced hypersensitivity reactions with carbamazepine have approximately a 25% to 30% chance of experiencing hypersensitivity reactions with oxcarbazepine. Therefore, patients should be questioned with regard to prior exposure to carbamazepine prior to initiating oxcarbazepine therapy. Oxcarbazepine is supplied as 150-, 300-, and 600-mg film-coated tablets in bottles of 100 and 1,000.
Pantoprazole Sodium
(Protonix) Pantoprazole is a proton pump inhibitor that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Pantoprazole is indicated for the short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease. Pantoprazole is to be administered for up to 8 weeks in the healing and symptomatic relief of erosive esophagitis; however, an additional 8-week course of therapy may be administered for those patients not healed after 8 weeks of therapy. The recommended oral dose of pantoprazole is 40 mg administered once daily. No dosage adjustment is necessary in patients with mild, moderate, or severe renal insufficiency or in elderly patients. Patients should be instructed to swallow pantoprazole delayed-release tablets whole, with or without food. Additionally, patients should be advised not to crush, split, or chew pantoprazole tablets. Pantoprazole is primarily metabolized by the CYP2C19 and CYP3A4 isoenzymes. Studies evaluating the interaction potential of pantoprazole have not demonstrated a possibility of interaction with other drugs metabolized by CYP2C19 and CYP3A4. However, due to pantoprazole’s profound and lasting inhibition of gastric acid secretion, it is theoretically possible that pantoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of their bioavailability (ie, ketoconazole, ampicillin, and iron). The most frequently reported adverse effects associated with pantoprazole administration are headache, diarrhea, flatulence, abdominal pain, and rash. Pantoprazole is supplied as 40-mg delayed-release tablets in bottles of 90.
Rivastigmine Tartrate
(Exelon) Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of mild-to-moderate dementia of the Alzheimer’s type. The recommended starting dose of rivastigmine is 1.5 mg twice daily. If this dose is well tolerated, after a minimum of 2 weeks of treatment, the dose may be increased to 3 mg twice daily. Subsequent increases to 4.5 mg twice daily and 6 mg twice daily should be attempted after a minimum of 2 weeks at the previous dose level. If adverse effects cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then start at the next lower dosage level. However, if therapy at higher than the recommended starting dose is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose and titrated back to the maintenance dose as described above. The most common adverse effects associated with rivastigmine therapy are nausea, vomiting, anorexia, dyspepsia, and asthenia. Patients and caregivers should be advised of the high incidence of nausea and vomiting associated with rivastigmine therapy along with the possibility of anorexia and weight loss. Patients and caregivers should be encouraged to monitor for these adverse effects and inform their physicians or pharmacists if they occur. Rivastigmine, because of its mechanism of action, cholinesterase inhibition, has the potential to interfere with the activity of anticholinergic medications. Additionally, a synergistic effect may be expected when rivastigmine is given concurrently with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol. Rivastigmine is supplied as 1.5-, 3-, 4.5-, and 6-mg capsules in bottles of 60 and 500.
Tinzaparin Sodium
(Innohep) Tinzaparin sodium is the sodium salt of a low-molecular-weight heparin obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. Tinzaparin is indicated for the treatment of acute symptomatic deep vein thrombosis (DVT) with or without pulmonary embolism when administered in conjunction with warfarin sodium. The safety and effectiveness of tinzaparin were established in hospitalized patients. The recommended dose of tinzaparin for the treatment of DVT with or without pulmonary embolism is 175 anti-Xa units/kg of body weight, administered subcutaneously once daily for at least 6 days and until the patient is adequately anticoagulated with warfarin and an INR of at least 2 for 2 consecutive days is achieved. Warfarin sodium therapy should be initiated when appropriate, usually within 1 to 3 days of initiation of tinzaparin therapy. Tinzaparin is not intended for intramuscular or intravenous administration. Since they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosage, tinzaparin cannot be used interchangeably, unit for unit, with heparin or other low-molecular-weight heparins. Each of these medications has its specific directions for use. Bleeding is the most common adverse event associated with tinzaparin, however the incidence of major bleeding is low. Additional adverse effects occurring with tinzaparin therapy are chest pain, injection site hematoma, hypotension, anemia, and epistaxis. Tinzaparin is contraindicated in patients with active major bleeding and in patients with active or a history of heparin-induced thrombocytopenia. Patients with a known hypersensitivity to heparin, sulfites, benzyl alcohol, or pork products should not be treated with tinzaparin. When neuraxial anesthesia, epidural/spinal anesthesia, or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma—possibly resulting in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by concomitant use of drugs affecting hemostasis (ie, NSAIDs, platelet inhibitors, or other anticoagulants). The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Tinzaparin is supplied in a multiple-dose 2-mL vial containing 20,000 anti-Xa units per mL in boxes of 1 and 10 vials.
