New Drugs of 2003

MARCH 01, 2004
Michael A. Mancano, PharmD

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

  1. Discuss the clinical indications of the new drugs approved by the FDA in 2003.
  2. Explain the various mechanisms of action of the drugs discussed in this article.
  3. Recognize the clinically relevant drug interactions for the drugs reviewed in this article.
  4. Identify the most common adverse reactions for the new drugs approved in 2003.
  5. Explain the approved dosing guidelines and recommended dosage adjustments for the drugs reviewed.

During 2003, the FDA approved many unique and important medications. I have selected 9 new drugs for an in-depth review.

The drug reviews include the current FDA-approved indication, the current dosing guidelines, contraindications to therapy, and common adverse effects for each drug. This article is designed to focus on the new molecular entities and biological approvals that may be unique or with which pharmacists will be most likely to come into contact in their practice. See the Table for a complete list of the new molecular entities and biologicals approved by the FDA during 2003.

Alfuzosin HCl Extended-Release Tablets (UroXatral)


Alfuzosin HCl is a selective antagonist of postsynaptic alpha1-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Alfuzosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. It is not indicated for the treatment of hypertension.

The recommended dosage is a single 10-mg extended-release tablet daily, to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

Alfuzosin should not be used in patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), because alfuzosin blood levels are increased in these patients. CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. Therefore, this drug should not be coadministered with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir, because alfuzosin blood levels are increased. Postural hypotension with or without symptoms (eg, dizziness) may develop within a few hours following administration of alfuzosin. As with other alpha-blockers, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result if syncope were to occur. Care should be taken when alfuzosin is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

Alfuzosin can have a small effect on the QT interval. Patients with congenital or acquired QT prolongation or patients who are taking medications known to prolong the QT interval should receive alfuzosin with caution. There has, however, been no sign of torsades de pointes in the extensive postmarketing experience with alfuzosin outside the United States.

Common adverse reactions occurring with the administration of alfuzosin are dizziness, upper respiratory infection, headache, and fatigue. Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning alfuzosin, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period.

Alfuzosin is supplied as 10-mg extended-release tablets in bottles containing 30 or 100 tablets.

Aprepitant Capsules (Emend)


Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 receptors. It has little or no affinity for the serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting. Aprepitant is indicated to be administered in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.

It is suggested that aprepitant be given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of aprepitant is 125 mg orally 1 hour prior to chemotherapy treatment (day 1) and 80 mg once daily in the morning on days 2 and 3. Aprepitant has not been studied for the treatment of established nausea and vomiting. It may be taken with or without food. No dosage adjustment is necessary for the elderly. Also, no dosage adjustment is necessary for patients with renal insufficiency or for patients with end-stage renal disease undergoing hemodialysis. In addition, no dosage adjustment is necessary for patients with mild-to-moderate hepatic insufficiency (Child-Pugh score 5-9). There are no clinical data regarding patients with severe hepatic insufficiency (Child-Pugh score >9).

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 and also an inducer of CYP2C9. Because aprepitant is a moderate CYP3A4 inhibitor, it should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

Additionally, aprepitant should be used with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, aprepitant was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. Because of the small number of patients in clinical studies who received the CYP3A4 substrates docetaxel, vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised with patients receiving those agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. The effect of aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is expected to be greater than the effect of aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates.

Chronic continuous use of aprepitant for the prevention of nausea and vomiting is not recommended because it has not been studied. Also, the druginteraction profile may change during chronic continuous use.

Coadministration of aprepitant with warfarin may result in a clinically significant decrease in the international normalized ratio (INR) or prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored during the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.

The efficacy of oral contraceptives during the administration of aprepitant may be reduced. Although effects on contraception with a 3-day regimen of aprepitant given concomitantly with oral contraceptives have not been studied, alternative or backup methods of contraception should be used.

The most common adverse reactions encountered with the use of aprepitant are asthenia, fatigue, diarrhea, and hiccups.

Aprepitant is supplied as 80- and 125-mg capsules in bottles of 30 capsules or unit-dose packages containing 5 capsules.

