New Drugs of 2004

MAY 01, 2005
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 2004.
  2. Explain the various mechanisms of action of the drugs discussed within this program.
  3. Recognize the clinically relevant drug interactions for the drugs reviewed in this program.
  4. Identify the most common adverse reactions for the new drug approvals of 2004.
  5. Explain the approved dosing guidelines and recommended dosage adjustments for the drugs reviewed.

During 2004, the FDA approved many unique and important medications. Due to space constraints and the large number of new drugs approved during 2004, I have selected 8 new drugs for in-depth review in this continuing education program. New treatments were approved for macular degeneration, depression, management of overactive bladder, and various types of cancer, to name 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 indication. This review is designed to focus on the new molecular entities and biological approvals that may be unique or which pharmacists will most likely come in contact with in their practice. The reader is directed to the Table in this continuing education program for a complete list of the new molecular entities and biologicals approved by the FDA during 2004.

Acamprosate Calcium Tablets (Campral)

Forest Pharmaceuticals

Acamprosate is a synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter ?-aminobutyric acid (GABA) and the amino acid neuromodulator taurine. Acamprosate is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Acamprosate seems to positively affect abstinence by reducing the patient's cravings for alcohol, and the exact mechanism is unknown. The efficacy of acamprosate in promoting abstinence has not been demonstrated in subjects who have not undergone detoxification and not achieved alcohol abstinence prior to beginning acamprosate treatment. In addition, the efficacy of acamprosate in promoting abstinence from alcohol in polysubstance abusers has not been adequately assessed.

The recommended dose of acamprosate is two 333-mg tablets taken orally 3 times daily. The dose may be taken without regard to meals. Treatment with acamprosate should be initiated as soon as possible after the period of alcohol withdrawal, when the patient has achieved abstinence, and should be maintained if the patient relapses. Acamprosate should be used as part of a comprehensive psychosocial treatment program. The use of acamprosate does not eliminate or diminish withdrawal symptoms. Acamprosate is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion.

Adverse reactions experienced during acamprosate therapy are diarrhea, anxiety, nausea, and depression. In controlled studies, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall but were more common with acamprosate-treated patients than in patients treated with placebo.

Acamprosate is contraindicated in patients with severe renal impairment or creatinine clearance (CrCl) =30 mL/min and does not require a dose reduction in patients with moderate renal impairment (CrCl 30-50 mL/min).

Acamprosate is supplied as 333-mg enteric-coated tablets in bottles containing 180 tablets.

Apomorphine HCl Injection (Apokyn)

Mylan Bertek

Apomorphine HCl is a nonergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, moderate affinity for the dopamine D2, D3, and D5 and adrenergic a1D, a2B, a2C receptors, and low affinity for the dopamine D1, serotonin 5HT1A, 5HT2A, 5HT2B, and 5HT2C receptors. Apomorphine is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced Parkinson's disease as an adjunct to other medications. Its precise mechanism of action as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate putamen in the brain.

The prescribed dose of apomorphine should always be expressed in mL to avoid confusion, and doses greater than 0.6 mL (6 mg) are not recommended. Patients and caregivers must receive detailed instructions in the preparation and injection of doses, with particular attention paid to the correct use of the dosing pen. Apomorphine is indicated for subcutaneous administration only. Serious adverse events, such as intravenous (IV) crystallization of apomorphine, leading to thrombus formation and pulmonary embolism, have followed IV administration. Consequently, apomorphine should not be administered intravenously.

At the recommended doses of apomorphine, severe nausea and vomiting can be expected. Apomorphine should not be initiated without use of a concomitant antiemetic. Most antiemetic experience is with trimethobenzamide, and this should generally be used. Trimethobenzamide (300 mg 3 times daily, orally) should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class (including, for example, ondansetron, granisetron, dolasetron, palonosetron, and alosetron) is contraindicated.