Triptorelin Pamoate
(Trelstar Depot) Triptorelin pamoate is a synthetic agonist analog of luteinizing hormone-releasing hormone (LHRH) or GnRH, with greater potency than the naturally occurring LHRH. Triptorelin is indicated for the palliative treatment of advanced prostate cancer. It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient. Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Following the first administration there is a transient surge in circulating levels of LH, FSH, testosterone, and estradiol. After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular and ovarian steroidogenesis is observed. In men, a reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after cessation of therapy. The recommended dose of triptorelin is 3.75 mg incorporated in a depot formulation and administered monthly as a single intramuscular injection. After reconstitution with sterile water, the suspension should be discarded if not used immediately after reconstitution. As with other drugs administered by intramuscular injection, the injection site should be altered periodically. Related adverse events associated with triptorelin therapy are pain at injection site, hot flushes, pain, hypertension, headache, vomiting, skeletal pain, insomnia, and impotence. Initially, triptorelin, like other LHRH agonists, causes a transient increase in testosterone levels. As a result, isolated cases of worsening signs and symptoms of prostate cancer during the first weeks of treatment have been reported with LHRH agonists. Patients may experience a worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LHRH agonists. Triptorelin is supplied as a single-dose vial containing sterile lyophilized triptorelin pamoate microgranules equivalent to 3.75 mg of triptorelin peptide base. Triptorelin should be stored at 77oF, however excursions to 59oF to 86oF are permitted.
Unoprostone Isopropyl
(Rescula) Unoprostone isopropyl is a docosamoid, a structural analog of an inactive biosynthetic cyclic derivative of arachidonic acid, 13,14-dihydro-15-keto-prostaglandin F2a. Unoprostone isopropyl ophthalmic solution is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure-lowering medications or insufficiently responsive to other intraocular pressure-lowering medication. When instilled in the eye, unoprostone isopropyl is believed to reduce elevated intraocular pressure, by increasing the outflow of aqueous humor; however, the exact mechanism is unknown at this time. The recommended dosage is 1 drop in the affected eye(s) twice daily. Unoprostone isopropyl may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If two drugs are used, they should be administered at least 5 minutes apart. Unoprostone isopropyl should not be administered while wearing contact lenses because the benzalkonium chloride contained in the ophthalmic drops may be adsorbed by the contact lenses. Lenses should be removed prior to administration of the solution and can be reinserted 15 minutes following administration of unoprostone isopropyl. Unoprostone isopropyl has been reported to cause changes to pigmented tissue. These changes may be permanent. Unoprostone isopropyl may gradually change eye color, increasing the amount of brown pigment in the iris. The long-term effects and the consequences of potential injury to the eye are currently unknown. The change in iris color occurs slowly and may not be noticeable for several months to years. Patients should be informed of the possibility of iris color change. The most common ocular adverse events associated with unoprostone isopropyl administration were burning, stinging, dry eyes, itching, and increased length of eyelashes. Approximately 14% of patients were observed to have an increase in the length of eyelashes at 12 months, while 7% of patients were observed to have a decrease in the length of eyelashes. Patients have also experienced abnormal vision, eyelid disorders, foreign body sensation, and lacrimation disorders upon use of unoprostone isopropyl. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products; patients, who in most cases had a concurrent corneal disease or a disruption of the ocular epithelial surface, inadvertently contaminated the multiple-dose containers. Unoprostone isopropyl should be used with caution in patients with active intraocular inflammation. Unoprostone isopropyl has not been evaluated for the treatment of angle-closure, inflammatory, or neovascular glaucoma. Unoprostone isopropyl ophthalmic solution is supplied as 5 mL of a 0.15% solution (1.5 mg/mL) in a 7.5-mL dropper bottle.
Zonisamide
(Zonegran) Zonisamide is an antiseizure medication chemically classified as a sulfonamide and unrelated to other antiseizure medications. The precise mechanism of action of zonisamide is unknown, however zonisamide may produce effects through action at sodium and calcium channels. Zonisamide blocks sodium channels and reduces voltage-dependent, transient-inward currents, consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. Zonisamide also has effects at the gamma-aminobutyric acid/ benzodiazepine receptor ionophore complex, which may also contribute to its mechanism of action. Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. The initial dose of zonisamide is 100 mg daily. After 2 weeks, the dose may be increased to 200 mg daily for at least 2 weeks. It can be increased to 300 mg daily and 400 mg daily, with the dose stable for at least 2 weeks to achieve steady state at each dosage level. Many of the adverse effects of zonisamide are more frequent at doses of 300 mg daily and above. Although there is some evidence of greater response at doses above 100 mg to 200 mg daily, the increase appears small and formal dose-response studies have not been conducted with zonisamide. In patients with renal or hepatic disease, zonisamide should be administered with caution; with these patients slower titration and more frequent monitoring is required. Zonisamide is metabolized by the CYP3A4 isoenzyme of the P450 system. Concomitant administration of drugs that either induce or inhibit CYP3A4 may alter serum concentrations of zonisamide. Therefore, enzyme-inducing antiseizure medications (ie, phenobarbitol, phenytoin, carbamazepine) would be expected to decrease serum concentrations of zonisamide. Patients receiving zonisamide should be instructed to swallow the capsule whole and not to bite or break the capsule. Zonisamide can also be taken without regard to food intake. Patients should also drink six to eight glasses of water daily to help prevent the formation of kidney stones. The most common side effects experienced during zonisamide therapy are drowsiness, loss of appetite, dizziness, headache, nausea, agitation, and irritability. These side effects can occur at any time, however they often occur in the first 4 weeks of therapy.
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