Daptomycin Injection (Cubicin)

Cubist Pharmaceuticals Inc

Daptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. It is a natural product that has clinical utility in the treatment of infections caused by aerobic gram-positive bacteria. Its in vitro spectrum of activity encompasses most clinically relevant gram-positive pathogenic bacteria. Daptomycin retains potency against antibioticresistant gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid. It exhibits rapid, concentration-dependent bactericidal activity against grampositive organisms in vitro.

The mechanism of action of daptomycin is distinct from that of any other antibiotic. It binds to bacterial membranes and causes a rapid depolarization of membrane potential. The loss of membrane potential leads to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.

Daptomycin is indicated for the treatment of complicated skin and skin-structure infections caused by susceptible strains of the following gram-positive microorganisms: Staphylococcus aureus (including methicillinresistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin- susceptible strains only). Combination therapy may be clinically indicated if the documented or presumed pathogens include gram-negative or anaerobic organisms.

Daptomycin 4 mg/kg should be administered over a 30-min period by intravenous infusion in 0.9% sodium chloride injection once every 24 hr for 7 to 14 days.

Because daptomycin is eliminated primarily by the kidney, a dosage modification is recommended for patients with creatinine clearance (CrCl) <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The recommended dosing regimen is 4 mg/kg once every 24 hours for patients with CrCl >30 mL/min and 4 mg/kg once every 48 hours for patients with CrCl <30 mL/min, including those on hemodialysis or CAPD. When possible, daptomycin should be administered following hemodialysis on hemodialysis days.

Patients receiving daptomycin should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. Creatine phosphokinase (CPK) levels should be monitored weekly in patients who receive daptomycin. Patients who develop unexplained elevations in CPK while receiving daptomycin should be monitored more frequently. Consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving daptomycin.

Most adverse events reported in clinical studies with daptomycin were described as mild or moderate in intensity. The most commonly reported adverse events were constipation, nausea, diarrhea, vomiting, abnormal liver function, urinary tract infections, hypotension, and dyspnea.

Daptomycin for injection is supplied as a lyophilized cake in 10-mL single-use vials containing 250 or 500 mg of the drug.

Enfuvirtide Injection (Fuzeon)


Enfuvirtide is an inhibitor of the fusion of HIV-1 with CD4+ cells. Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

Enfuvirtide, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. Enfuvirtide must be taken as part of a combination antiretroviral regimen. The use of this drug alone may lead to the rapid development of virus resistant to enfuvirtide and possibly to other agents of the same class.

The recommended dose of enfuvirtide for adults is 90 mg (1 mL), injected subcutaneously twice daily. The recommended dose for pediatric patients 6 to 16 years of age is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily, injected subcutaneously. Enfuvirtide is not recommended for patients less than 6 years of age. Subcutaneous injections should be in the upper arm, anterior thigh, or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. Enfuvirtide should not be injected into moles, scar tissue, bruises, or the navel.

The most common adverse events associated with enfuvirtide use are local injection-site reactions. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. In trials, 9% of patients had local reactions and required analgesics or limited usual activities. An increased rate of bacterial pneumonia also was observed in patients treated with enfuvirtide in clinical trials. It is unclear whether the increased incidence of pneumonia is related to enfuvirtide use. Because of this finding, however, patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions that may predispose them to pneumonia.

Hypersensitivity reactions have been associated with enfuvirtide therapy and may recur on rechallenge. These reactions have included (individually and in combination) rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum transaminases.

Patients and caregivers must be instructed in the use of aseptic technique when administering enfuvirtide in order to avoid injection-site infections. Appropriate training for enfuvirtide reconstitution and self-injection must be given by a health care provider. Enfuvirtide contains no preservatives. Once reconstituted, the drug should be injected immediately or kept refrigerated in the original vial until use. Reconstituted enfuvirtide must be used within 24 hours.

Enfuvirtide is available in a convenience kit containing 60 single-use vials of enfuvirtide, 60 vials of sterile water for injection (1.1 mL per vial), 60 3-mL reconstitution syringes, 60 1-mL administration syringes, and alcohol swabs.

Influenza Virus Vaccine, Live, Intranasal (FluMist)

MedImmune Vaccines Inc

Influenza virus vaccine live, intranasal, is a live, trivalent nasally administered vaccine intended for active immunization for the prevention of influenza. This vaccine is indicated for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents 5 to 17 years of age and in healthy adults 18 to 49 years of age. It is not indicated for immunization of individuals less than 5 years of age or 50 years of age and older, or for therapy of influenza. It also will not protect against infections and illnesses caused by infectious agents other than influenza A or B viruses.