The dose of apomorphine must be titrated on the basis of effectiveness and tolerance, starting at 0.2 mL (2 mg) and up to a maximum recommended dose of 0.6 mL (6 mg) as follows: Patients in an "off" state should be given a 0.2-mL (2-mg) test dose in a setting where blood pressure can be closely monitored by medical personnel. Both supine and standing blood pressure should be checked predose and at 20, 40, and 60 minutes post dose. Patients who develop clinically significant orthostatic hypotension in response to this test dose of apomorphine should not be considered candidates for treatment with apomorphine. If the patient tolerates the 0.2-mL (2-mg) dose, and responds, the starting dose should be 0.2 mL (2 mg) used on an as-needed basis to treat existing "off" episodes. If needed, the dose can be increased in 0.1-mL (1-mg) increments every few days on an outpatient basis. When dosing patients with mild and moderate hepatic impairment, caution should be exercised due to the increased Cmax and area under the curve in these patients. For patients with mild and moderate renal impairment, the testing dose and subsequently the starting dose should be reduced to 0.1 mL (1 mg).

Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after months of treatment). Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been sitting or lying for prolonged periods and especially at the initiation of treatment with apomorphine.

Alcohol, antihypertensive medications, and vasodilating medications may potentiate the hypotensive effect of apomorphine. Patients should be alerted to the potential sedating effects of apomorphine, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with apomorphine to gauge whether or not it affects their mental and/or motor performance adversely.

Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (eg, watching television, passenger in a car, etc) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with apomorphine.

The most common adverse events seen in controlled trials were yawning, dyskinesias, nausea and/or vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, and pallor.

Apomorphine is supplied as a 10-mg/mL solution containing apomorphine hydrochloride (as apomorphine hydrochloride hemihydrate), as a clear, colorless, sterile solution in 2-mL glass ampules and 3-mL cartridges. The 3-mL glass cartridges are used with a manual reusable, multiple-dose injector pen. The pen can deliver doses up to 1 mL in 0.02-mL increments. The pen is provided in a package with 6 needles and a carrying case. The 2- mL glass ampules are provided in cartons of five 2-mL ampules, and the 3-mL glass cartridges are provided in cartons of five 3-mL cartridges.

Duloxetine HCl Capsules (Cymbalta)

Eli Lilly

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, the antidepressant and pain inhibitory actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the central nervous system (CNS). Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.

Duloxetine is indicated for the treatment of major depressive disorder; however, its effectiveness in hospitalized patients with major depressive disorder and its effectiveness in longterm use for major depressive disorder, that is, for more than 9 weeks, has not been systematically evaluated in controlled trials. Duloxetine is also indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy.

When utilized in the treatment of major depressive disorder, duloxetine should be administered at a total dose of 40 mg/day (given as 20 mg bid) to 60 mg/day (given either once a day or as 30 mg bid) without regard to meals. There is no evidence that doses greater than 60 mg/day confer any additional benefits. Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.

The dosage of duloxetine for the treatment of diabetic peripheral neuropathic pain is a total dose of 60 mg/day given once a day, without regard to meals. While a 120-mg/day dose was shown to be safe and effective, there is no evidence that doses higher than 60 mg confer additional significant benefit, and the higher dose is clearly less well tolerated. For patients in whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment.

Duloxetine is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min). It is also recommended that duloxetine not be administered to patients with any hepatic insufficiency.

When switching patients to or from a monoamine oxidase inhibitor (MAOI), at least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with duloxetine. In addition, at least 5 days should be allowed after stopping duloxetine before starting an MAOI.

Symptoms associated with discontinuation of duloxetine and other selective serotonin reuptake inhibitors and SSNRIs have been reported to be dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmares. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, continued decreasing of the dose but at a more gradual rate is prudent.

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Concomitant use of duloxetine with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of duloxetine. Some quinolone antibiotics would be expected to have similar effects, and these combinations should be avoided. Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine.