FluMist should be administered according to the following schedule:

  • For healthy children aged 5 through 8 years who have not previously received FluMist vaccine, one 0.5-mL dose, followed by a second 0.5-mL dose given at least 6 weeks later
  • For all other healthy individuals, including children aged 5 to 8 years who have previously received at least one dose of Flu- Mist, a single dose

Under no circumstances should this vaccine be administered parenterally. The safety and immunogenicity of FluMist when administered concurrently with other vaccines have not been determined. Therefore, FluMist should not be administered concurrently with other vaccines.

FluMist should be administered prior to exposure to influenza. The peak of influenza activity is variable from year to year, but it generally occurs in the United States between late December and early March. Because the duration of protection induced by FluMist is not known and yearly antigenic variation in influenza strains is possible, annual revaccination may increase the likelihood of protection.

FluMist must be thawed prior to administration. It may be thawed by holding the sprayer in the palm of the hand and supporting the plunger rod with the thumb. It should be administered immediately after thawing. Alternatively, FluMist may be thawed in a refrigerator and stored at 2 to 8?C (36-46?F) for no more than 24 hours prior to use.

Vaccine recipients or their parents/ guardians should be informed by the health care provider of the potential benefits and risks of FluMist, and of the need for 2 doses for the first use of FluMist in 5- to 8-year-olds. Because of the possible transmission of vaccine virus, vaccine recipients or their parents/ guardians should be advised to avoid close contact (eg, within the same household) with immunocompromised individuals for at least 21 days. The vaccine recipient or the parent/ guardian accompanying the vaccine recipient should be told to report any suspected adverse events to the physician or to the clinic where the vaccine was administered.

Individuals with a history of hypersensitivity, especially anaphylactic reactions, to any component of the vaccine (including eggs or egg products) should not receive this product. FluMist is contraindicated in children and adolescents (5-17 years of age) who are receiving aspirin therapy or aspirin-containing therapy, because of the association of Reye?s syndrome with aspirin and wild-type influenza infection. This product also should not be administered to individuals who have a history of Guillain-Barr? syndrome.

As with other live virus vaccines, FluMist should not be administered to individuals with known or suspected immune deficiency diseases, including combined immunodeficiency, agam- maglobulinemia, thymic abnormalities, and such conditions as HIV infection, malignancy, leukemia, or lymphoma. In addition, it is contraindicated in patients who may be immunosuppressed or have altered or compromised immune status as a consequence of treatment with systemic corticosteroids, alkylating drugs, antimetabolites, radiation, or other immunosuppressive therapies.

The safety of FluMist in individuals with asthma or reactive airways disease has not been established. In a large safety study of children 1 to 17 years of age, children <5 years of age who received FluMist were found to have an increased rate of asthma within 42 days of vaccination, when compared with placebo recipients. Therefore, this drug should not be administered to individuals with a history of asthma or reactive airways disease.

Across all clinical studies, the incidence of selected adverse reactions that may be complications of influenza (such as pneumonia, bronchitis, bronchiolitis, or central nervous system events) was similar in the FluMist and placebo groups. Adverse events observed in clinical trials included runny nose/nasal congestion, sore throat, cough, irritability, headache, chills, vomiting, muscle aches, and decreased activity with a feeling of tiredness/weakness.

FluMist is supplied for intranasal delivery in a package of 10 prefilled, single-use sprayers. FluMist should be stored at or below -15?C (5?F).

Memantine HCl Tablets (Namenda)

Forest Laboratories Inc

Memantine is an orally active Nmethyl- D-aspartate (NMDA) receptor antagonist. It is indicated for the treatment of moderate-to-severe dementia of the Alzheimer?s type.

Persistent activation of the central nervous system NMDA receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer?s disease. Memantine is postulated to exert its therapeutic effect through its action as a low-to-moderate affinity uncompetitive (open-channel) NMDA receptor antagonist, which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer?s disease.

The dosage of memantine shown to be effective in controlled trials is 20 mg daily. The recommended starting dose is 5 mg once daily. The dose should be increased in 5-mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and then 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is 1 week. Memantine can be taken with or without food.

Dose reduction in patients with moderate renal impairment should be considered. For patients with severe renal impairment, the use of memantine has not been systematically evaluated and is not recommended. Adverse events reported with the use of memantine are fatigue, pain, hypertension, dizziness, headache, constipation, back pain, and confusion. Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine.

Memantine is supplied as 5- and 10- mg tablets in bottles of 60 tablets.

Rosuvastatin Calcium Tablets (Crestor)


Rosuvastatin calcium is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Rosuvastatin is indicated as an adjunct to diet to reduce elevated total-cholesterol (total-C), low-density-lipoprotein (LDL)-C, apolipoprotein B (ApoB), non-high-density-lipoprotein (HDL)- C, and triglyceride (TG) levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb); as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); and to reduce LDL-C, total-C, and ApoB in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Before instituting therapy with rosuvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet and exercise, weight reduction in obese patients, and treatment of underlying medical problems. The dose range for rosuvastatin is 5 to 40 mg once daily. Therapy with rosuvastatin should be individualized according to the goal of therapy and the response. The usual recommended starting dose is 10 mg once daily. Initiation of therapy with 5 mg once daily may be considered for patients who require less aggressive LDL-C reductions or who have predisposing factors for myopathy. For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. The 40-mg dose of rosuvastatin should be reserved for those patients who have not achieved goal LDL-C at 20 mg. After initiation and/or upon titration of rosuvastatin, lipid levels should be analyzed within 2 to 4 weeks, and dosage should be adjusted accordingly.

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is Ndesmethyl rosuvastatin, which is formed principally by cytochrome P- 450 2C9. In vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one sixth to one half the HMG-CoA reductase inhibitory activity of rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin. In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P- 450 3A4 to a clinically significant extent. This finding has been confirmed in studies with known cytochrome P-450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).

Coadministration of rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2-3). In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs. Once a stable INR time has been documented, INR can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of rosuvastatin is changed, the same procedure should be repeated. Rosuvastatin therapy has not been associated with bleeding or with changes in INR in patients not taking anticoagulants.

Rosuvastatin is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases. HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. The incidence of persistent elevations (>3 times the upper limit of normal occurring on 2 or more consecutive occasions) in serum transaminases in fixed-dose studies was 0.4%, 0%, 0%, and 0.1% in patients who received rosuvastatin 5, 10, 20, and 40 mg, respectively. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were 2 cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, and which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (eg, semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with rosuvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in alanine transaminase or aspartate aminotransferase of >3 times the upper limit of normal persist, reduction of dose or withdrawal of rosuvastatin is recommended.

Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of rosuvastatin. Rosuvastatin is generally well tolerated. Adverse reactions usually have been mild and transient. The most frequent adverse events thought to be related to rosuvastatin were myalgia, constipation, asthenia, abdominal pain, and nausea. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and with other drugs in this class. Rosuvastatin should be prescribed with caution to patients with predisposing factors for myopathy, such as renal impairment, advanced age, and hypothyroidism. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if it is accompanied by malaise or fever. Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or if myopathy is diagnosed or suspected. The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of other lipid-lowering therapies or cyclosporine.

The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be weighed carefully against the potential risks of this combination. Combination therapy with rosuvastatin and gemfibrozil generally should be avoided. Rosuvastatin therapy also should be temporarily withheld from any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (eg, sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures).

Rosuvastatin is supplied as 5-, 10-, and 20-mg tablets in bottles of 30 and 90 tablets and as 40-mg tablets in bottles of 30 tablets.

Tadalafil Tablets (Cialis)


Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 and is indicated for the treatment of erectile dysfunction. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE-5) enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE-5 by tadalafil has no effect in the absence of sexual stimulation.

The recommended starting dose of tadalafil in most patients is 10 mg, taken prior to anticipated sexual activity. The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients. Tadalafil was shown to improve erec- tile function, compared with placebo, up to 36 hours following dosing. Therefore, when advising patients on the optimal use of tadalafil, this result should be considered. Tadalafil may be taken without regard to food.