Duloxetine is a moderate inhibitor of CYP2D6. Therefore, coadministration of duloxetine with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines, and Type 1C antiarrhythmics (eg, propafenone, flecainide), should be considered with caution. Plasma TCA concentrations may need to be monitored, and the dose of the TCA may need to be reduced if a TCA is coadministered with duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, duloxetine and thioridazine should not be coadministered.

Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability to engage in such activities. Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, duloxetine should ordinarily not be prescribed for patients with substantial alcohol use.

Duloxetine has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that may slow gastric emptying (eg, patients with diabetic gastroparesis). Drugs that raise the gastrointestinal (GI) pH may lead to an earlier release of duloxetine. However, coadministration of duloxetine with aluminum-and magnesium-containing antacids (51 mEq) or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.

Adverse reactions noted during the use of duloxetine are nausea, dizziness, somnolence, fatigue, dry mouth, constipation, decreased appetite, and increased sweating. Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal relationship has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose increases or decreases. Consideration should be given to changing the therapeutic regimen, including discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, is abrupt in onset, or was not part of the patient's presenting symptoms.

Concomitant use of duloxetine in patients taking MAOIs is contraindicated. Duloxetine use is associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrowangle glaucoma.

Duloxetine is available as 20-, 30-, and 60-mg delayed-release capsules. Twenty-milligram capsules are available in bottles of 60 capsules, and 30- and 60-mg strengths are available in bottles of 30, 90, and 100 capsules.

Eszopiclone Tablets (Lunesta)


Eszopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties. Eszopiclone's therapeutic effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

Eszopiclone is indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, eszopiclone administered at bedtime decreased sleep latency and improved sleep maintenance.

The dose of eszopiclone should be individualized. The recommended starting dose for eszopiclone for most nonelderly adults is 2 mg immediately before bedtime. Dosing can be initiated at or raised to 3 mg if clinically indicated, since 3 mg is more effective for sleep maintenance. The recommended starting dose of eszopiclone for elderly patients whose primary complaint is difficulty falling asleep is 1 mg immediately before bedtime. In these patients, the dose may be increased to 2 mg if clinically indicated. For elderly patients whose primary complaint is difficulty staying asleep, the recommended dose is 2 mg immediately before bedtime.

The starting dose of eszopiclone should be 1 mg in patients with severe hepatic impairment, and eszopiclone should be used with caution in these patients. The starting dose of eszopiclone should not exceed 1 mg in patients coadministered eszopiclone with potent CYP3A4 inhibitors. If needed, the dose can be raised to 2 mg. Taking eszopiclone with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone on sleep latency.

Eszopiclone is a Schedule IV controlled substance under the Controlled Substances Act. Other substances under the same classification include benzodiazepines and the nonbenzodiazepine hypnotics zaleplon and zolpidem. While eszopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, it shares some of the pharmacologic properties of the benzodiazepines.

CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The AUC of eszopiclone was increased 2.2-fold by coadministration of ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days. Cmax and half-life were increased 1.4-fold and 1.3-fold, respectively. Other strong inhibitors of CYP3A4 (eg, itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Drugs that induce CYP3A4, such as rifampicin, can decrease racemic zopiclone exposure by 80%. A similar effect would be expected with eszopiclone.

Eszopiclone, like other hypnotics, has CNS-depressant effects. Because of the rapid onset of action, eszopiclone should be ingested only immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep. Patients receiving eszopiclone should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination (eg, operating machinery or driving a motor vehicle) after ingesting the drug, and be cautioned about potential impairment of the performance of such activities on the day following ingestion of eszopiclone. Eszopiclone, like other hypnotics, may produce additive CNS-depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs that themselves produce CNS depression. Eszopiclone should not be taken with alcohol. Dose adjustment may be necessary when eszopiclone is administered with other CNS-depressant agents, because of the potentially additive effects.