For patients with moderate renal insufficiency (CrCl 31-50 mL/min), a starting dose of 5 mg not more than once daily is recommended, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. For patients with severe renal insufficiency on hemodialysis (CrCl <30 mL/min), the maximum recommended dose is 5 mg. For patients with mild or moderate degrees of hepatic impairment (Child-Pugh category A or B), the dose of tadalafil should not exceed 10 mg once daily. In patients with severe hepatic impairment (Child-Pugh category C), the use of tadalafil is not recommended.

Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. This finding is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Administration of tadalafil to patients taking any alpha-adrenergic antagonist (other than 0.4-mg once-daily tamsulosin) is contraindicated. In a drug?drug interaction study, when tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), there was a significant augmentation of the blood pressure-lowering effect of doxazosin.

Tadalafil is a substrate of and is predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 (ie, ritonavir, ketoconazole, erythromycin) can increase tadalafil exposure, and drugs that induce CYP3A4 (ie, rifampin, carbamazepine, phenobarbital) can decrease tadalafil exposure.

Physicians should consider the cardiovascular status of their patients, because there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. In addition, patients with left ventricular outflow obstruction (eg, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE-5 inhibitors.

Common adverse effects experienced by patients receiving tadalafil are headache, dyspepsia, back pain, myalgia, nasal congestion, and flushing. There have been rare reports of prolonged erections greater than 4 hours, as well as priapism (painful erections greater than 6 hours in duration), for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention.

Tadalafil is supplied as 5-, 10-, and 20-mg tablets in bottles of 30 tablets.

Vardenafil HCl Tablets (Levitra)


Vardenafil is a selective inhibitor of cGMP-specific PDE-5 and is indicated for the treatment of erectile dysfunction. For most patients, the recommended starting dose of vardenafil is 10 mg, taken orally approximately 60 minutes before sexual activity. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg, based on efficacy and side effects. The maximum recommended dosing frequency is once per day. Vardenafil can be taken with or without food. Sexual stimulation is required for response to treatment.

A starting dose of 5 mg should be considered for patients >65 years of age. Vardenafil clearance is reduced in patients with moderate hepatic impairment (Child-Pugh category B), and a starting dose of 5 mg of vardenafil is recommended. The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh category C). No dosage adjustment is necessary for patients with mild (CrCl 50-80 mL/min), moderate (CrCl 30-50 mL/min), or severe (CrCl <30 mL/min) renal impairment. Vardenafil has not been evaluated in patients on renal dialysis.

Because vardenafil is eliminated predominantly by hepatic metabolism? mainly by CYP3A4 and to a minor extent by CYP2C isoforms?the dosage of vardenafil may require adjustment in patients receiving certain CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, indinavir, and erythromycin).

Administration of vardenafil with nitrates, either regularly or intermittently, and nitric oxide donors is contraindicated. Consistent with the effects of PDE-5 inhibition on the nitric oxide/cGMP pathway, PDE-5 inhibitors may potentiate the hypotensive effects of nitrates. A suitable time interval should follow vardenafil dosing, because the safe administration of nitrates or nitric oxide donors has not been determined. Coadministration of alpha-blockers and vardenafil can produce hypotension; therefore, vardenafil is contraindicated in patients taking alpha-blockers.

Common adverse reactions are headache, flushing, rhinitis, dyspepsia, sinusitis, dizziness, and nausea.

Vardenafil is supplied as 2.5-, 5-, 10-, and 20-mg tablets in bottles of 30 tablets and 10- and 20-mg tablets in packages of 6 tablets.

For a bibliography list, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to:

New Drugs of 2003

This educational lesson will be available to pharmacists online at Based on the article starting on page 91). Choose the 1 most correct answer.

1. Which of the following is indicated for the palliative treatment of advanced symptomatic prostate cancer?

  1. Emtricitabine
  2. Enfuvirtide
  3. Gefitinib
  4. Plenaxis

2. Which of the following medications can have a small effect on the QT interval, such that patients with congenital or acquired QT prolongation or patients who are taking medications known to prolong the QT interval should receive this medication with caution?

  1. Alfuzosin
  2. Bortezomib
  3. Daptomycin
  4. Epinastine

3. Which of the following is a selective high-affinity antagonist of human substance P/neurokinin 1 receptors?

  1. Letrozole
  2. Aprepitant
  3. Memantine HCl
  4. Palonosetron HCl

4. Which of the following can be utilized as an adjunct to hemostasis in patients undergoing liver surgery?

  1. Plenaxis
  2. Sertaconazole nitrate
  3. Fibrin sealant, human
  4. Tositumomab

5. Which of the following exerts its therapeutic effect by binding to bacterial membranes and causing a rapid depolarization of membrane potential, with the loss of membrane potential leading to inhibition of protein, DNA, and RNA synthesis and resulting in bacterial cell death?