Adverse reactions noted during the use of eszopiclone are headache, anxiety, depression, somnolence, viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste. A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (eg, aggressiveness and extroversion that seem out of character)?similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking, has been reported in association with the use of sedative/hypnotics. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are druginduced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Eszopiclone is supplied as 1-, 2-, and 3-mg tablets in bottles containing 100 tablets.

Insulin Glulisine Recombinant Injection (Apidra)

Aventis Pharmaceuticals

Insulin glulisine is a human insulin analogue that is a rapid-acting, parenteral (administered subcutaneously, not intravenously) blood glucose-lowering agent. Insulin glulisine is produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine, and the lysine in position B29 is replaced by glutamic acid. Insulin glulisine is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. Insulin glulisine has a more rapid onset of action and a shorter duration of action than regular human insulin and should normally be used in regimens that include a longer-acting insulin or basal insulin analogue. Insulin glulisine may also be infused subcutaneously by external insulin infusion pumps.

Insulin glulisine is a recombinant insulin analogue that has been shown to be equipotent to human insulin. One unit of insulin glulisine has the same glucose-lowering effect as one unit of regular human insulin. After subcutaneous administration, it has a more rapid onset and shorter duration of action. Insulin glulisine should be given within 15 minutes before a meal or within 20 minutes after starting a meal. The dosage of insulin glulisine should be individualized and determined based on the physician's advice in accordance with the needs of the patient.

Insulin glulisine should be administered by subcutaneous injection in the abdominal wall, the thigh, or the upper arm or by continuous subcutaneous infusion in the abdominal wall. As with all insulins, injection sites and infusion sites within an injection area (abdomen, thigh, or upper arm) should be rotated from one injection to the next. As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by injection site, exercise, and other variables.

If insulin glulisine is mixed with NPH human insulin, insulin glulisine should be drawn into the syringe first. The mixture should be injected immediately after mixing. No data are available on mixing insulin glulisine with insulin preparations other than NPH, and it should not be mixed with insulin preparations other than NPH. Mixtures should not be administered intravenously.

Overall, clinical studies comparing insulin glulisine with short-acting insulins did not demonstrate a difference in frequency of adverse events. Adverse events commonly associated with human insulin therapy include the following: allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, and hypoglycemia.

Insulin glulisine differs from regular human insulin by its rapid onset of action and shorter duration of action. When used as a mealtime insulin, the dose of insulin glulisine should be given within 15 minutes before or immediately after a meal. As with all insulin preparations, the time course of insulin glulisine action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress.

Insulin glulisine is supplied as a sterile, clear aqueous and colorless solution containing 100 units per mL (U-100) and is available in 10-mL vials. Unopened vials should be stored in a refrigerator at 36?F to 46?F (2?C -8?C) and protected from light. Insulin glulisine should not be stored in the freezer, and it should not be allowed to freeze. Discard vial if frozen. Opened vials of insulin glulisine, whether or not refrigerated, must be used within 28 days and must be discarded if not used within 28 days. If refrigeration is not possible, an open vial in use can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 77?F (25?C).

Lanthanum Carbonate Hydrate Tablets (Fosrenol)

Shire Pharm

Lanthanum carbonate is indicated to reduce serum phosphate in patients with end-stage renal disease (ESRD). Lanthanum is a naturally occurring rare earth element. Lanthanum carbonate is practically insoluble in water. Patients with ESRD can develop hyperphosphatemia that may be associated with secondary hyperparathyroidism and elevated calcium phosphate product. Elevated calcium phosphate product increases the risk of ectopic calcification. Treatment of hyperphosphatemia usually includes all of the following: reduction of dietary intake of phosphate, removal of phosphate by dialysis, and inhibition of intestinal phosphate absorption with phosphate binders. Lanthanum does not contain calcium or aluminum.

Lanthanum carbonate dissociates in the acid environment of the upper GI tract to release lanthanum ions that bind dietary phosphate released from food during digestion. Lanthanum inhibits absorption of phosphate by forming highly insoluble lanthanum phosphate complexes, consequently reducing both serum phosphate and calcium phosphate product.

The recommended initial total daily dose of lanthanum is 750 to 1500 mg. The total daily dose of lanthanum should be divided and taken with meals. The dose should be titrated every 2 to 3 weeks until an acceptable serum phosphate level is reached. Serum phosphate levels should be monitored as needed during dose titration and on a regular basis thereafter. In clinical studies of ESRD patients, lanthanum doses up to 3750 mg were evaluated. Most patients required a total daily dose between 1500 and 3000 mg to reduce plasma phosphate levels to less than 6.0 mg/dL. Doses were generally titrated in increments of 750 mg/day at 2-to 3-week intervals. Lanthanum tablets should be chewed completely before swallowing. Intact tablets should not be swallowed.

Lanthanum is not metabolized and is not a substrate of CYP450. Studies in healthy subjects have shown that lanthanum does not adversely affect the pharmacokinetics of warfarin, digoxin, or metoprolol.

The most common adverse events for lanthanum were GI events, such as nausea and vomiting, and they generally abated over time with continued dosing.

Patients with acute peptic ulcer disease, ulcerative colitis, Crohn's disease, or bowel obstruction were not included in lanthanum clinical studies. Caution should be used in patients with these conditions.

Lanthanum carbonate hydrate is supplied as 250-and 500-mg chewable tablets with the dosage strength corresponding to the content of elemental lanthanum. Lanthanum is available in bottles containing 100 tablets.

Pegaptanib Injection (Macugen)


Pegaptanib is indicated for the treatment of neovascular (wet) age-related macular degeneration. Pegaptanib 0.3 mg should be administered once every 6 weeks by intravitreous injection into the eye to be treated. Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration, a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathologic ocular neovascularization.

Serious adverse events related to the injection procedure occurring in <1% of intravitreous injections included endophthalmitis, retinal detachment, and iatrogenic traumatic cataract. The most frequently reported adverse events in patients treated with pegaptanib 0.3 mg for up to 2 years were anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These events occurred in approximately 10% to 40% of patients.

Following the injection of pegaptanib, patients should be monitored for elevation in IOP and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between 2 and 7 days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

Pegaptanib is contraindicated in patients with ocular or periocular infections. Intravitreous injections, including those with pegaptanib, have been associated with endophthalmitis. Proper aseptic injection technique should always be utilized when administering pegaptanib. In addition, patients should be monitored during the week following the injection to permit early treatment, should an infection occur. Increases in IOP have been seen within 30 minutes of injection with pegaptanib. Therefore, IOP as well as the perfusion of the optic nerve head should be monitored and managed appropriately.

Pegaptanib sodium injection is supplied in a single-use 1-mL glass syringe with a gray rubber plunger containing 0.3 mg in a 90-?L deliverable volume. Each syringe is fitted with a fixed 27-gauge needle covered with a gray rubber needle shield and a rigid plastic outside sheath. All are contained in a foil pouch. The accompanying polystyrene plunger rod and white flange are in a separate foil pouch. The two foil pouches are packaged in a carton. Pegaptanib should be stored in the refrigerator at 2? to 8?C (36? -46?F) and not frozen or shaken vigorously.

Tinidazole Tablets (Tindamax)

Presutti Labs

Tinidazole is a synthetic antiprotozoal agent indicated for the treatment of trichomoniasis caused by T vaginalis in both female and male patients. Tinidazole is also indicated for the treatment of giardiasis caused by G duodenalis (also termed G lamblia) and for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in patients older than 3 years of age. It is not indicated in the treatment of asymptomatic cyst passage.