  1. Bortezomib
  2. Daptomycin
  3. Emtricitabine
  4. Gefitinib

6. Which of the following is an inhibitor of the fusion of HIV-1 with CD4+ cells and interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes?

  1. Enfuvirtide
  2. Atazanavir
  3. Bortezomib
  4. Enfuvirtide

7. Which of the following is contraindicated in children and adolescents (5-17 years of age) who are receiving aspirin therapy or aspirin-containing therapy, because of the association of Reye?s syndrome with aspirin?

  1. Pegvisomant
  2. Tadalafil
  3. Tositumomab
  4. FluMist

8. Which of the following is indicated for first-line treatment of postmenopausal women with hormonereceptor- positive or hormone-receptorunknown locally advanced or metastatic breast cancer and also is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy?

  1. Gefitinib
  2. Letrozole
  3. Gemifloxacin mesylate
  4. Ibandronate sodium

9. Which of the following is indicated for the treatment of interdigital tinea pedis?

  1. Sertaconazole nitrate
  2. Miglustat
  3. Palonosetron HCl
  4. Pegvisomant

10. Which of the following is an orally active N-methyl-D-aspartate receptor antagonist and is indicated for the treatment of moderate-to-severe dementia of the Alzheimer?s type?

  1. Ibandronate sodium
  2. Memantine
  3. Miglustat
  4. Plenaxis

11. Which of the following can be utilized to treat contamination that may occur as a result of detonation of a ?dirty bomb??

  1. Gefitinib
  2. Miglustat
  3. Prussian blue
  4. Plenaxis

12. Which of the following, when administered to patients on stable warfarin therapy, resulted in clinically significant rises in international normalized ratio (>4, baseline 2-3)?

  1. Rosuvastatin
  2. Letrozole
  3. Palonosetron HCl
  4. Tadalafil

13. Which of the following is a selective inhibitor of cyclic guanosine monophosphate?specific phosphodiesterase type 5 and is indicated for the treatment of erectile dysfunction?

  1. Enfuvirtide
  2. Epinastine HCl
  3. Tadalafil
  4. Gefitinib

14. Which of the following is indicated for the prevention of itching associated with allergic conjunctivitis?

  1. Letrozole
  2. Epinastine HCl
  3. Miglustat
  4. Vardenafil HCl

15. Which of the following is indicated for the treatment of locally advanced or metastatic non?small-cell lung cancer?

  1. Daptomycin
  2. Emtricitabine
  3. Gefitinib
  4. Ibandronate sodium

16. Which of the following is indicated for the treatment of Gaucher?s disease in adults?

  1. Aprepitant
  2. Miglustat
  3. Bortezomib
  4. Emtricitabine

17. Which of the following is indicated for the treatment of CD20 positive, follicular non-Hodgkin?s lymphoma?

  1. Tositumomab
  2. Memantine HCl
  3. Pegvisomant
  4. Plenaxis

18. Which of the following is indicated for the treatment of known or suspected internal contamination with radioactive cesium and thallium?

  1. Prussian blue
  2. Letrozole
  3. Memantine HCl
  4. Bortezomib

19. Which of the following is indicated for the treatment of acromegaly?

  1. Enfuvirtide
  2. Aprepitant
  3. Pegvisomant
  4. Atazanavir

20. When coadministered with an alpha-blocker, which agent can produce hypotension and is therefore contraindicated in patients taking alpha-blockers?

  1. Plenaxis
  2. Vardenafil
  3. Alfuzosin HCl
  4. Ibandronate sodium


  1. Each participant achieving a passing grade of 70% or higher on any examination will receive a statement of credit stating the number of CE credits earned. This form should be safeguarded and may be used as documentation of credits earned.
  2. Participants receiving a failing grade on any exam will be notified and permitted to take 1 reexamination at no extra cost.
  3. All answers should be recorded on the answer form attached. For each question, decide which choice is the best answer, and circle the letter of the response representing your choice.
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