The recommended dosage of tinidazole for the treatment of trichomoniasis in both females and males is a single 2-g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time. The recommended dosage for the treatment of giardiasis in adults is a single 2-g dose taken with food. In pediatric patients older than 3 years of age, a single dose of 50 mg/kg (up to 2 g) is recommended with food. As with metronidazole, it is advisable to take tinidazole with food to minimize the incidence of epigastric discomfort and other GI side effects. Food does not affect the oral bioavailability of tinidazole.

The recommended dosage for the treatment of intestinal amebiasis in adults is a 2-g dose per day for 3 days taken with food. In pediatric patients older than 3 years of age, 50 mg/kg/day (up to 2 g per day) for 3 days with food should be used. It is recommended that, for the treatment of amebic liver abscess in adults, a 2 g-dose per day for 3 to 5 days should be taken with food. In pediatric patients older than 3 years of age, the recommendation is 50 mg/kg/day of tinidazole (up to 2 g per day) for 3 to 5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without reported adverse events. Children should be closely monitored when treatment durations exceed 3 days. For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup to be taken with food.

As with other nitroimidazole derivatives, tinidazole may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This potential interaction should be considered when tinidazole is prescribed for patients on this type of anticoagulant therapy. The dosage of oral anticoagulants may need to be adjusted during tinidazole coadministration and up to 8 days after discontinuation. Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last 2 weeks.

Metronidazole has been reported to elevate serum lithium levels. It is not known if tinidazole shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and tinidazole treatment to detect potential lithium intoxication. Tinidazole also has the potential to increase levels of fosphenytoin, tacrolimus, cyclosporin, and fluorouracil.

Simultaneous administration of tinidazole with drugs that induce liver microsomal enzymes (cytochrome P- 450) such as phenobarbital, rifampin, phenytoin, and fosphenytoin may accelerate the elimination of tinidazole, decreasing the plasma level of tinidazole. Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, such as cimetidine and ketoconazole, may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma level of tinidazole.

Reported adverse effects from clinical trials have generally been mild and self-limiting. Adverse reactions observed with the use of tinidazole are metallic/bitter taste, nausea, anorexia, dyspepsia, cramps, epigastric discomfort, vomiting, constipation, weakness, fatigue, malaise, dizziness, and headache.

Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with nitroimidazole drugs including tinidazole and metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of tinidazole therapy.

Tinidazole should be administered with caution to patients with CNS diseases. Tinidazole is contraindicated in patients with hypersensitivity to tinidazole, any component of the tablet, or other nitroimidazole derivatives. Tinidazole is contraindicated during the first trimester of pregnancy. Tinidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasias. Alcoholic beverages should be avoided while taking tinidazole and for 3 days afterward.

Tinidazole is supplied as 250-mg tablets in bottles containing 40 and 100 tablets and as 500-mg tablets in bottles containing 20 and 60 tablets.

Michael A. Mancano, PharmD: Associate Professor of Clinical Pharmacy, Associate Chair, Department of Pharmacy Practice, Temple University School of Pharmacy; Clinical Consultant, Department of Pharmacy, Northeastern Hospital

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

MWC Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is approved for 1.5 contact hours (0.15 CEU) under the ACPE universal program number of 290-000-05- 006-H01. The program is available for CE credit through May 31, 2008.


1. Each participant achieving a passing grade of 70% or higher on any examination will receive a statement of credit giving 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.

4. Mail your completed exam form with your payment to the following address: Pharmacy Times, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432.


1. Mail with your payment.

2. Fax: 703-404-1801.

3. This lesson is FREE on-line; receive instant grading, as well as download your certificate?

Please print clearly?certificate will be issued from information given.

Please mail payment and completed forms to: Pharmacy Times CE Department, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432


This educational lesson will be available to pharmacists on-line at

(Based on the article starting on page 90.) Choose the 1 most correct answer.

1. Which of the following agents is indicated for the treatment of trichomoniasis in both women and men?

  1. Pentetate calcium trisodium
  2. Pregabalin
  3. Tinidazole
  4. Ziconotide

2. Which of the following agents is indicated for the treatment of insomnia?

  1. Clofarabine
  2. Duloxetine
  3. Erlotinib
  4. Eszopiclone

3. Which of the following agents is indicated for the treatment of major depressive disorder and the management of neuropathic pain associated with diabetic peripheral neuropathy?

  1. Cinacalcet
  2. Clofarabine
  3. Duloxetine
  4. Lanthanum

4. Which of the following agents is indicated for the treatment of advanced non-small cell lung cancer unresponsive to first-line therapy?

  1. Cetuximab
  2. Cinacalcet
  3. Erlotinib
  4. Gadobenate dimeglumine

5. Which of the following agents is indicated for the treatment of relapsed or refractory pediatric acute lymphoblastic leukemia?

  1. Bevacizumab
  2. Cetuximab
  3. Cinacalcet
  4. Clofarabine

6. Which of the following agents is indicated for the treatment of myelodysplastic syndrome?

  1. Acamprosate
  2. Apomorphine
  3. Azacitidine
  4. Bevacizumab

7. Which of the following agents is indicated for the treatment of alcohol dependency?

  1. Acamprosate
  2. Cinacalcet
  3. Clofarabine
  4. Palifermin

8. Which of the following agents is indicated for the treatment of pulmonary arterial hypertension?

  1. Secretin
  2. Hyaluronidase
  3. Iloprost
  4. L-glutamine

9. Which of the following agents is indicated to reduce serum phosphate in patients with end-stage renal disease?

  1. Gadobenate dimeglumine
  2. Lanthanum carbonate hydrate
  3. L-glutamine
  4. Palifermin

10. Which of the following agents is indicated for the treatment of traveler's diarrhea?

  1. Rifaximin
  2. Solifenacin succinate
  3. Telithromycin
  4. Tinidazole

11. Which of the following agents is indicated for the prevention and treatment of oral mucositis in bone marrow transplant patients?

  1. Lutropin alfa
  2. Omega-3-acid ethyl esters
  3. Palifermin
  4. Poly-L-lactic acid

12. Which of the following agents is indicated for the treatment of hypomobility in Parkinson's disease?

  1. Apomorphine
  2. Acamprosate
  3. Duloxetine
  4. Eszopiclone

13. Which of the following agents is indicated for the treatment of internal contamination with americium, plutonium, or curium to enhance elimination?

  1. Palifermin
  2. Pemetrexed disodium
  3. Pentetate calcium trisodium
  4. Poly-L-lactic acid

14. Which of the following agents is indicated for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease?

  1. Pentetate zinc trisodium
  2. Rifaximin
  3. Telithromycin
  4. Tiotropium bromide monohydrate

15. Which of the following agents is indicated for the treatment of severe refractory chronic pain?

  1. Rifaximin
  2. Solifenacin succinate
  3. Tiotropium bromide monohydrate
  4. Ziconotide

16. Which of the following agents is indicated for the treatment of neovascular (wet) age-related macular degeneration?

  1. Palifermin
  2. Pegaptanib
  3. Pentetate zinc trisodium
  4. Pregabalin

17. Which of the following agents is indicated for the treatment of facial wasting disease in HIV patients?

  1. L-glutamine
  2. Lutropin alfa
  3. Poly-L-lactic acid injection
  4. Pregabalin

18. Which of the following agents can produce a disulfiram-like reaction when administered with alcohol?

  1. Pregabalin
  2. Rifaximin
  3. Telithromycin
  4. Tinidazole

19. Strong inhibitors of CYP3A4 would be expected to approximately double the levels of this agent.

  1. Eszopiclone
  2. Gadobenate
  3. L-glutamine
  4. Rifaximin

20. Which of the following agents has an enteric coating and requires caution when using it in patients with conditions that may slow gastric emptying?

  1. Duloxetine
  2. Erlotinib
  3. Omega-3-acid ethyl esters
  4. Palifermin